Background

Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity. In PAPILLON (NCT04538664), ami plus carboplatin-pemetrexed (ami-chemo) significantly prolonged progression-free survival (PFS) vs chemo (median, 11.4 vs 6.7 months [mo]; HR, 0.40; [95% CI, 0.30–0.53]; P<0.001; Zhou NEJM 2023). We evaluated time to symptomatic progression (TTSP) and patient-reported outcomes (PROs) from PAPILLON.

Methods

These analyses included 153 patients (pts) randomized to ami-chemo and 155 to chemo (intent-to-treat population [ITT]) who died or discontinued treatment. TTSP was defined as time from randomization to onset of new/worsening lung cancer symptoms requiring change in anticancer therapy, another clinical intervention, or death, whichever occurred first. PROs were measured using the EORTC-QLQ-C30 and PROMIS-PF 8c instruments; P values were nominal.

Results

At a median follow-up of 14.9 mo, median TTSP was significantly longer for ami-chemo vs chemo (NE vs 20.1 mo; HR, 0.67 [95% CI, 0.46–0.98]; P=0.04). Median treatment duration was 9.7 mo for ami-chemo and 6.7 mo for chemo. At 6 mo (189 days), the percentage of ITT pts with improved/stable physical functioning relative to baseline was 54% for ami-chemo vs 41% for chemo (P<0.02). There were higher percentages of pts with improved or stable emotional functioning (63% vs 47%; P=0.01), cognitive functioning (47% vs 38%), role functioning (50% vs 41%), and global health status (51% vs 42%) for ami-chemo vs chemo, respectively (P>0.05 for all). At 6 mo, 43% vs 25% of pts reported no dyspnea (P<0.01), 36% vs 31% reported no pain (P>0.05), and 18% vs 8% reported no fatigue for ami-chemo vs chemo (P<0.02), respectively. Updated results will include data from PROMIS-PF 8c.

Conclusions

Ami-chemo significantly prolonged time to symptomatic progression vs chemo. More pts in the ITT population reported improved or stable functioning and absence of lung cancer-related symptoms for ami-chemo vs chemo. The deeper tumor responses and improved disease control observed with ami-chemo corresponded with improved patient-relevant endpoints in first-line EGFR Ex20ins advanced NSCLC.

Clinical trial identification

NCT04538664.

Editorial acknowledgement

Medical writing assistance was provided by Lumanity Communications Inc and funded by Janssen Global Services LLC.

Legal entity responsible for the study

Janssen Pharmaceuticals.

Funding

Janssen Pharmaceuticals.

Disclosure

L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, President.ASEICA(Spanish Association of Cancer Research ): ASEICA; Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group. R. Veillon: Financial Interests, Institutional, Research Grant: AstraZeneca, AbbVie, Merck Serono, Bristol Myers Squibb, Sanofi, GSK, Novartis, Gilead, Roche, Janssen; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Takeda, Sanofi; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Janssen, Takeda, Sanofi. M. Majem: Financial Interests, Personal, Advisory Board: Amgen, Roche, AstraZeneca, Takeda, Janssen, Cassen Recordati, BMS, Sanofi; Financial Interests, Personal, Invited Speaker: Amgen, Roche, AstraZeneca, Pfizer, Takeda, Helsinn; Financial Interests, Institutional, Funding: BMS, AstraZeneca, Roche; Non-Financial Interests, Personal, Leadership Role, Board Member: Associacio Contra El Cancer Barcelona. C. Zhou: Financial Interests, Personal, Invited Speaker, Honoraria: Eli Lilly, Roche, Sanofi, Qilu Pharma, Hengrui, Innovent Biologics, C-Stone, LUYE Pharma, TopAlliance Biosciences Inc; Financial Interests, Personal, Invited Speaker, BI: BI; Financial Interests, Personal, Invited Speaker, MSD:MSD; Financial Interests, Personal, Advisory Board, Advisor: Amoy Diagnositics. S. Kim: Financial Interests, Institutional, Other, Provision of study materials: Janssen. N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati, Amgen, Novartis, Sanofi, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Pfizer, Janssen, Boehringer, Novartis, Sanofi, AbbVie, Amgen, Lilly, Grunenthal, Takeda, Owkin, Leo Pharma, Daiichi Sankyo, Ipsen; Financial Interests, Institutional, Research Grant, Local: Roche, Sivan, Janssen; Financial Interests, Institutional, Funding: BMS, Leo Pharma; Financial Interests, Institutional, Research Grant: MSD; Other, Personal, Other, Family member is an employee: AstraZeneca. R.E. Sanborn: Financial Interests, Personal, Advisory Board: AstraZeneca, EMD Serono, Daiichi Sankyo, Lilly Oncology, Janssen Oncology, Macrogenics, Sanofi Aventis, Regeneron, Mirati Therapeutics, GSK, G1 Therapeutics; Financial Interests, Personal, Invited Speaker: Illumina, GSK, Janssen Oncology; Financial Interests, Institutional, Funding, Funding for investigator-sponsored trial: Merck, AstraZeneca; Financial Interests, Institutional, Other, Institutional research support: BMS; Financial Interests, Institutional, Funding, Clinical trial funding: Jounce. A.S. Mansfield: Financial Interests, Institutional, Research Grant: Novartis, Verily; Financial Interests, Institutional, Other, Consulting fees: Rising Tide – grant reviewer, TRIPTYCH Health Partners Expert Think Tank; Financial Interests, Institutional, Other, Steering committee: Janssen - steering committee, Johnson & Johnson Global Services – steering committee; Financial Interests, Institutional, Invited Speaker: BeiGene, Chugai Pharmaceutical Co Ltd (Roche), Immunocore - presentation; Financial Interests, Institutional, Invited Speaker, Moderator: Ideology Health LLC (formerly Nexus Health Media) - moderator; Financial Interests, Personal, Invited Speaker, CME presentation: Antoni van Leeuwenhoek Kanker Instituut – CME presentation; Financial Interests, Institutional, Invited Speaker, CME presentation: AXIS Medical Education, Inc. – CME presentation, Intellisphere LLC (OncLive Summit Series) – CME presentation, Answers in CME – CME presentation; Financial Interests, Personal, Invited Speaker: University of Miami Int’l Mesothelioma Symposium – speaker; Financial Interests, Personal, Other, Travel: Shanghai Roche; Financial Interests, Institutional, Advisory Board: AbbVie, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Takeda Oncology; Non-Financial Interests, Personal, Leadership Role, Non-remunerated Director: Mesothelioma Applied Research Foundation, Friends of Patan Hospital; Financial Interests, Personal, Other, Study funding, article processing charges: Bristol Myers Squibb. K. Park: Financial Interests, Personal, Advisory Board: JNJ, AstraZeneca, Daiichi Sankyo, Eli Lilly, Samsung Medical Center; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Other, DMC member: BeiGene, Incyte; Financial Interests, Personal, Other, Advisor/Consultant: Genius, IMBdx; Financial Interests, Personal, Other, Advisor: ABION; Financial Interests, Personal, Stocks/Shares, Stock option: IMBDx, GENIUS. J. Sermon, J. Schuchard, A. Bhattacharya, P. Lorenzini, M. Baig,T. Agrawal, R.E. Knoblauch: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson. A. Ono: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Janssen Research & Development. J. Sabari: Financial Interests, Personal, Advisory Board: AstraZeneca, Genentech, Janssen, Pfizer, Regeneron, Sanofi Genzyme, Takeda, Mirati Therapeutics. All other authors have declared no conflicts of interest.

Background

Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity. In MARIPOSA-2 (NCT04988295), ami plus carboplatin-pemetrexed (ami-chemo) significantly prolonged progression-free survival (PFS) vs chemo (HR, 0.48; P<0.001) in patients (pts) with EGFR-mutant advanced NSCLC after progression on osimertinib (Passaro Ann Oncol 2023). We evaluated time to symptomatic progression (TTSP) and patient-reported outcomes (PROs) from MARIPOSA-2.

Methods

Analyses included 131 pts randomized to ami-chemo and 263 pts to chemo (intent-to-treat population [ITT]) who died or discontinued treatment. TTSP was defined as time from randomization to onset of new/worsening lung cancer symptoms requiring change in anticancer therapy, another clinical intervention, or death, whichever occurred first. PROs were measured using EORTC-QLQ-C30, NSCLC-SAQ, and PROMIS-PF 8c instruments; P values were nominal.

Results

At a median follow-up of 8.7 mo, a trend towards improvement in TTSP was observed for ami-chemo vs chemo (median, 14.9 vs 13.0 mo; HR, 0.74 [95% CI, 0.51–1.07]; P=0.10). Median treatment duration was 6.3 mo for ami-chemo vs 3.7 mo for chemo. At 6 mo (189 days), the percentage of ITT pts who remained on treatment and had improved or stable physical functioning relative to baseline was 37% for ami-chemo vs 21% for chemo; P<0.01). There were higher percentages of pts with improved or stable emotional functioning (38% vs 21%; P<0.01), cognitive functioning (38% vs 20%; P<0.01), role functioning (30% vs 19%; P=0.2), and global health status (40% vs 19%; P<0.01) for ami-chemo vs chemo, respectively. Based on data from EORTC-QLQ-C30, at 6 mo 28% vs 13% pts reported no dyspnea (P<0.01), 23% vs 15% reported no pain (P<0.05), and 10% vs 5% reported no fatigue for ami-chemo vs chemo (P>0.05), respectively. Updated results will include data from the NSCLC-SAQ and PROMIS-PF 8c instruments.

Conclusions

Ami-chemo numerically prolonged TTSP vs chemo. More pts in the ITT population reported improved or stable functioning and absence of lung cancer-related symptoms for ami-chemo vs chemo in pts with EGFR-mutant advanced NSCLC after disease progression on osimertinib.

Clinical trial identification

NCT04988295.

Editorial acknowledgement

Medical writing assistance was provided by Lumanity Communications Inc.

Legal entity responsible for the study

Janssen Pharmaceuticals.

Funding

Janssen Pharmaceuticals.

Disclosure

P. Tomasini: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Lilly, Janssen, Amgen, Takeda; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Janssen, Amgen, Lilly, Takeda. A. Blasco Cordellat: Financial Interests, Personal, Speaker’s Bureau: Roche Pharma, Clover, Sanofi, Janssen Cilag, Takeda, GSK; Financial Interests, Personal, Other, Travel: Roche, Bristol, Takeda. C. Dooms: Financial Interests, Personal, Advisory Board: Advisory Board for Janssen-JNJ. M. Mackean: Financial Interests, Personal, Other, Consulting Fees: Boehringer Ingelheim, Roche, Takeda, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Takeda; Financial Interests, Personal, Other, Travel: Takeda, Bristol Myers Squibb, Janssen-Cilag, MSD, Roche. A. Bearz: Financial Interests, Personal, Advisory Board: Pfizer, Roche; Financial Interests, Personal, Invited Speaker: BMS, Pfizer, Eli Lilly, Janssen, Novartis; Non-Financial Interests, Personal, Principal Investigator: Roche, Pfizer, Gilead, MSD. O.J. Juan Vidal: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharp & Dohme, Lilly, Takeda, AstraZeneca, Janssen; Financial Interests, Personal, Invited Speaker: Roche/Genentech; Financial Interests, Institutional, Funding: AstraZeneca. D.M. Kowalski: Financial Interests, Personal, Other, Consulting Fees: Advisory Board: BMS, MSD, Pfizer, AstraZeneca, Novartis, Roche, Takeda, Boehringer-Ingelheim, Sanofi-Aventis, Amgen, Johnson & Johnson, Merck; Financial Interests, Personal, Leadership Role: Polish Lung Cancer Study Group. K. Stencel: Financial Interests, Personal, Other, provision of study materials, medical writing, article processing charges: Janssen; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, BMS, MSD, Takeda, Roche, Janssen, Pfizer, Amgen; Financial Interests, Personal, Other, Travel: MSD, Roche; Financial Interests, Personal, Advisory Board:MSD, Amgen; Financial Interests, Personal, Writing Engagements: BMS. A. Zer: Financial Interests, Personal, Invited Speaker: Roche, BMS, MSD, Takeda, Pfizer, Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca, Steba, Oncohost; Financial Interests, Personal, Other, Safety Review Committee Member: Beyond Air; Financial Interests, Personal, Stocks/Shares: Nixio; Financial Interests, Institutional, Research Grant: BMS. J. Schuchard, J. Diels, P. Chu, S. Shah, B. Diorio, A. Garvin, J.M. Bauml: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Personal, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Personal, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Personal, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. All other authors have declared no conflicts of interest.

Background

In FLAURA2 (NCT04035486), 1L osi + platinum-pemetrexed (pem) chemotherapy (CTx) (n=279) significantly improved PFS vs osi alone (n=278) in EGFRm advanced NSCLC (HR 0.62; 95% CI 0.49, 0.79; p<0.0001 per investigator). Safety of osi + CTx was consistent with individual Tx profiles and was associated with higher incidence of G≥3 AEs vs osi. Most G≥3 AEs occurred during platinum-based CTx induction phase (pem + platinum CTx, 4 cycles Q3W) but reduced during maintenance. We report FLAURA2 PROs.

Methods

Symptoms, function and HRQoL were measured using EORTC QLQ-C30/LC13 questionnaires (Table). Score (range 0–100) changes from baseline (BL) to progression/19 mos were analysed by a mixed-effects model. A clinically meaningful within-pt change was defined as ≥10 point change from BL. Tolerability was assessed with PRO-CTCAE items.

Results

EORTC questionnaire completion/PRO-CTCAE visit compliance was ≥80/≥75% to Wk 82. Non-clinically meaningful improvements in global health status/quality of life (GHS/QoL) and physical function were seen in both arms: average least-squares mean (LSM) change in GHS/QoL from BL (95% CI) over all visits was 3.32 (1.67, 4.98) with osi + CTx and 7.38 (5.70, 9.07) with osi. Non-clinically meaningful worsening of fatigue/appetite loss (LSM change from BL [95% CI]) was seen with osi + CTx in induction (10 wks: 2.98 [0.65, 5.32]/9.30 [6.13, 12.46]), but improved during maintenance (28 wks: -0.33 [-2.66, 2.00]/5.52 [2.60, 8.44]). A trend to improvement in dyspnoea, chest pain and cough was seen in both arms; clinically meaningful improvement for cough from Wks 5 (osi + CTx) and 6 (osi). PRO-CTCAE results showed osi + CTx and osi were similarly well tolerated except nausea/vomiting (more common with osi + CTx).

Conclusions

A trend to improved HRQoL and several symptoms was seen after induction CTx. Negative changes in HRQoL from adding CTx to osi were not clinically meaningful and were mostly transient (trended back to BL post-induction CTx). Table: 9P

Clinical trial identification

NCT04035486.

Editorial acknowledgement

The authors would like to acknowledge Kiara Whelan, BSc, of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

C.K.K. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Takeda, Pfizer, Novartis, GSK, Merck KGA, Roche, Janssen, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca, Amgen, Roche, Merck KGA. K. Laktionov: Other, Personal and Institutional, Speaker’s Bureau: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad; Other, Personal and Institutional, Advisory Board: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad, Pfizer; Other, Personal and Institutional, Funding: AstraZeneca; Other, Personal and Institutional, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad. S. Kim: Other, Personal and Institutional, Invited Speaker: Boehringer Ingelheim; Other, Personal and Institutional, Advisory Board: Terapex; Other, Personal and Institutional, Principal Investigator: Yuhan; Other, Personal and Institutional, Advisory Role: AstraZeneca, Amgen, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Takeda. T. Kato: Financial Interests, Personal, Full or part-time Employment, Family Member: Lilly; Financial Interests, Institutional, Research Grant: Chugai Pharma, Merck Sharp & Dohme, Pfizer, AstraZeneca, Lilly, AbbVie, Regeneron, Novartis, Amgen, Merck KGaA, Takeda, Haihe Biopharma, Blueprint Medicines, Turning Point Therapeutics, Daiichi Sankyo, BeiGene; Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, Pfizer, Merck Serono, BeiGene, Novartis, Daiichi Sankyo, Janssen; Financial Interests, Personal, Other, Honoraria: Chugai Pharma, Ono Pharmaceutical, Lilly, AstraZeneca, Taiho Pharmaceutical, Pfizer, Merck Sharp & Dohme, Novartis, Takeda, Daiichi Sankyo, GSK, Amgen, Merck KGaA, BeiGene, Boehringer Ingelheim, Janssen. P. Mitchell: Financial Interests, Personal and Institutional, Advisory Board: Amgen, AstraZeneca, BMS, Roche, MSD, Novartis, Pfizer; Financial Interests, Personal and Institutional, Advisory Role: Grey Wolf; Other, Personal and Institutional, Other, Coordinating Investigator: AstraZeneca, Amgen. S. Kuyama: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Other, Institutional, Principal Investigator: AstraZeneca. F.A. Shepherd: Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Lilly; Financial Interests, Institutional, Funding: AstraZeneca/MedImmune, Squibb, Lilly, Roche Canada, Pfizer. L. Poole: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Lilly, Takeda. M. Albayaty: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca; Financial Interests, Institutional, Stocks/Shares: AstraZeneca. N.P. Amin: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. K. Kobayashi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Takeda Pharmaceutical Co.; Financial Interests, Personal, Expert Testimony: Daiichi Sankyo Co. J.E. Gray: Other, Personal, Advisory Board, Consultant / Advisor: AbbVie, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Inc, EMD Serono, Gilead Sciences, Inc, IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc, Merck & Co, Inc, Novartis, OncoCyte Biotechnology, Spectrum ODAC, Takeda Pharmaceuticals, Triptych Health Partners; Other, Personal, Officer, Chair: SWOG Lung Committee; Other, Personal, Member of Board of Directors: IASLC Board of Directors Member; Other, Personal, Full or part-time Employment: Moffitt Cancer Center; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co, Inc, Novartis, Pfizer; Other, Personal and Institutional, Leadership Role, Ex-Chair: ASCO Education Committee; Other, Personal and Institutional, Leadership Role, Chair: SWOG Lung Committee; Other, Personal and Institutional, Other: AbbVie, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Inc, EMD Serono, Gilead Sciences, Inc, IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc, Merck & Co, Inc, Novartis, OncoCyte Biotechnology, Spectrum ODAC, Takeda Pharmaceuticals, Triptych Health Partners. All other authors have declared no conflicts of interest.

Background

In FLAURA2 (NCT04035486) 1L osi with addition of platinum-pemetrexed chemotherapy (osi+CTx) showed significant PFS benefit vs osi alone (HR 0.62 [95% CI 0.49, 0.79] p<0.0001, per investigator) in EGFRm advanced NSCLC. Higher ≥Grade 3 (G3) AE rates were seen with osi+CTx vs osi, driven by well-recognised CTx-related AEs. We report additional safety analyses of specific AEs of interest from FLAURA2.

Methods

Eligible pts (≥18 years with EGFRm advanced NSCLC, no prior tx for advanced NSCLC; stable CNS metastases allowed) were randomised 1:1 to osi+CTx (osi once daily [QD] + pemetrexed and cisplatin or carboplatin for 4 cycles every 3 weeks (Q3W) [induction], followed by osi QD + pemetrexed Q3W [maintenance]) or osi alone until disease progression/unacceptable toxicity/other discontinuation criteria. Safety was assessed via AE reporting (until 28 days after tx discontinuation) and clinical investigations. Data cutoff: 03 Apr 2023.

Results

The safety analysis set included pts who received ≥1 dose of study tx: osi+CTx n=276; osi n=275. In the osi+CTx arm, median duration of exposure was: osi 22.3, platinum CTx 2.8 and pemetrexed 8.3 months (mos). AE onset frequency and severity (osi+CTx arm) were highest during the induction period (∼0–<3 mos) and reduced over time during the maintenance period (>3 mos); ≥G3 AEs (64% overall for osi+CTx arm) reduced by approximately half from 49% (during 0–<3 mos) to 24% (during 3–‍<9 mos), and remained around this level for the rest of the tx period. The majority of ≥G3 AEs (osi+CTx arm) were haematological toxicities (neutropenia and anaemia), as expected from CTx-related AEs. AEs leading to osi discontinuation in the osi+CTx arm vs osi arm were 11% vs 6%; the most frequently reported events leading to discontinuation of osi in both arms were primarily those which mandated tx discontinuation by protocol, ILD (2% vs 2%) and pneumonitis (1% vs <1%).

Conclusions

As expected, AE onset frequency and severity (osi+CTx arm) were highest during induction with clear reductions over time in the maintenance period. The addition of CTx had minimal impact on osi discontinuations. In FLAURA2, osi+CTx safety was consistent with the established profiles of osi and CTx, and manageable with standard medical practice.

Clinical trial identification

NCT04035486.

Editorial acknowledgement

The authors would like to acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

C.K.K. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Takeda, Pfizer, Novartis, GSK, Merck KGA, Roche, Janssen, MSD; Financial Interests, Personal, Research Grant: AstraZeneca, Amgen, Roche, Merck KGA. D. Planchard: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre Fabre, Takeda, ArriVent, Mirati, Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AbbVie, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Merck, Novartis, Janssen, Pfizer, Roche, Pierre Fabre, Takeda, ArriVent, Mirati, Seagen; Non-Financial Interests, Personal, Other, Co-ordinating PI: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, AbbVie, Janssen, Pierre Fabre, Takeda, ArriVent, Mirati, Seagen. C. Ruscanu, S. Taggart, M. Albayaty: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. D. Kulkarni: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Tolerable therapies are needed for previously treated pts with advanced EGFRm NSCLC. The ph 2 HERTHENA-Lung01 trial (NCT04619004) showed meaningful efficacy and a manageable safety profile. To extend these safety observations, we present data with an additional 6 mo of follow-up.

Methods

Pts (N=225) previously treated with EGFR TKI and platinum-based chemotherapy received HER3-DXd 5.6 mg/kg IV Q3W.

Results

Median treatment (TX) duration was 5.5 (range, 0.7-23.7) mo. 224 pts (99.6%) had any-grade (G) TEAEs; 147 (65.3%) had G ≥3. Most common any-G TEAEs were nausea (66.2%), thrombocytopenia (43.6%), and decreased appetite (42.2%); most common G ≥3 were thrombocytopenia (20.9%), neutropenia (19.1%), and anemia (15.1%). 88.9% of pts had a GI TEAE; 8% had a G ≥3 event. Incidence of GI TEAEs generally decreased over the course of TX. 2 pts (0.9%) experienced G ≥3 bleeding unrelated to TX within ±14 d of G ≥3 decreased platelet count. 2 pts (0.9%) experienced G ≥3 infections unrelated to TX within ±14 d of G ≥3 decreased neutrophil count. Febrile neutropenia occurred in 7 pts (3.1%; all G ≥3). G-CSF was used to manage neutropenia in 23 pts (10.2%). 14 pts (6.2%) had centrally adjudicated TX-related interstitial lung disease (G 1/2, n=9; G 3, n=4; G 5, n=1); 2 events occurred in the 6-mo follow-up. Median time to onset and duration were 70.5 (range, 9-474) and 40 (range, 6-207) d. 4 pts had TX-related TEAEs associated with death (pneumonitis, GI perforation, pneumonia, respiratory failure [n=1 each]). TEAEs associated with dose interruption occurred in 41.3% of pts, dose reduction in 22.2%, and discontinuation in 8.4%. Hematologic AEs occurred early in TX, were transient, and managed by dose modifications and supportive care. No pts discontinued TX due to thrombocytopenia; 20 (8.9%) received platelet transfusions. Anemia was associated with TX discontinuation in 1 pt (0.4%); 28 (12.4%) received RBC transfusions.

Conclusions

HER3-DXd demonstrated a manageable safety profile, consistent with previous reports. Hematologic and GI TEAEs typically occurred in early TX cycles. No additional safety signals were observed.

Clinical trial identification

NCT04619004.

Editorial acknowledgement

Medical editorial assistance was provided by Allison Lytle, PhD, CMPP (Nucleus Global).

Legal entity responsible for the study

Daiichi Sankyo, Inc.

Funding

Daiichi Sankyo, Inc.

Disclosure

H. Hayashi: Financial Interests, Personal, Other, Honoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, Lilly, Boehringer Ingelheim, AstraZeneca Japan, Chugai Pharma, Pfizer, MSD, Novartis, Merck Serono, Amgen, Daiichi Sankyo/UCB Japan, Guardant Health, Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Janssen; Financial Interests, Personal, Research Grant: Ono Pharmaceutical, Boehringer Ingelheim, AstraZeneca; Financial Interests, Institutional, Research Grant: AbbVie, AC Medical, Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Lilly Japan, EPS Associates Co., Ltd, GSK, Japan Clinical Research Operations, Kyowa Hakko Kirin, Merck Serono, Novartis, Otsuka, PAREXEL, Pfizer, PPD-SNBL, Quintiles Inc, Taiho Pharmaceutical, Takeda, Yakult Honsha, Chugai Pharma, Sysmex; Financial Interests, Personal, Royalties: Sysmex. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fischer; Financial Interests, Personal, Other, Travel Grant: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Guardant Health, Preferred Network; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Non-Financial Interests, Personal, Member of Board of Directors: Cancer Net Japan, JAMT. H.A. Yu: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, AbbVie; Financial Interests, Institutional, Research Grant: AstraZeneca, Astellas Pharma, Lilly, Novartis, Pfizer, Daiichi Sankyo, Cullinan Oncology, Janssen Oncology, Erasca, Inc, Blueprint Medicines, Black Diamond Therapeutics; Financial Interests, Personal, Other: Astellas Pharma. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Allorion Therapeutics, Accutar Biotech, AbbVie, Duality Biologics; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Advisory Board, Consulting fee for advice on drug development: Merus, Frontier Medicines; Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development.: Hongyun Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. J.C. Yang: Financial Interests, Personal, Other, Honoraria: Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Lilly, Pfizer; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, Lilly, MSD Oncology, Merck Serono, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda, Amgen, Incyte; Financial Interests, Institutional, Advisory Role: Boehringer Ingelheim, Merck Serono, Janssen, GSK, Amgen, Takeda, Daiichi Sankyo, AstraZeneca, Novartis, MSD Oncology; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Pfizer. M. Reck: Financial Interests, Personal, Advisory Role: Lilly, MSD Oncology, Merck Serono, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, AbbVie, Amgen, Mirati Therapeutics, Samsung Bioepis, Sanofi/Regeneron, Daiichi Sankyo Europe GmbH; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech, Lilly, MSD Oncology, Merck Serono, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics, Sanofi/Aventis. K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Amgen, Takeda, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Lilly, Daiichi Sankyo, AbbVie, Taiho, MSD, Takeda, Amgen, Boehringer Ingelheim, Chugai. S. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca/MedImmune, Roche, Merck, Pfizer, Lilly, BMS/Ono, Takeda, Janssen, IMBdx; Financial Interests, Personal, Invited Speaker: AstraZeneca/MedImmune, Roche, Merck, Lilly, Amgen; Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Lunit. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-Cilag international NV, NOoartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, President. ASEICA(Spanish Association of Cancer Research ): ASEICA; Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group. B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, Beigene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi Aventis, Springer Healthcare Ltd, 4D Pharma; Financial Interests, Institutional, Expert Testimony: AbbVie, Da voltera, Eli Lilly, Ellipse pharma Ltd, F-Star, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Socar research, Taiho oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD, AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi Sankyo, GSK, Janssen, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Turning Point Therapeutics, Genmab, Taiho, Nuvalent, Enliven, Prelude therapeutics; Financial Interests, Institutional, Funding: Cristal Therapeutics. P. Bironzo: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, MSD Oncology, Roche, Takeda, Novartis, Sanofi; Financial Interests, Personal, Advisory Role: Roche, Janssen Oncology, Pierre Fabre, Amgen, Seagen, Regeneron; Financial Interests, Institutional, Research Grant: Roche, Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen, Daiichi Sankyo/Arqule. D. Kim: Financial Interests, Personal, Invited Speaker: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Japan Cancer Association; Financial Interests, Personal, Other, Scientific Advisor: Health Insurance Review & Assessment Service, Korea; Financial Interests, Personal, Invited Speaker, Medical writing assistance: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda, Yuhan; Financial Interests, Institutional, Invited Speaker, Clinical Trial Funding: Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang, Bridge BioTherapeutics, GSK; Financial Interests, Institutional, Research Grant, Laboratory research funding to my institution: InnoN; Non-Financial Interests, Personal, Advisory Role: Amgen, BMS / Ono Pharmaceuticals, Daiichi Sankyo, Janssen, GSK, Pfizer, AstraZeneca, SK Biopharm, Takeda, Yuhan; Non-Financial Interests, Personal, Member of Board of Directors: Korean Society of Medical Oncology, Korean Association for Lung Cancer, Asian Thoracic Oncology Research Group; Non-Financial Interests, Personal, Advisory Role, Member of Scientific Advisory Board: Novelty Nobility; Other, Personal, Other, Clinical trial research funding to my institution: Asian Thoracic Oncology Research Group. Z. Piotrowska: Financial Interests, Personal, Invited Speaker, Participated in a Janssen-sponsored educational program: Janssen; Financial Interests, Personal, Advisory Board: Janssen, Takeda, Cullinan, C4 Therapeutics, Taiho, Sanofi; Financial Interests, Personal, Invited Speaker, Participated as an invited speaker in an internal education program at Daiichi Sankyo: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Participated in a (non-promotional) Eli Lilly sponsored medical education event about biomarker testing in NSCLC: Eli Lilly; Financial Interests, Institutional, Research Grant, Institutional research funding for clinical trial: Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan, Daiichi Sankyo, AbbVie, Janssen, Blueprint; Financial Interests, Personal, Invited Speaker: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: Cullinan, AstraZeneca. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics. A. Sporchia: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo Europe GmbH, MorphoSys. K.H. Sullivan: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo, Inc. Q. Dong: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. P. Shrestha: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Daiichi Sankyo. J. Shah: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo, Inc. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Personal, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Personal, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Personal, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí.

Background

ABC-lung explores the potential synergistic effect of combining atezolizumab and bevacizumab with pemetrexed (ABPem) or carboplatin/paclitaxel (ABCPac) in pts with EGFR-mutant NSCLC, resistant to tyrosine kinase inhibitors (TKIs).

Methods

ABC-lung is a 1:1 randomised, non-comparative, international phase II trial evaluating atezolizumab (1200 mg, Q3W) and bevacizumab (15mg/kg, Q3W) until progression (PD) with either carboplatin (AUC5, Q3W) and paclitaxel (175-200 mg/m², Q3W) 4-6 cycles or pemetrexed (500 mg/m², Q3W) until PD. The study was stratified by prior treatment with a 3^rd-generation EGFR TKI and aimed to improve the 1-year (1y) progression-free survival (PFS) rate from 18% to 37%, assessed per RECIST v1.1 and tested separately in each arm. To reject the null hypothesis, at least 14 of 45 evaluable pts in each arm needed to be progression-free at 1y (power 83%, 1-sided a=0.023, exact binomial test). Secondary endpoints included overall survival (OS), objective response rate (ORR), PFS, quality of life (QoL) and adverse events (AEs).

Results

From 09/2020-09/2022, 95 pts were randomised to account for potential attritions: 45 to ABCPac, and 50 to ABPem. Median age was 62 years, 63% of pts were females, 60% never smokers, 55% Asians, 60% had an exon 19 deletion and 33%/66% had stage IVa/IVb NSCLC. From the 43 evaluable pts with ABCPac and the 45 with ABPem, 9 and 11 pts reached 1y without progression, respectively, missing the success criterion of 14 pts. The 1y PFS rate for randomised pts (median follow-up 19 months, m) was 25% for both ABCPac and ABPem, with median PFS of 6.4m and 7.6m, median OS of 15.4m and 15.6m and ORR of 47% and 32%, respectively. The median number of cycles for bevacizumab and atezolizumab was 8-9. Grade≥3 treatment-related AEs were experienced by 50% of pts with ABCPac and 42% with ABPem. There were no grade 5 AEs. Results from QoL and PD-L1 testing will be included in the presentation.

Conclusions

The observed 1y PFS rate with atezolizumab, bevacizumab in combination with either carboplatin-paclitaxel or pemetrexed was similar in both arms and below the aspired rate of 37%. The safety is consistent with the known toxicity profiles.

Clinical trial identification

NCT04245085.

Legal entity responsible for the study

ETOP IBCSG Partners Foundation.

Funding

F. Hoffmann-La Roche AG.

Disclosure

M. Frueh: Financial Interests, Institutional, Advisory Board: BMS, AstraZeneca, MSD, Takeda, Roche, Eli Lilly, Boehringer Ingelheim, Novartis, Amgen; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca. R.A. Soo: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Lily, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan, Janssen, Merck Serono, Puma Biotech, Thermo Fisher; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Pfizer. B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Medpacto, Blueprint medicines, RandBio, Hanmi, GC Cell, Gilead, Ridgeline Discovery GmbH; Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc, Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, Amgen, AstraZeneca, Regeneron, Seagen, Samsung Bioepis; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: CHA Bundang Medical Center, MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, Gradiant Bioconvergence, Therapex, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, JINTSbio, Hanmi, Daewoong Pharmaceutical Co., Ltd., Vertical Bio AG, Korea Institute of Oriental Medicine, National Research Foundation of Korea, KHIDI; Other, Personal, Other, Founder: DAAN Biotherapeutics; Other, Personal, Other, Invited speaker: ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer, Liangyihui Network Technology Co., Ltd. M. Majem: Financial Interests, Personal, Advisory Board: Amgen, Roche, AstraZeneca, Takeda, Janssen, Cassen Recordati, Bms, Sanofi; Financial Interests, Personal, Invited Speaker: Amgen, Roche, AstraZeneca, Pfizer, Takeda, Helsinn; Financial Interests, Institutional, Funding: Bms, AstraZeneca, Roche; Non-Financial Interests, Personal, Leadership Role, Board Member: Associacio Contra El CANCER BARCELONA. D. Rodriguez Abreu: Financial Interests, Personal, Advisory Board:MSD, Novartis, Roche/Genentech, Pfizer, Bristol Myers Squibb, AstraZeneca, Regeneron, Gilead, Sanofi, Amgen, Takeda, Eli Lilly, Incyte, Merck Serono; Financial Interests, Personal, Invited Speaker: MSD, Novartis, Roche/Genentech, Pfizer, Bristol Myers Squibb, AstraZeneca, Regeneron, Gilead, Sanofi, Amgen, Takeda, Eli Lilly, Merck Serono; Financial Interests, Personal, Other, Travel expenses: MSD, Novartis, Roche/Genentech, Pfizer. A. Callejo Perez: Financial Interests, Personal, Advisory Board: Boehringer, Pfizer, BMS; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Other, Travel accommodation: MSD; Financial Interests, Personal, Other, Travel accommodation: Takeda. M. Domine Gomez: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, MSD oncology, Roche, Takeda; Financial Interests, Institutional, Advisory Board: Pfizer. M. Provencio Pulla: Financial Interests, Personal, Advisory Board: BMS, MSD, Bayer, Lilly, Roche, Takeda, Janssen; Non-Financial Interests, Personal, Leadership Role, President of Spanish Lung cancer Group: President; Non-Financial Interests, Personal, Leadership Role, Insutituto Investigación Sanitaria Puerta de Hierro: Director. A. Addeo: Financial Interests, Institutional, Advisory Board: BMS, AZD, Roche, Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer, Takeda, MSD; Financial Interests, Institutional, Invited Speaker: Novartis. J. Han: Financial Interests, Personal, Advisory Board: Norvatis, Lantern, Takeda, Janssen, Merck, Pfizer, Amgen, AstraZeneca, Oncobix; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, Merck, Roche, Yuhan, Pfizer, Norvatis, AstraZeneca. U. Dafni: Financial Interests, Personal, Other, Member of the Tumor Agnostic Evidence Generation working Group: Roche; Financial Interests, Personal, Expert Testimony, Statistical review and assessment of a Clinical Trial: AstraZeneca; Non-Financial Interests, Personal, Leadership Role, Member of the BoD & Manager of this not for profit organization providing statistical expertise and support in Clinical trials, primarily in cancer: FRONTIER SCIENCE FOUNDATION - HELLAS. S. Peters: Financial Interests, Institutional, Advisory Board: Vaccibody, Takeda, Seattle Genetics, Sanofi, Roche/Genentech, Regeneron, Phosplatin Therapeutics, PharmaMar, Pfizer, Novartis, Mirati, Merck Serono, MSD, Janssen, Incyte, Illumina, IQVIA, GSK, Gilhead, Genzyme, Foundation Medicine, F-Star, Eli Lilly, Debiopharm, Daiichi Sankyo, Boehringer Ingelheim, Blueprint Medicines, Biocartis, Bio Invent, BeiGene, Bayer, BMS, AstraZeneca, Arcus, Amgen, AbbVie, iTheos, Novocure; Financial Interests, Institutional, Invited Speaker: Takeda, Sanofi, Roche/Genentech, RTP, Pfizer, PRIME, PER, Novartis, Medscape, MSD, Imedex, Illumina, Fishawack, Eli Lilly, Ecancer, Boehringer Ingelheim, BMS, AstraZeneca, Oncology Education, RMEI, Mirati; Financial Interests, Personal, Other, Associate Editor Annals of Oncology and Deputy Editor Lung Cancer: Elsevier; Financial Interests, Institutional, Advisory Board, Permanent independent scientific advisor: Hutchmed; Financial Interests, Institutional, Member of Board of Directors, Swiss network of pharmacies: Galenica; Financial Interests, Institutional, Invited Speaker, MERMAID-1: AstraZeneca; Financial Interests, Institutional, Invited Speaker, MERMAID-2, POSEIDON, MYSTIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering committee CheckMate 743, CheckMate 73L, CheckMate 331 and 451: BMS; Financial Interests, Institutional, Invited Speaker, RELATIVITY 095: BMS; Financial Interests, Institutional, Invited Speaker, BGB-A317-A1217-301/AdvanTIG-301: BeiGene; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair ZEAL-1: GSK; Financial Interests, Institutional, Invited Speaker, Clinical Trial steering Committee PEARLS, MK-7684A:MSD; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering Committee SAPPHIRE: Mirati; Financial Interests, Institutional, Invited Speaker, LAGOON: PharmaMar; Financial Interests, Institutional, Invited Speaker, phase I/II trials: Phosplatin Therapeutics; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair Skyscraper-01; chair ALEX; steering committee BFAST; steering committee BEAT-Meso; steering committee ImPower-030, IMforte: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Phase 2 Inupadenant with chemo: iTeos; Non-Financial Interests, Personal, Officer, ESMO President 2020-2022: ESMO; Non-Financial Interests, Personal, Officer, Council Member & Scientific Committee Chair: ETOP/IBCSG Partners; Non-Financial Interests, Personal, Officer, Vice-President Lung Group: SAKK; Non-Financial Interests, Personal, Other, Involved in Swiss politics: Swiss Political Activities; Non-Financial Interests, Personal, Officer, President and Council Member: Ballet Béjart Lausanne Foundation; Non-Financial Interests, Personal, Principal Investigator, Involved in academic trials: ETOP / EORTC / SAKK; Non-Financial Interests, Personal, Member: Association of Swiss Physicians FMH (CH), ASCO, AACR, IASLC; Non-Financial Interests, Personal, Leadership Role, ESMO President: ESMO; Non-Financial Interests, Personal, Member, Vice-President Lung Group: SAKK; Non-Financial Interests, Personal, Leadership Role, Vice -President: SAMO; Non-Financial Interests, Personal, Member, Association of Swiss interns and residents: ASMAC/VSAO. R.A. Stahel: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, MSD, Pfizer, Roche, GSK, Eisai, Guardant, Merck, Novocure, PharmaMar; Financial Interests, Personal, Other, Editor in Chief: Lung Cancer; Financial Interests, Personal, Other, Editor: CTR; Financial Interests, Institutional, Research Grant, ETOP study: Roche, AstraZeneca, BMS, MSD, Pfizer, Mirati, Janssen, Amgen; Financial Interests, Institutional, Research Grant, IBCSG study: Novartis, Ipsen, Pierre Fabre, MSD, Pfizer, Roche, AstraZeneca, Celgene; Non-Financial Interests, Personal, Member of Board of Directors, PresidentFoundation Council: ETOP IBCSG PartnersFoundation. All other authors have declared no conflicts of interest.

Background

This multicenter, open-label, phase II study evaluated TIS plus platinum-based chemo (cohort 1) or TIS plus mono-chemo and beva (cohort 2) in EGFR-mutated nsq-NSCLC patients (pts) who progressed on EGFR-TKI therapies. Our previous results showed that cohort 1 met its primary endpoint (1-year PFS rate, 23.8%). Here, we reported the primary analysis results of cohort 2 and updated results of cohort 1.

Methods

In cohort 2, pts received TIS plus nab-paclitaxel and beva (induction), followed by TIS plus beva (maintenance). Primary endpoint was 1-year PFS rate; we planned to enroll 54 pts (85% power to detect an increase from historical control of 7% to 23% at a one-side 0.05 significance level). Updated efficacy analysis was provided for cohort 1.

Results

For cohort 2 (median follow-up:10.5 months [mo]), 54 pts were enrolled. Among 52 pts in efficacy analysis set, 1-year PFS rate was 46.1% (90% CI 32.5-58.7), which met the primary endpoint. Median PFS was 10.9 (95% CI 6.4-15.1) mo. The ORR and DCR were 55.8% (95% CI 41.3-69.5) and 96.2% (95% CI 86.8-99.5), respectively. Grade 3-4 TRAEs occurred in 31.5% (17/54) of pts. 38.9% (21/54) of pts experienced irAEs. For cohort 1 (median follow-up: 20.4 mo), median PFS and OS were 7.6 (95% CI 5.8-9.4) mo and 27.1 (95% CI 16.1-NE) mo, respectively. Pts with EGFR exon 19 deletion or progressed on 1^st/2^nd and 3^rd generation (G) EGFR-TKIs have significant shorter PFS compared to pts with EGFR exon 21 L858R mutation or progressed on 1^st/2^nd G EGFR-TKIs in cohort 1; while no significant differences were observed in cohort 2 (Table).

Table: 13P

Subgroup analysis of PFS by cohort

Conclusions

For pts with EGFR-mutated nsq-NSCLC after EGFR-TKI failure, TIS plus mono-chemo and beva (cohort 2) was effective with favorable safety profile; TIS plus platinum-based chemo (cohort 1) demonstrated encouraging OS benefit. This study provides extended treatment options for this patient population.

Clinical trial identification

NCT04405674.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The efficacy and safety of consolidative stereotactic body radiation therapy (SBRT) in patients with EGFR-mutant NSCLC who developed oligo-residual disease after first-line third-generation EGFR TKIs is unknown.

Methods

A single-arm, multicenter, phase II trial was conducted in patients with EGFR-mutant NSCLC who receiced SBRT for oligo-residual disease after first-line third-generation EGFR TKIs. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and toxicity graded using CTCAE. A propensity score-matched comparison was also conducted with a contemporary cohort of patients who received EGFR TKIs alone.

Results

Sixty-four patients were enrolled in the trial. With a median follow-up of 18.2 (IQR, 13.6-26.4) months, the median PFS in all patients was 29.9 (95%CI, 21.0-38.8) months, with the lower boundary exceeding the predefined threshold. The median OS time had not been reached (95%CI, NA) and the 2-year OS rate was 88.8% (95%CI 70.3%-96.0%). In patients with cranial oligo-residual disease and receiving cranial SBRT, the median PFS was 27.0 (95%CI, 8.2-45.8) months. Adverse events (AE) were manageable, with pneumonitis and esophagitis being the most common toxicities. Four patients (6.3%) reported grade ≥3 AEs, each for pneumonitis, esophagitis, leukopenia and radiation necrosis. Propensity score-matched analysis showed significantly prolonged PFS in the SBRT+TKI group compared to the TKI alone group (HR 0.45, 95%CI 0.25-0.79; p =0.005).

Conclusions

Consolidative SBRT in patients with oligo-residual disease after first-line third-generation EGFR TKIs showed promising efficacy and acceptable toxicity profiles. This treatment approach may delay acquired resistance and improve survival outcomes. Further validation in larger prospective studies is warranted.

Clinical trial identification

NCT04764214.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Furmonertinib is a novel third-generation EGFR-TKI with high brain penetration, wide therapeutic range and minimal toxicity. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis. There is limited data of third-generation TKI combined with anlotinib in the naïve patients with EGFR-mutated NSCLC. For the L858R population, associated with a worse prognosis, combining a third-generation TKI with an anti-angiogenic drug could offer a potential strategy to enhance efficacy in this population.

Methods

FOCUS-A study is a prospective multicenter phase II trial, enrolled 40 patients who were locally advanced or metastatic NSCLC with EGFR-sensitive mutations. Patients with stable brain metastasis can be enrolled. The regimen is consisting of furmonertinib (80mg, qd) and anlotinib (10 mg qd, day 1 to 14 every 21-days /cycle). The primary endpoint is objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), Disease Control Rate (DCR), Duration of Response (DOR), safety, etc.

Results

Until Data Cut-Off 2023.12.21, 40 patients have been fully enrolled, with 22 of them having the L858R mutation. For L858R subgroup, efficacy were all completed with at least 2 time assessment and median follow-up was 13.96 months. The baseline characteristics were as follows: the median age was 62.5 years (range 50-71), female (63.6%), never smokers (86.4%), stage IV adenocarcinoma (90.9%) and CNS metastases (36.4%). The ORR was 95.45%（95%CI, 77.2-99.9）assessed by the investigator with RECIST1.1 criteria, with 21 patients achieved partial response (PR) and 1 patient stable disease (SD), DCR was 100%. Median Depth of response (DpR) was 42.0%. Grade≥3 TRAEs were experienced by 5 (22.7%) patients the most common adverse reactions were hypertension and elevation of creatinine. The follow-up remains ongoing.

Conclusions

FOCUS-A study demonstrated that furmonertinib plus anlotinib as first-line treatment for advanced EGFR L858R mutant NSCLC had an outstanding efficacy with manageable safety.

Clinical trial identification

NCT04895930.

Legal entity responsible for the study

The authors.

Funding

Shanghai Allist Pharmaceuticals.

Disclosure

All authors have declared no conflicts of interest.

Background

In preclinical studies, EGFR TKI resistant cells displayed vulnerabilities to aurora kinase inhibitors. LY3295668 is an oral, selective aurora kinase A inhibitor with monotherapy RP2D at 25mg twice-daily (BID). The most common adverse events (AEs) were mucositis, diarrhea and corneal deposition. This phase I/II trial (NCT05017025) was designed to evaluate the safety and establish osimertinib combination RP2D in EGFR-mutant NSCLC patients (pts); and preliminarily evaluate the clinical efficacy of the combination in pts whose tumors progress on osimertinib.

Methods

Pts with NSCLC harboring EGFR mutations and progressed on EGFR TKIs were enrolled. Up to 3 prior lines of therapies were allowed. LY3295668 was administered at 25mg BID with osimertinib 80mg daily. The primary endpoint for safety run-in was DLT; co-primary endpoints for the efficacy cohort were progression-free survival (PFS) at 6 months and best objective response rate (BRR).

Results

30 pts were enrolled (Mar 2022 - Feb 2023) and received at least one dose of treatment (intent-to-treat [ITT] cohort); 27 pts had at least one efficacy scan (efficacy cohort). Median age in ITT was 60, 77% female, 60% whites, 27% Asians. In the safety (n=10) and the entire cohort, there was no DLT. The RP2D was determined at LY3295668 25mg BID plus osimertinib 80mg daily. In the efficacy cohort (n=27), 6-month PFS rate was 37% (10/27). Three partial responses (PRs, 11%), 17 stable diseases (SD, 63%) and 7 progressive diseases (PD, 26%) were observed, with a disease control rate (DCR 74%). At the data cut-off on 12/12/2023, 5 pts were still on treatment. In the ITT cohort, 100% of pts had any AEs. Treatment-related AEs (TRAEs) were 80%, including 3% grade 4 (n=1, thrombocytopenia), 13% grade 3 (thrombocytopenia, lymphopenia, neutropenia, diarrhea, abdominal pain), and 63% grade 1-2. The most common TRAEs are diarrhea (73%), thrombocytopenia (60%), anemia (47%) and elevated transaminases (47%).

Conclusions

The combination of LY3295668 25mg BID plus osimertinib 80mg daily was found to be safe in EGFR-mutant NSCLC pts. The combination yields a 6-month PFS rate of 37% with 11% PR and 63% SD, demonstrating moderate clinical efficacy.

Clinical trial identification

NCT05017025.

Legal entity responsible for the study

Eli Lilly and MD Anderson Cancer Center.

Funding

Eli Lilly.

Disclosure

X. Le: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck KGaA, Spectrum Pharmaceutics, Novartis, Boehringer Ingelheim, Eli Lilly, Hengrui, Janssen, Blueprint, Daiichi Sankyo, Regeneron, ArriVent, Abion, Pinetree therapeutics, AbbVie; Financial Interests, Institutional, Invited Speaker: Eli Lilly, EMD Serono, Regeneron, Janssen; Financial Interests, Institutional, Research Grant: ArriVent; Financial Interests, Institutional, Funding: Teligene. L.A. Byers: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme Corp, Arrowhead, Chugai Pharmaceutical Co., Genentech Inc, AbbVie, Jazz Pharmaceuticals, Puma Biotechnology, Amgen, Daiichi Sankyo Sanyo, BeiGene; Financial Interests, Personal, Advisory Board, Per our institutional policy compensation from any consulting/etc. would always be <25000 for any 12 month period: AstraZeneca Pharmaceuticals; Financial Interests, Institutional, Funding, Research funding: AstraZeneca Pharmaceuticals, Amgen. C. Gay: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Monte Rosa Therapeutics, Aptitude Health; Financial Interests, Personal, Invited Speaker: BeiGene, AstraZeneca, Research to Practice, Peerview; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca. A.S. Tsao: Financial Interests, Personal, Advisory Board: Genentech, BMS, Eli Lilly, Roche, Novartis, Ariad, EMD Serono, Merck, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, GSK, Pfizer, Gilead Sciences, Inc., Summit Therapeutics; Financial Interests, Institutional, Research Grant: Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Epizyme, Genentech, Merck, Millennium, Novartis, Polaris, Settle Genetics. S. Heeke: Financial Interests, Personal, Invited Speaker: AstraZeneca, Guardant Health; Financial Interests, Personal, Research Grant: Thermo Fisher. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Allorion Therapeutics, Accutar Biotech, AbbVie, Duality Biologics; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Advisory Board, Consulting fee for advice on drug development: Merus, Frontier Medicines; Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development.: Hongyun Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. J. Heymach: Financial Interests, Personal, Advisory Board: Genentech, Mirati Therapeutics, Eli Lilly & Co., Janssen Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca, BioAlta, Sanofi, Spectrum Pharmaceuticals, GSK; Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Financial Interests, Personal, Invited Speaker: Spectrum; Financial Interests, Institutional, Other, International PI for clinical trials: AstraZeneca; Financial Interests, Institutional, Other, International PI for two clinical trials: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Other, Developed a drug: Spectrum; Financial Interests, Institutional, Invited Speaker: Takeda. All other authors have declared no conflicts of interest.

Background

The current standard treatment for EGFR mutated NSCLC patients progressed on third-generation EGFR TKI was chemotherapy. For patients retaining EGFR mutations after resistance, switching to more potent TKI provided another strategy. Furmonertinib was designed with unique chemical structure to improve potency and specificity targeting various EGFR mutations, and has been verified its superior efficacy and favorable safety profile in clinical trials. This study described the real-world efficacy and safety of furmonertinib as salvage treatment for EGFR-mutated NSCLC patients progressed on other third-generation EGFR TKIs.

Methods

We retrospectively examined advanced NSCLC patients with EGFR mutations progressed on osimertinib and/or aumolertinib who were treated with furmonertinib with or without other treatment from Apr 12, 2021, to Dec 20, 2023. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety were assessed.

Results

We included 43 patients, of which 37.2% progressed on first-line 3^rd generation EGFR TKI, 23.2% patients failed to both osimertinib and aumolertinib, and 37.2% patients progressed in intracranial lesion. The median follow-up time was 6.1 months (range 0.9 - 27.1). The ORR and DCR were 18.6% and 79.1% respectively, the median PFS was 6.1 months (95% CI 4.2 - 8.0). In those patients received furmonertinib after failure of first-line 3^rd generation EGFR TKI, the ORR and DCR were 25% and 87.5% respectively, the median PFS was 10.5 months (95% CI 0.0 - 23.6). In addition, treatment-emergent adverse events (TEAEs) of any grade occurred in 4.7% of patients (2/43), with no grade ≥3 TEAE was observed.

Conclusions

Furmonertinib showed encouraging anti-tumor activity and an acceptable safety profile as salvage treatment for patient with EGFR mutated NSCLC progressed on 3^rd generation EGFR TKI, especially in those with first-line 3^rd generation EGFR TKI.

Legal entity responsible for the study

The authors.

Funding

1. Guangzhou Science and Technology Program (grant number: 202002020074) 2. Natural Science Foundation of Guangdong Province (grant number: 2022A1515012582).

Disclosure

All authors have declared no conflicts of interest.

Background

Central nervous system (CNS) metastases are common and life-threatening complications in non-small cell lung cancer (NSCLC) patients with EGFR mutations treated with EGFR-TKIs. At the 2022 ASCO annual meeting, the analysis of phase III AENEAS study showed that aumolertinib, a novel third-generation EGFR-TKI, significantly improved median CNS PFS(CNS mPFS) compared to gefitinib in treatment-naive EGFR-mutant NSCLC patients with CNS metastases (29.0 vs 8.3months, hazard ratios: 0.319). However, for patients without baseline CNS metastasis, data regarding the incidence of symptomatic CNS metastasis with aumolertinib treatment and its risk factors are still rare.

Methods

All consecutive first-line aumolertinib-treated EGFR-mutant advanced NSCLC patients without baseline CNS metastasis after drug registration (April 2020 to February 2023) were included. The cumulative incidence of subsequent symptomatic CNS metastases, CNS mPFS, and their risk factors were estimated using the Kaplan–Meier method and the log-rank test.

Results

Data were retrieved from 63 patients who all received aumolertinib monotherapy as first-line treatment. The median follow-up was 27.4 months. There were 10 pts who developed symptomatic CNS metastases. The CNS mPFS was not reached, with the 12, 18, and 24-month CNS mPFS rate being 100%, 96.3%, and 93.6%, respectively. The cumulative incidence of symptomatic CNS metastasis at 12, 18, and 24 months were 0%, 3.7%, and 6.4 %, respectively. The cumulative incidence with aumolertinib was lower than historical data from first-generation EGFR-TKIs as first-line treatment(2.8-13.9% at 12 months; 9.3-34.6% at 24 months). Moreover, aumolertinib showed equivalent advantages in delaying symptomatic CNS metastasis in patients with L858R and 19del mutations (p=0.9345). Patients with concurrent TP53 mutations, especially mutations in exons 5 or 8, exhibited a higher risk of developing CNS metastasis than those without TP53 mutations or with an unknown status (p=0.0324).

Conclusions

This is the first study to suggest that aumolertinib can reduce the risk of CNS metastasis and prolong CNS disease control in untreated NSCLC patients without baseline CNS metastasis better than first-generation TKIs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Osimertinib is the preferred first-line treatment for patients (pts) with EGFRm aNSCLC. However, most pts treated with osimertinib will develop resistance. We present the preliminary resistance mechanism results from FLOURISH study.

Methods

FLOURISH was a multi-center, prospective, non-interventional study to investigate the incidence of resistance among pts on osimertinib as first-line treatment for EGFRm aNSCLC (NCT04391283). 473 eligible pts were recruited from 22 sites from Jul 27, 2020 to Apr 27, 2022. Here included 68 pts who progressed after osimertinib and performed next-generation sequencing. 28 pts had paired pre-treatment samples.

Results

The data cut-off date was Dec 4, 2023. Among the 68 pts, 45.6% (31) had detected genetic resistance after progression, including 29.4% (20) were off-target (EGFR-independent), 10.3% (7) were on-target (EGFR-dependent) and 5.9% (4) were both. MET amplification (amp) 8.8% (6), EGFR amp 7.4% (5), and EGFR L718Q 7.4% (5) were the most prevalent resistance, followed by PIK3CA mutation (mut) 5.9% (4) and FGFR mut 5.9% (4), C797S 4.4% (3) and MET 14 deletion (del) 1.5% (1). Of the 28 paired pts, 39.3% (11) were 19 del and 60.7% (17) were 21 L858R, 92.9% (26) were adenocarcinoma, 60.7% (17) were paired plasma and 39.3% (11) were paired tissue. 39.3% (11) had acquired genetic resistance, with 28.6% (8) were off-target and 10.7% (3) were on-target (Table). Table: 19P

Conclusions

The acquired genetic resistance rate to first-line osimertinib in FLOURISH study was consistence with previous data, and in which MET amp, FGFR mut and EGFR L718Q were common acquired resistance mechanisms among paired pts.

Clinical trial identification

NCT04391283.

Legal entity responsible for the study

Guangdong Association of Clinical Trials.

Funding

AstraZeneca China.

Disclosure

All authors have declared no conflicts of interest.

Background

Osimertinib represents the current standard treatment for advanced EGFR-mutated NSCLC in the first-line (1L) setting. Acquired resistance inevitably occurs. The exploration of genomic profiles in resistant patients (pts) is vital.

Methods

EGFR mutant locally advanced or metastatic NSCLC pts post osimertinib 1L treatment failure were prospectively enrolled. Genomic profiles of paired tissues and plasma samples at progression were analyzed using NGS. Considering tissues as references, the sensitivity and specificity of EGFR amplification (amp), MET amp, EGFR C797S mutation and other non-sensitive EGFR mutations in plasma samples were analyzed.

Results

From Feb 2022 to Oct 2023, 86 pts were analyzed with paired tissue and plasma samples. The median age was 63 years (range, 33-84 years), and 45.3% were males. The majority had ECOG PS 0-1 (97.7%). At progression, EGFR C797S mutation (3.5%), other non-sensitive EGFR mutation (15.1%), EGFR amp (30.2%), MET amp (27.9%), other amps (16.3%), cell cycle gene alterations (25.6%), fusion (11.6%) and other mutations (20.9%) in tissue samples were detected. Two pts (2.3%) had histological transformation, one experienced SCLC transformation, the other one experienced squamous carcinoma transformation. Same genomic profile with different proportions were detected in paired plasma samples, including EGFR C797S mutation (4.7%), other non-sensitive EGFR mutation (17.4%), EGFR amp (10.5%), MET amp (8.1%), other amps (7.0%), cell cycle gene alterations (4.7%), fusion (14.0%) and other mutations (11.6%). Using tissues as references, the sensitivity of EGFR amp, MET amp, EGFR C797S mutation and other non-sensitive EGFR mutation were 34.62%, 16.67%, 66.67% and 76.92%, respectively in paired plasma samples. The specificity were 100.00%, 95.16%, 97.59% and 93.15%, respectively in paired plasma samples.

Conclusions

Genomic profiles were complicated in EGFR mutant locally advanced or metastatic NSCLC pts post osimertinib 1L treatment failure, with the most common being EGFR amp and MET amp. Plasma genotyping is an alternative method to identify resistance profiles when tissues are not available.

Clinical trial identification

NCT05219162.

Editorial acknowledgement

Medical writing and editorial support were provided by Hangzhou Tigermed Consulting Co.,Ltd, which was funded by AstraZeneca China.

Legal entity responsible for the study

AstraZeneca China.

Funding

AstraZeneca China.

Disclosure

All authors have declared no conflicts of interest.

Background

MET amplification is one of acquired resistance mechanism to EGFR-TKIs in EGFRm advanced NSCLC patients(pts). However, comprehensive data using NGS and FISH for detecting MET amplification is limited in Chinese patients.

Methods

Patients progressed after 1st-, 2nd-, or 3rd-generation EGFR-TKIs were enrolled. Tissue biopsy samples were performed for MET amplification detection via both NGS and FISH. Paired plasma samples were also collected for MET amplification detection by NGS. The sensitivity, specificity and agreement were analyzed between NGS and FISH.

Results

116 post EGFR-TKI resistant pts were analyzed. 45(38.8%) pts were male. 34(29.3%) pts were after 1^st or 2^nd generation EGFR-TKI, 80(69.0%) pts after 3^rd generation EGFR-TKI, while 2(1.7%) pts with lack of data on specific EGFR-TKI drug or combined 1^st and 3^rd EGFR-TKI. MET amplification was detected in 43(37.1%) patients by FISH, including 19(16.4%) with polysomy and 24(20.7%) with focal amplification. The positive rate of MET amplification in post 3^rd gen EGFR-TKI and post 1^st/2^nd gen EGFR-TKI resistant pts was 45.0% (36/80) and 20.6% (7/34), respectively. Using FISH as reference, the sensitivity, specificity and agreement of detecting MET amplification by NGS in tissue were 39.5%(17/43), 98.6% (72/73) and 76.7% (89/116), respectively. For focal MET amplification in tissue, the sensitivity, specificity and agreement were 66.7%(16/24), 98.6% (72/73) and 90.7%(88/97), respectively. For focal MET amplification in plasma, the sensitivity, specificity and agreement were 29.2%(7/24), 94.5%(69/73) and 78.4%(76/97). Results were both shown in the table.

Table: 21P

Performance of NGS in tissue and plasma

Conclusions

NGS is an alternative method for MET focal amplification detection in tissue. While the sensitivity of NGS testing in plasma needs further improvement to maximize identification of pts with potential benefit from dual-targeted therapy.

Legal entity responsible for the study

Department of Pulmonary and Critical Care Medicine, West China Hospital.

Funding

AstraZeneca.

Disclosure

The author has declared no conflicts of interest.

Background

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard First-line treatments for advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, despite optimal therapies, not all patients have a positive response. The existence of simultaneous mutations may contribute to resistance. The objective of this study was to evaluate the effect of simultaneous mutations on the prognosis of patients receiving first-line EGFR TKI treatment for EGFR-mutated NSCLC.

Methods

This was a single center, retrospective cohort study that included patients aged 19 or older with EGFR-mutant advanced NSCLC using Next Generation Sequencing (NGS). Participants were treated with first-line EGFR-TKIs. The primary endpoint was time-to-treatment discontinuation (TTD).

Results

254 patients were enrolled in the study from January 2017 to December 2022. Median age was 62.5 (range 37-75), and 44.5% (113/254) was males. The most common tumor type was Adenocarcinoma (250/254, 98.42%). Among Co-mutation, the most common mutation was TP53(157/254, 61.8%). The overall median TTD of this cohort was 17 months. There were differences in median TTD between EGFR mutation without TP53 and EGFR mutation with TP53 (25 vs 16 months, P value= 0.032) (Table). Baseline characteristics of study population and time-to-treatment discontinuation (TTD) of 1^st line EGFR TKI in EGFR-mutant NSCLC by Next Generation Sequencing. Table: 22P

Conclusions

Advanced EGFR mutant NSCLC patients with TP53 had a shorter time-to-treatment discontinuation(TTD) compared to those with EGFR mutation. Further investigations are needed for prognostic and response evaluations with other identified mutations.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The concurrence of EGFR mutations with ALK, ROS1, RET fusions, or MET exon 14 skipping mutations is rare in non-small cell lung cancer (NSCLC) and lacks reliable predictive biomarkers. This study aims to evaluate the prevalence, clinical characteristics, and prognostic factors of these co-mutations in a Chinese NSCLC cohort.

Methods

A retrospective analysis of 3,669 pathologically confirmed NSCLC patients (2020–2023) was conducted. High-throughput sequencing was used to identify co-mutations of EGFR with ALK, ROS1, RET fusions, or MET exon 14 skipping mutations in tissues. Correlation analyses were performed between these co-mutations and clinicopathological parameters, as well as survival outcomes.

Results

Co-mutations were identified in 42 patients, including EGFR-ALK fusions (n=22), EGFR -ROS1 fusions (n=5), EGFR-MET exon 14 skipping mutations (n=3), and EGFR-RET fusions (n=12). These patients had a median age of 60.5 years, and 92.9% were diagnosed with adenocarcinoma. Patients with co-mutations had a lower incidence of smoking (26.2% vs 49.0%, p<0.01) and a higher proportion of advanced-stage disease (64.3% vs 47.0%, p<0.05) compared to patients without co-mutations. The EGFR-RET co-mutation group had a higher proportion of patients aged ≤ 60 years (83.3%) compared to other groups (p<0.05). The median overall survival (OS) for the 25 stage IV patients treated with tyrosine kinase inhibitors (TKIs) was 25 months. No significant difference was found in OS between mono-targeted and dual-targeted therapy groups, or among different co-mutation groups. Superior OS was observed in non-smokers compared to smokers (HR=7.9, p<0.001), in females compared to males (HR=3.6, p=0.019), and in early-stage patients (I-II) compared to advanced-stage patients (III-IV) (HR=3.88E+08, p=0.002).

Conclusions

This study highlighted the occurrence and clinical characteristics of EGFR-involved co-mutations in a Chinese NSCLC cohort. Non-smoking, female gender, and younger age were identified as favorable prognostic factors in this co-mutated population.

Legal entity responsible for the study

Affiliated Cancer Hospital of Chongqing University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Mutations (single nucleotide variants), deletions, and insertions in the kinase domain of EGFR gene are oncogenic drivers in NSCLC. These alterations can co-occur with one another (compound mutations) or exist as single mutations. The compound vs single mutation frequencies for classical and EGFR P-loop and αC-helix compressing (PACC) mutations have not been characterized and the impact of compound mutations on treatment outcomes are not understood.

Methods

Guardant Health liquid biopsy database was queried for NSCLC samples for their genetic profiling. Incidences EGFR mutations as single and compound mutations (excluding T790M and C797S) were analyzed and compared. A systematic literature search was performed and analyzed for esponse to different TKIs.

Results

Of the 104,393 lung cancer samples queried, 32,700 had an EGFR SNV/indel, of which, 17,488 (16.8%) had at least one SNV/indel within the kinase domain. The most frequent mutations were ex19del (6,670, 38.1%), L858R (4,700, 26.9%), G719 (712, 4.1%), S768 (335, 1.9%), and G709 (207, 1.2%). Classical EGFR mutations occur more frequently as a single mutation, each at 89.6% (5,970/6,665) and 76.7% (3,606/4,700) respectively. In comparison, PACC mutations occur more frequently as compound mutations (Table), G719 at 73.2% (521/712), S768 at 86.9% (291/335) and G709 at 97.1% (201/207). The most frequent compound mutation with G719 is G709 and S768, with S768 is V769, and with G709 is G719. A total of 852 cases with clinical response to EGFR TKIs from a clinical cohort were identified and analyzed by PACC mutation single (693) vs compound (159) (Table). As expected, PACC mutations responded better to 2nd-generation TKIs than 1st- or 3rd-generation TKIs. Compound mutations responded better than single mutations for each PACC mutation. Table: 24P

Conclusions

Compared to classical EGFR mutations, PACC mutations frequently occur as compound mutations, and tend to have improved response to EGFR TKIs than single PACC mutations.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding

Disclosure

X. Le: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck KGaA, Spectrum Pharmaceutics, Novartis, Boehringer Ingelheim, Eli Lilly, Hengrui, Janssen, Blueprint, Daiichi Sankyo, Regeneron, ArriVent, Abion, Pinetree therapeutics, AbbVie; Financial Interests, Institutional, Invited Speaker: Eli Lilly, EMD Serono, Regeneron, Janssen; Financial Interests, Institutional, Research Grant: Arrivent; Financial Interests, Institutional, Funding: Teligene. M. Stamboulian: Financial Interests, Personal, Full or part-time Employment: Guardant Health. S. Heeke: Financial Interests, Personal, Invited Speaker: AstraZeneca, Guardant Health; Financial Interests, Personal, Research Grant: Thermo Fisher. C. Lewis: Financial Interests, Personal, Full or part-time Employment: Guardant Health. L. Drusbosky: Financial Interests, Personal, Full or part-time Employment: Guardant Health. J. Heymach: Financial Interests, Personal, Advisory Board: Genentech, Mirati Therapeutics, Eli Lilly & Co., Janssen Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca, BioAlta, Sanofi, Spectrum Pharmaceuticals, GSK; Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Financial Interests, Personal, Invited Speaker: Spectrum; Financial Interests, Institutional, Other, International PI for clinical trials: AstraZeneca; Financial Interests, Institutional, Other, International PI for two clinical trials: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Other, Developed a drug: Spectrum; Financial Interests, Institutional, Invited Speaker: Takeda. A. Addeo: Financial Interests, Institutional, Advisory Board: BMS, AZD, Roche, Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer, Takaeda, MSD; Financial Interests, Institutional, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.

Background

Osi is a third-generation, central nervous system (CNS)-active, oral EGFR-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It is the preferred 1L therapy for EGFRm advanced NSCLC. However, patients (pts) may progress after 1L osi and need subsequent therapy. Real-world second-line (2L) therapy data in this population are lacking. Hence, we characterised 2L treatment patterns and outcomes after 1L osi in a US cohort.

Methods

Pts with EGFRm advanced NSCLC treated with 1L osi from 2018–2020 were identified from the Flatiron Health Database. Line of therapy was considered new if there was a gap of >120 days between sequential drug episodes. 2L therapies were described and overall survival (OS) was summarised by 2L therapy.

Results

In total, 773 pts were assessed. At data cut-off (Jan 2023; median overall follow-up: 24 months; median follow-up for pts with subsequent therapy: 29 months), of the 773 assessable pts, 299 (39%) received 2L therapy, 173 (22%) remained on 1L osi, 251 (32%) had died with no subsequent therapy and 50 (7%) were alive with no subsequent therapy. The most common 2L therapy was osi combination therapy (26%), followed by immunotherapy (IO) + chemotherapy (CTx) (25%), EGFR-TKIs alone (16%), CTx alone (15%), IO alone (9%), and clinical study drug (8%). Most pts receiving osi combinations received osi + CTx (59%). Median OS (95% confidence interval [CI]) following 2L treatment is shown in the table. There was substantial variation in 2L treatment patterns by CNS metastasis at baseline and EGFR mutation subtype; these data will be presented. Table: 25P

Conclusions

Over a third of pts received no 2L therapy after 1L osi. The most frequent 2L therapies were osi combination therapy and IO + CTx. Our results emphasise that pts should receive the most effective therapy in the 1L setting. OS by 2L therapy.

Editorial acknowledgement

Medical writing support was provided by Hedley Coppock, Ph.D., of Ashfield MedComms, an Inizio company, for medical writing support that was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

F. Griesinger: Financial Interests, Institutional, Research Grant: ASTRA, Boehringer Ingelheim, BMS, Lilly, Novartis, Roche, MSD, Pfizer, Takeda, Siemens, Amgen, GSKD, Sanofi; Financial Interests, Personal, Other, Consulting fees; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Support for attending meetings and/or travel; Participation on a Data Safety Monitoring Board or Advisory Board: ASTRA; Financial Interests, Personal, Other: Boehringer Ingelheim, BMS, Lilly, Novartis, Roche, MSD, Pfizer, Takeda, Siemens, Amgen, GSK, Sanofi, Daiichi Sankyo, BeiGene. D. Shah: Financial Interests, Institutional, Funding: ANTHOS Inc, Guardant, AstraZeneca. R.J. Salomonsen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. J. Chapaneri: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. M. Cooper: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. P.S. Karia: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Royalties: UpToDate. J.J. Nieva: Financial Interests, Personal, Invited Speaker: Genentech; Financial Interests, Personal, Writing Engagements: AstraZeneca; Financial Interests, Personal, Ownership Interest: Cansera; Financial Interests, Personal, Stocks/Shares: Amgen, Johnson & Johnson, Novartis; Financial Interests, Personal, Research Grant: Merck, Genentech; Financial Interests, Personal, Advisory Role: ANP Technologies, Aadi Biosciences, BioAtla, G1 Therapeutics, Mindmed, Naveris, Kalivir.

Background

Osi is a 3rd-generation EGFR TKI indicated for 1st- (1L) and 2nd-line (2L) treatment of adult pts with advanced NSCLC with common EGFR mutations (cEGFRm; exon 19 deletions [ex19del] or exon 21 L858R mutations). Not all patients benefit from osi Tx, and most eventually develop resistance. There are currently few approved targeted Tx for cEGFRm NSCLC. Here we characterise pt profiles with cEGFRm NSCLC to describe the population and existing unmet medical need.

Methods

This retrospective study uses data from the Epidemiological Strategy and Medical Economics (ESME; France) and the Rigshospitalet (RH; Denmark) databases. Eligible pts were adults with histologically confirmed primary cEGFRm NSCLC who were prescribed 1L or 2L osi. The primary objective was to describe pt profiles and outcomes and identify characteristics that are potential prognostic factors for overall survival (OS), progression-free survival (PFS), time to next therapy (TNT), and time to treatment discontinuation (TTD).

Results

Current results are from 624 pts from ESME; analysis of 127 pts from RH is ongoing: median age at diagnosis, 68.5 y; 73.4% female; 42.0% and 58.8% had L858R and ex19del, respectively. Of the 198 pts that received 1L osi, 24% died before 2L and 34% had subsequent Tx. Of the 426 who received 2L osi, 30% died before 3L and 47% had subsequent Tx. Among pts receiving subsequent Tx after 1L or 2L osi, the most common Tx was platinum-based chemo (1L, 34%; 2L, 45%). For 1L osi, median OS, PFS, TNT, and TTD were 27.0, 12.4, 19.5, and 17.6 mo, respectively. For 2L osi, median OS, PFS, TNT, and TTD were 18.6, 7.4, 11.9, and 11.5 mo, respectively. In both 1L and 2L, OS and PFS are substantially lower than those reported in clinical trials. While different sets of prognostic factors were observed for different outcomes and lines, ECOG performance and presence of L858R mutation were consistently prognostic across all settings.

Conclusions

This retrospective analysis based on real-world data on 1L and 2L osi efficacy confirms the poor outcomes with osi shown in clinical trials, with 24% of pts with 1L osi dying before receiving a 2L Tx. These results highlight the unmet need for new Tx options in cEGFRm NSCLC.

Editorial acknowledgement

Medical writing assistance was provided by Lumanity Communications Inc and funded by Janssen Global Services LLC.

Legal entity responsible for the study

Janssen Pharmaceuticals.

Funding

Janssen Pharmaceuticals.

Disclosure

M. Pérol: Financial Interests, Personal, Funding: Janssen; Financial Interests, Personal, Other, Consulting Fees: Bristol Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Roche, Daiichi Sankyo, Janssen, Ipsen, Esai, GSK, Eli Lilly, Pfizer, Takeda, Novocure; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Merck Sharp and Dohme, AstraZeneca, AnHeart Therapeutics, Sanofi, Pfizer, Takeda, Janssen; Financial Interests, Personal, Expert Testimony: Bristol Myers Squibb, AstraZeneca, Roche, Janssen; Financial Interests, Personal, Other, Attending Meeting/Travel: Bristol Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Roche, Pfizer, Takeda; Financial Interests, Personal, Advisory Board: Roche, PharmaMar. C. Chouaid: Financial Interests, Personal, Funding: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer and Amgen; Financial Interests, Institutional, Research Grant: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer and Amgen; Financial Interests, Personal, Other, Consulting Fees: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer and Amgen; Financial Interests, Personal, Invited Speaker, Attending Meetings/Travel: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer and Amgen. A. Bjerrum: Financial Interests, Institutional, Funding: Johnson & Johnson; Financial Interests, Institutional, Research Grant: Roche, Eli Lilly, Novartis; Financial Interests, Personal, Other, Attending Meetings/Travel: Gilead. J. Cabrieto, I. Luccarini: Financial Interests, Personal, Full or part-time Employment: JnJ Innovative Medicine; Financial Interests, Personal, Stocks/Shares: JnJ Innovative Medicine. N. Perualila: Financial Interests, Personal, Full or part-time Employment: JnJ Innovative Medicine; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson stock or stock options. J. Edwards: Financial Interests, Personal, Full or part-time Employment: J&J innovative Medicine; Financial Interests, Personal, Stocks/Shares, Past employee share options: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Platinum(pt)-based chemotherapy (CTx) is the current standard treatment option in patients (pts) with EGFR mutant NSCLC who progress on osimertinib (osi). However, outcomes with CTx are dismal and CNS disease is an unmet need in this setting.

Methods

Pts with EGFR mutant NSCLC who were candidate to receive osi in the metastatic setting at our center from 2015 to 2022 were retrospectively evaluated to identify pts who received standard pt-based CTx post-osi. Data were collected on outcomes to standard CTx with focus on brain metastases and progression patterns.

Results

220 pts received indication for osi in the study period, n=181 had adequate follow up data. Overall, 110 pts experienced disease progression on osi. Median time to osi PD was 43 months (95% CI 37-63). Of them, 55 patients (50%) had no access to further treatment lines because of death. Of the remaining 55 pts, 10 received experimental treatments in clinical trials, whereas 45 received standard pt-based CTx and were considered for this study. Median duration of CTx was 3 months (95% CI 2-5), best responses among 40 pts evaluable were observed as following: 15% PR/CR, 45% SD, 40% PD. Median PFS and OS were 3 (95% CI 2-4) and 10 (95% CI 6-15) months, respectively. All patients had baseline and follow up brain radiologic assessment (n=29 CT scan, n=16 MRI), 18 had baseline brain metastases at the time of CTx start, 4 received previous brain RT for CNS oligo-PD on osimertinib. With a median follow-up of 9 months, intracranial PD occurred in 12 (30%) pts (67% among those with baseline CNS metastases), being the first site of PD in 75% of cases, symptomatic in 42%. Median time for IC PD was 2 months (95% CI 1-NA). IC PD occurred as oligometastatic PD in 42%, whereas in 58% of cases it was associated with systemic PD. The preferred approaches to treat IC PD were SBRT (16%), WBRT (16%), new systemic treatment (42%), BSC (25%).

Conclusions

CNS-progression is confirmed as an unmet need in EGFR mutant NSCLC pts. Clinical and CNS-specific outcomes in pts receiving standard CTx after failure of osi are disappointing. Novel treatment options with demonstrated better CNS outcomes may help in addressing this important issue.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

I. Attili: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb. A. Passaro: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, Medscape, eCancer; Financial Interests, Institutional, Invited Speaker, Steering Committee Member PALOMA-3 trial: Janssen; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, Janssen; Non-Financial Interests, Personal, Other, Scientific Commitee for Lung Cancer Guideline: AIOM; Non-Financial Interests, Personal, Officer, ESMO Council Member & Chair of Communication Committee: ESMO. F. de Marinis: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Pfizer, Novartis, Takeda, Xcovery. All other authors have declared no conflicts of interest.

Background

Osi, a 3^rd-generation, central nervous system-active, EGFR-TKI, is the preferred 1L tx for EGFRm advanced NSCLC. We report interim results from a German cohort of a global rw prospective, observational study of long-term survival and tx patterns in pts with EGFRm advanced NSCLC who received 1L osi.

Methods

Data for pts aged ≥18 yrs with EGFRm advanced NSCLC initiating 1L osi in Germany (1 Jun 2018–31 Dec 2020) were extracted from the CRISP registry. Primary endpoints: rw overall survival (OS), time to next tx or death (TTNTD) and tx patterns; secondary endpoints: baseline characteristics and time to tx discontinuation (TTD). Exploratory endpoints included rw progression-free survival (PFS; defined as time from 1L initiation to disease progression or death) and rwOS by EGFR mutation type. Outcomes were also assessed in a pt subset to approximate the FLAURA trial population (NCT02296125; FLAURA-like cohort) and pts with baseline brain metastases (mets).

Results

In 224 pts, median age was 68 yrs (interquartile range [IQR] 59–77; 66% were female, 47% had never smoked, 38% had baseline brain mets and 39/34/13% had Ex19del/L858R/uncommon EGFR mutations (including ex20ins; G719X; L861Q; S768I; Group I; T790M). At data cutoff (30 Jun 2022), median follow-up was 23.8 mos (IQR 21.7–27.5) and 124/224 (55%) pts had a progression event. The table shows outcomes in all pts, the FLAURA-like cohort and pts with baseline brain mets. Overall, 80/224 (36%) pts remained on osi and 50 (22%) pts received second-line tx (most commonly immunotherapy + chemotherapy [n=26], TKIs [n=11] and chemotherapy [n=9]). Table: 28P

Conclusions

Our results reinforce the effectiveness of 1L osi for EGFRm advanced NSCLC in a rw setting. Median rwOS and rwPFS in this German cohort were comparable with results from the FLAURA trial (Ramalingam NEJM 2020; Soria NEJM 2018).

Editorial acknowledgement

The authors would like to acknowledge Caroline Allinson, BSc, contracted by Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

F. Griesinger: Financial Interests, Institutional, Research Grant: ASTRA, Boehringer Ingelheim, BMS, Lilly, Novartis, Roche, MSD, Pfizer, Takeda, Siemens, Amgen, GSKD, Sanofi; Financial Interests, Personal, Other, Consulting fees; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Support for attending meetings and/or travel; Participation on a Data Safety Monitoring Board or Advisory Board: ASTRA, Boehringer Ingelheim, BMS, Lilly, Novartis, Roche, MSD, Pfizer, Takeda, Siemens, Amgen, GSKD, Sanofi, Daiichi Sankyo, BeiGene. P. Steffens: Other, Institutional, Full or part-time Employment: AstraZeneca. R. Schuh: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. M. Cooper: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J. Chapaneri: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R.J. Salomonsen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. P.S. Karia: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Royalties: UpToDate. M. Thomas: Other, Personal, Advisory Board, Financial and non-financial (travel cost) interests: Amgen; Other, Personal, Advisory Board: AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GSK, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Merck, Roche, Takeda. All other authors have declared no conflicts of interest.

Background

The aim of this study was to better understand the real-world safety profile of osimertinib in Chinese NSCLC patients (pts).

Methods

This was a prospective, observational study conducted in Chinese NSCLC pts who received ≥1 dose of osimertinib. Pts were followed up for 12 months after enrolment or until 30 days after osimertinib discontinuation, whichever occurred earlier. The primary endpoint was the incidence of adverse drug reactions (ADRs) in the overall pts. Secondary endpoints included the incidences of adverse events (AEs), serious AEs (SAEs), AEs of special interests (AESIs) in the overall pts, and the incidences of ADRs, AEs, SAEs, and AESIs in pts ≥65 years old. AESIs assessed in this study were QTc prolongation and interstitial lung disease/pneumonitis-like events.

Results

From 20 Apr 2020 to 1 Aug 2022, 1,700 pts were enrolled from 30 centres in China. By the data cut-off (3 Aug 2023), 1,301 (76.5%) pts completed the study. Of the enrolled pts, median age (Q1, Q3) was 62 (54, 69) years, with 706 (41.5%) ≥65 years old. Osimertinib was administered as first-line, second-line, ≥third-line, adjuvant, and neo-adjuvant therapy in 764 (44.9%), 581 (34.2%), 243 (14.3%), 77 (4.5%), and 4 (0.2%) pts. Median total exposure of osimertinib (Q1, Q3) was 384 (322, 479) days in the overall pts and 376 (299, 470) days in pts ≥65 years old. In overall pts, ADRs, AEs, and SAEs occurred in 627 (36.9%), 959 (56.4%), and 102 (6.0%) patients, respectively. AESIs occurred in 59 (3.5%) patients, with 41 (2.4%) and 19 (1.1%) patients experiencing QTc prolongation and interstitial lung disease/pneumonitis-like events, respectively. The safety profile of pts ≥65 years old was consistent with that of the overall pts. Table: 29P

Safety summary

Conclusions

In this largest real-word study of NSCLC patients receiving osimertinib in Chinese real-world clinical practice, osimertinib was well-tolerated and no new safety signals were identified.

Clinical trial identification

NCT03485326.

Editorial acknowledgement

Medical writing and editorial support were provided by Costello Medical, which was funded by AstraZeneca China.

Legal entity responsible for the study

AstraZeneca China.

Funding

AstraZeneca China.

Disclosure

All authors have declared no conflicts of interest.

Background

Uncommon EGFR mutations represents a rare subgroup of non-small cell lung cancer. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations is scattered and limited to mostly retrospective small cohorts, as these patients were usually excluded from clinical trials.

Methods

This was a systematic review on the efficacy of TKIs in patients harboring uncommon EGFR mutations, defined as mutations other than ex20ins or T790M. Response rates (RRs) for different generations of TKIs were determined for individual uncommon mutations, compound mutations, and according to classical-like and P-loop alpha helix compressing mutations classes (PACC). This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results

1,836 patients from 38 studies were included in the final analysis. Most available data (92.6%) were from patients treated with first or second-generation TKIs. G719X, S768I, E709X, L747X and E709-T710delinsD demonstrated RRs ranging from 47.8%-72.3% to second-generation TKIs, generally higher than for 1st or 3rd generation TKIs. L861Q mutation exhibited 75% (95% CI: 56.6-88.5%) RRs to 3rd generation TKIs. Compound mutations with G719X, E709X or S768I consistently showed RRs above 50% to 2nd and 3rd generation TKIs, though fewer data were available for 3rd generations. For classical-like mutations, RRs were 35.4% (95% CI: 27.2-44.2%), 51.9% (95% CI: 44.4-59.3%) and 67.9% (95% CI: 47.6-84.1%) to first, second and third generation TKIs, while for PACC mutations, RRs were 37.2% (95% CI: 32.4-42.1%), 59.6% (95% CI: 54.8-64.3%) and 46.3% (95% CI: 32.6-60.4%) respectively.

Conclusions

This systematic review supports the use of 2nd generation TKI afatinib for G719X, S768I, E709X and L747X mutations, as well as for compound uncommon mutations. For other uncommon mutations such as L861Q, 3rd generation TKI, such as osimertinib, seems a reasonable option, considering its activity and toxicity profile.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

K. Parikh: Financial Interests, Institutional, Other, Consulting fees: Jazz pharmaceuticals; Financial Interests, Institutional, Other, Consuling fees: Guardant Health, AstraZeneca; Financial Interests, Personal, Invited Speaker: MJH Life science; Financial Interests, Institutional, Invited Speaker: Dava Oncology; Financial Interests, Personal, Other, Support for attending meetings/travels: Dava Oncology. G.L. Banna: Financial Interests, Institutional, Speaker’s Bureau: Astellas, Amgen, astrazeneca; Financial Interests, Personal, Other, Support for attending meeting/travel: Janssen, Merck; Financial Interests, Personal, Other, Patent planned/issued: St Microelectronics. X. Le: Financial Interests, Personal, Other, Consulting fees: EMD Serono; Financial Interests, Institutional, Invited Speaker, Consuling fees: Eli Lilly, AstraZeneca, Spectrum pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint medicines, Sensei Biotherapeutics, Systimmune, ArriVent, Abion, AbbVie; Financial Interests, Personal, Stocks/Shares: BlossomHill; Financial Interests, Personal, Other, Support for attending meeting/travel: EMD Serono, Janssen, Spectrum pharmaceutics; Financial Interests, Personal and Institutional, Research Grant: Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, Thermo Fisher, Takeda, Boehringer Ingelheim. A. Addeo: Financial Interests, Institutional, Advisory Board: BMS, AZD, Roche, Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer, Takeda, MSD; Financial Interests, Institutional, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.

Background

The addition of carboplatin-doublet chemotherapy (CBCT) to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) improves progression-free survival in EGFR mutated NSCLC. However, both classes of agents are associated with myelosuppression presenting as neutropenia, anemia, and/or thrombocytopenia. We evaluated rates of myelosuppression (any grade) for EGFR-TKIs alone and in combination with CBCT.

Methods

A systematic literature review (SLR) was conducted to summarize the incidence of myelosuppression events reported in clinical trials evaluating EGFR-TKIs alone, CBCT alone, or both among patients with EGFR-mutant advanced NSCLC. Searches were conducted in Embase and MEDLINE to identify full-text articles and conference proceedings published between 2010 and 2023 that met prespecified inclusion criteria.

Results

Sixteen trials, including 14 randomized controlled trials, were included. Twelve trials evaluated first-line treatments, and 4 evaluated second-line or later. Included trials assessed 1st- and 3rd-generation TKIs; none assessed 2nd generation TKIs. Across trials, the weighted average incidence of any-grade myelosuppressive events for 1st generation TKIs plus CBCT versus CBCT alone was 63.4% vs 44.7% for anemia, 61.8% vs 38.9% for neutropenia, and 48.2% vs 35.1% for thrombocytopenia. The incidence for any-grade myelosuppressive events for 3rd generation TKIs plus CBCT versus CBCT alone was 71.7% vs 44.7% for anemia, 88.7% vs 38.9% for neutropenia, and 73.6% vs 35.1% for thrombocytopenia. Table: 31P

Conclusions

Adding EGFR TKIs to CBCT results in higher rates of cytopenic events than seen with CBCT or TKI monotherapy alone. Risk was higher for 3rd generation TKIs, especially for neutropenia and thrombocytopenia.

Editorial acknowledgement

Medical writing assistance was provided by Evidera and Lumanity Communications Inc and funded by Janssen Global Services LLC.

Legal entity responsible for the study

Janssen Pharmaceuticals.

Funding

Janssen Pharmaceuticals.

Disclosure

N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati, Amgen, Novartis, Sanofi, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Pfizer, Janssen, Boehringer, Novartis, Sanofi, AbbVie, Amgen, Lilly, Grunenthal, Takeda, Owkin, Leo Pharma, Daiichi Sankyo, Ipsen; Financial Interests, Institutional, Research Grant, Local: Roche, Sivan, Janssen; Financial Interests, Institutional, Funding: BMS, Leo Pharma; Financial Interests, Institutional, Research Grant: MSD; Other, Personal, Other, Family member is an employee: AstraZeneca. S.V. Liu: Financial Interests, Personal, Advisory Board, Consultant: AstraZeneca, Elevation Oncology, Genentech / Roche, Janssen, Jazz Pharmaceuticals, Novartis, Regeneron, Sanofi, Turning Point Therapeutics; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Catalyst, Eisai, Gilead, Guardant Health, Merus, Takeda; Financial Interests, Personal, Other, Consultant: Daiichi Sankyo, Merck; Financial Interests, Institutional, Invited Speaker: Alkermes, Elevation Oncology, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker, Local PI: Genentech; Non-Financial Interests, Personal, Member: ASCO, IASLC. W. Nassib William Junior: Financial Interests, Personal, Invited Speaker: Amgen, Genentech / Roche, Eli Lilly, BMS, Pfizer, Janssen, United Medical; Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, Bayer, Sanofi, Takeda, Novartis; Financial Interests, Personal, Expert Testimony: Boehringer Ingelheim. K. Schaible: Financial Interests, Personal, Full or part-time Employment: Evidera. D. Junqueira: Financial Interests, Personal, Full or part-time Employment: Evidera. H. Burnett: Financial Interests, Personal, Full or part-time Employment: Evidera. P. Mahadevia: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson. M. Chioda: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson. J.M. Bauml: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson. N. Leighl: Financial Interests, Personal, Other, CME/independent lectures: MSD, BMS, Hoffmann LaRoche, EMD Serono; Financial Interests, Personal, Invited Speaker, independent lectures: Novartis, Takeda; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Array, Bayer, EMD Serono, Guardant Health, Lilly, MSD, Pfizer, Roche, Takeda, Janssen.

Background

Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer (NSCLC). The aim of this retrospective study is to investigate the effectiveness and safety of furmonertinib in patients with advanced EGFR-mutated (EGFRm) NSCLC and LM.

Methods

Between February 2020 and March 2023, 31 patients with EGFR mutation-positive NSCLC with LM treated with furmonertinib for at least 8 weeks are eligible for this study. The objective was to assess confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Other efficacy assessments included baseline changes in cerebrospinal fluid (CFS) cytology and neurologic examination. Measurable lesions were assessed according to RECIST version 1.1 (RECIST 1.1). LM was assessed according to Neuro-Oncology LM (RANO-LM) criteria.

Results

The median PFS (mPFS) for the 31 patients was 11.70 months (95% CI 9.48-13.92months) and the median OS (mOS) was 18.40 months (95% CI 12.49-24.21months). The 1-year survival rate was 67%. The LM ORR and DCR were 75% and 95%, respectively, with a median DoR of 12.00 months (95% CI 7.40-16.60 months). The overall ORR and DCR were 22.6% and 93.5%, respectively, with a median DoR of 7.20 months (95% CI 3.60-10.80 months). Neurologic function improved in 18 (75.0%) of the 24 patients with abnormal baseline assessments. Logistic regression analysis showed that the therapeutic dose of furmonertinib was a positive predictor of OS in NSCLC patients harboring EGFR mutations with LM [HR: 2.679 (1.004-7.147), P=0.049]. The most common adverse events (AEs) are diarrhea, decreased appetite and rash. And are usually grade 1 to 2.

Conclusions

Our study provides real-world clinical evidence that furmonertinib shows a clinically meaningful therapeutic effect with a tolerable safety profile in patients with EGFRm NSCLC and LM. Our findings also suggest that the furmonertinib therapeutic dose may be an effective strategy for prolonging overall survival outcomes in these patients.

Legal entity responsible for the study

Henan Cancer Hospital.

Funding

Natural Science Foundation of Henan Province (No.212300410400).

Disclosure

All authors have declared no conflicts of interest.

Background

EGFR exon 20 insertions (ex20ins)-positive non-small cell lung cancer (NSCLC) is an uncommon disease with limited therapeutic options and a dismal prognosis. Furmonertinib is a novel 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor designed with a unique chemical structure to improve potency and specificity targeting various EGFR mutations and has been verified its superior efficacy and favorable safety profile in previous studies. We performed this study to investigate the efficacy and safety of furmonertinib for advanced NSCLC patients harboring EGFR ex20ins mutations.

Methods

We retrospectively collected data of metastatic NSCLC patients with EGFR ex20ins mutations treated with furmonertinib 80 mg or 160 mg once daily in our center in South China from June 2022 to May 2023. Progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs) were assessed.

Results

A total of 48 patients with EGFR ex20ins mutations were included, and the major insertion variants were H773_V774ins (12.5%) and V769_D770insASV (14.58%). Eleven patients showed partial response, 30 patients with stable disease and 3 showed progressive disease as the best response to furmonertinib (ORR 22.92%, DCR 85.42%). The median PFS (mPFS) in all patients was 7.93 months (95%CI 6.57-14.8). Median PFS was not significantly different between patients who received furmonertinib 80mg or 160mg once daily (10.4 vs 7.53 months, P=0.49), neither with significance in first-line setting or above (10.4 vs. 6.5 months, P=0.069). Patients with brain metastases at baseline responded similarly to those without brain metastases (PFS 7.93 vs. 6.93 months, ORR 23.81% vs. 22.22%, P = 0.29). Patients in the near loop region showed a better mPFS in the first-line setting than in the second-line or above (10.2 vs 6.5 months, P= 0.043). No grade≥3 TRAEs were observed.

Conclusions

Furmonertinib showed encouraging anti-tumor activity and an acceptable safety profile in NSCLC patients with EGFR ex20ins mutation.

Legal entity responsible for the study

The authors.

Funding

This work was supported by the Natural Science Foundation of Guangdong Province (grant 2022A1515012582), the Sun Yat-sen University Young Teacher Plan (grant 19ykpy179), and the Guangzhou Science and Technology Program (grant 202002020074).

Disclosure

All authors have declared no conflicts of interest.

Background

Beamion LUNG-1 is an ongoing first-in-human Ph Ia/b trial assessing zongertinib in pts with HER2 aberration-positive solid tumours (Ph Ia) and HER2 m+ NSCLC (Ph Ib; NCT04886804). Here, we present updated Ph Ia (29 Sept 2023 cut-off) and interim Ph Ib (31 July 2023 cut-off) data.

Methods

Ph Ia recruited pts with HER2 aberration-positive (gene mutations or rearrangements, amplification or overexpression) advanced solid tumours who were treated with escalating doses of zongertinib BID (≥15 mg) or QD (≥60 mg). Primary endpoint: maximum tolerated dose (MTD). Ph Ib is recruiting patients with HER2 m+ advanced/metastatic NSCLC (Cohorts: 1, pre-treated HER2 TKD m+; 2, treatment [Tx]-naïve HER2 TKD m+; 3, previously treated non-TKD HER2 m+; 4, active brain metastases; 5, prior Tx with anti-HER2 antibody–drug conjugates). The primary endpoint was overall response rate (ORR) by investigator assessment.

Results

Ph 1a: pts (n=61) received zongertinib at 15/30/60/100/150 mg BID (n=3/3/4/4/3) and 60/120/180/240/300/360 mg QD (n=5/4/9/12/10/4). Median duration (range) of Tx: 4.8 (< 1─18.7) mos; ongoing in 35 pts. There were two dose-limiting toxicities during the MTD evaluation period (grade [G] 3 decreased platelets [360 mg QD]; G3 diarrhoea [240 mg QD]); the MTD was not reached for BID or QD. TRAEs (all/G3/G4/G5): 72/10/0/0%. Serious TRAEs: 2% (n=1; G3 AST/ALT). In 53 evaluable pts, ORR/disease control rate (DCR): 49/91%. Median DoR: 12.7 mos (95% CI: 4.2─12.7). In 36 evaluable NSCLC pts, ORR/DCR: 58/97%. As of 31 July 2023, 42 patients had been treated in Cohort 1 of Ph Ib (randomised to 120/240 mg QD). TRAEs (all/G3/G4/G5): 67/5/5/0%, most commonly diarrhoea (G1/G2/G≥3; 24/5/0%) and rash (17/5/0%). Most pts with diarrhoea (64%) had only one occurrence. Serious TRAEs: 5% (n=2; G4 decreased neutrophils, G4 immune thrombocytopenia). No AEs led to Tx discontinuation. ORR/DCR (n=23): 74/91%. All responding patients remained on Tx at data cut-off.

Conclusions

Zongertinib was well tolerated and exhibited promising efficacy in pts with HER2 TKD m+ NSCLC. Prespecified futility analysis was passed. The trial is ongoing.

Clinical trial identification

NCT04886804.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Lynn Pritchard DPhil, CMPP, of Ashfield MedComms, an Inizio Company, and funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

F. Opdam: Non-Financial Interests, Personal, Principal Investigator: GSK, Int1B3, AstraZeneca, Cytovation, Relay, Taiho, Roche, Merus, Boehringer Ingelheim, Crescendo, Pierre Fabre, Lilly, RevMed, Incyte. M. Barve: Financial Interests, Personal, Full or part-time Employment: Texas Oncology; Financial Interests, Personal, Stocks/Shares: Texas Oncology; Financial Interests, Institutional, Research Grant: Mary Crowley Research Center. H. Tu: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Eli Lilly, Roche, Pfizer, Boehringer Ingelheim. Y. Wu: Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Takeda; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol Myers Squibb, Hengrui Pharmaceutical, BeiGene Beijing; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Roche, Pfizer, Bristol Myers Squibb. D. Berz: Financial Interests, Personal, Speaker’s Bureau: Jazz Pharmaceutics, Sun Pharma; Financial Interests, Personal, Full or part-time Employment: Valkyrie Clinical Trials; Financial Interests, Personal, Leadership Role: Jazz Pharmaceutics, Sun Pharma; Financial Interests, Personal, Other, Honoraria: Jazz Pharmaceutics, Sun Pharma; Financial Interests, Personal, Other, Travel/accomodation: Jazz Pharmaceutics; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim, Ascendis, BeiGene, BioNTech, BMS, Black Diamond Therapeutics, eFFECTOR, Faeth, G1 Therapeutics, Genprex, Hongyun Biotech, Incyte, Inhibrx, Mirati, Seagen, Summit Therapeutics, WhiteOak, Xencor. M. Rohrbacher: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim . B. Sadrolhefazi: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim . J. Serra: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim . K. Yoh: Financial Interests, Personal, Invited Speaker: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Janssen, Kyowa Kirin, Lilly, Merck Serono, Novartis, Ono, Otsuka, Taiho, Takeda; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Seagen; Financial Interests, Institutional, Funding: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Lilly, MSD, Pfizer, Taiho, Takeda. N. Yamamoto: Financial Interests, Personal, Other, Honoraria: Chugai Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo/UCB Japan, Eisai; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Boehringer Ingelheim, Cimic, Chugai Pharmaceutical, Healios, Merck; Financial Interests, Personal, Funding, Research Funding; An Immediate Family Member: Chiome Biosciences, Otsuka; Financial Interests, Institutional, Research Grant, Research Funding: Chugai Pharmaceutical, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, MSD, AbbVie, Bristol Myers Squibb, Merck Serono, GSK, Sumitomo Dainippon, Carna Biosciences, Genmab/Seattle Genetics, Shionogi, Toray Indutries, Kaken Pharmaceutical, AstraZeneca, CMIC, InventisBio, Rakuten Medical. J. Heymach: Financial Interests, Personal, Advisory Board: Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAlta, Sanofi, Spectrum Pharmaceuticals, GSK, EMD Serono, BluePrint Medicine, Chugai Pharmaceutical; Financial Interests, Personal, Licensing Fees: Spectrum; Financial Interests, Personal, Royalties: Spectrum; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Spectrum, Mirati, Bristol-Myer Squibb, Takeda.

Background

Selpercatinib is a highly selective and potent CNS-active RET kinase inhibitor approved for the treatment of RET fusion-positive NSCLC based on the results of the phase I/II trial LIBRETTO-001 (NCT03157128). The final LIBRETTO-001 data for NSCLC is reported.

Methods

Patients with advanced, RET fusion-positive (identified by NGS, PCR or FISH) NSCLC who were treatment naïve or who had previously received platinum-based chemotherapy were enrolled at a selpercatinib dose of 160 mg BID. The primary end point was objective response rate (ORR) by RECIST 1.1 assessed by an independent review committee. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety.

Results

In 69 treatment naïve patients, the ORR was 83% with a mDoR of 20.3 mo (median follow-up 37.1 mo) and mPFS of 22.0 mo (Table). In 247 patients who had previously received platinum-based chemotherapy, the ORR was 62% with a mDoR of 31.6 mo (median follow-up 39.5 mo) and mPFS of 26.2 mo. Across both groups, 26 patients had measurable CNS metastases at baseline, the CNS-ORR was 85% with a CNS-mDoR of 9.4 mo (median follow up 25.8 mo) and CNS-mPFS of 11.0 mo. At the 36 mo landmark estimate, 57% of previously treated patients and 66% of treatment naïve patients were alive. The overall safety profile was consistent with previous reports. The most common adverse events (AEs) ≥G3 in ≥10% patients were hypertension and increased AST/ALT. Dose reduction from any cause occurred in 53% of patients. In total 11% discontinued treatment due to AEs, including 4% due to AEs related to selpercatinib as assessed by the investigator. Table: 35P

Conclusions

In the final analysis, selpercatinib continued to show durable responses and intracranial activity with a manageable safety profile in patients with RET fusion-positive NSCLC. These data and the recent positive results from the phase III trial LIBRETTO-431, reinforce the importance of genomic testing to identify RET fusions at initial diagnosis.

Clinical trial identification

NCT03157128.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company. Dr. Drilon was supported by the National Cancer Institute/National Institutes of Health P30CA008748, 1R01CA251591001A1, and 1R01CA273224-01, and Lungevity grants.

Disclosure

O. Gautschi: Financial Interests, Institutional, Other, Consultant: Amgen, Lilly; Financial Interests, Institutional, Advisory Board: Bayer, Novartis; Financial Interests, Institutional, Invited Speaker: Lilly. A. Drilon: Financial Interests, Personal, Advisory Board: 14ner/Elevation Oncology, AbbVie, Amgen, ArcherDX, AstraZeneca, BeiGene, BerGenBio, Blueprint Medicines, EcoR1, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Liberum, Loxo/Bayer/Lilly, Melendi, Monopteros, Monte Rosa, Novartis, Pfizer, Remedica Ltd., TP Therapeutics, Takeda/Ariad/Millennium, Tyra Biosciences, Verastem Oncology; Financial Interests, Personal, Other, CME: AiCME, Clinical Care Options, MJH Life Sciences, Med Learning, Medscape, Medscape, Onclive, Paradigm Medical Communications, PeerView Institute, PeerVoice, Physicians Education Resources, Targeted Oncology, WebMD; Financial Interests, Personal, Other, Consulting: Applied Pharmaceutical Science, Inc, EPG Health, Entos, Harborside Nexus, Merus, Nuvalent, Ology, Prelude, TouchIME, Treeline Bio, mBrace; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, RV More, Remedica Ltd; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, PharmaMar, GSK, Teva, Taiho; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Personal, Member: ASCO, AACR, IASLC; Other, Personal, Other, Food/Beverage: Merck, PUMA, Merus; Other, Personal, Other, Other: Boehringer Ingelheim. B. Solomon: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Merck, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Roche/Genentech; Financial Interests, Personal, Advisory Board: Amgen, Roche-Genentech, Eli Lilly, Takeda, Janssen; Financial Interests, Personal, Full or part-time Employment, Employed as a consultant Medical Oncologist at Peter MacCallum Cancer Centre: Peter MacCallum Cancer Centre; Financial Interests, Personal, Member of Board of Directors: Cancer Council of Victoria, Thoracic Oncology Group of Australasia; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Invited Speaker, Principal Investigator and Steering committee Chair: Roche/Genentech, Pfizer; Financial Interests, Institutional, Invited Speaker: Novartis. P. Tomasini: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Lilly, Janssen, Amgen, Takeda; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Janssen, Amgen, Lilly, Takeda. H.H.F. Loong: Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Eli-Lilly, Illumina, Bayer, Guardant Health; Financial Interests, Personal, Advisory Board: Novartis, Takeda. Tomasini: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Lilly, Janssen, Amgen, Takeda; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Janssen, Amgen, Lilly, Takeda. H.H.F. Loong: Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Eli Lilly, Illumina, Bayer, Guardant Health; Financial Interests, Personal, Advisory Board: Novartis, Takeda. F.G.M. De Braud: Financial Interests, Personal, Invited Speaker: Amgen, BMS, Dephaforum, ESO, Healthcare Research & Pharmacoepidemiology, Incyte,MSD, Merck Group, Nadirex, Pfizer, Roche, Sanofi, Seagen, Servier, Ambrosetti, BMS, Basilea Pharmaceutica International AG, Daiichi Sankyo Dev. F.G.M. De Braud: Financial Interests, Personal, Invited Speaker: Amgen, BMS, Dephaforum, ESO, Healthcare Research & Pharmacoepidemiology, Incyte, MSD, Merck Group, Nadirex, Pfizer, Roche, Sanofi, Seagen, Servier, Ambrosetti, BMS, Basilea Pharmaceutica International AG, Daiichi Sankyo Dev. Limited, Exelixis Inc, F.Hoffmann-LaRoche Ltd, IQVIA, Ignyta Operating INC, Janssen-Cilag International NV, Kymab, LOXO Oncology Incorporated, MSD, MedImmune LCC, Merck KGAA, Merck Sharp & Dohme Spa, Novartis, Pfizer, Tesaro; Financial Interests, Personal, Other, Consultant: Mattioli 1885; Financial Interests, Personal, Other, Think Thank: MCCann Health; Financial Interests, Personal, Other, Consultant Advisory Board: AstraZeneca, BMS, EMD Serono, Incyte, MSD, Menarini, NMS Nerviano Medical Science, Novartis, Pierre Fabre, Roche, Sanofi; Financial Interests, Personal, Other, Consultant Adv Board: Taiho. K. Goto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Amgen K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Amoy Diagnosties Co.,Ltd., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Guardant Health Inc., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., Taiho Pharmaceutical Co., Ltd., Syneos Health Clinical K.K., Life Technologies Japan Ltd.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K., Haihe Biopharma Co., Ltd.; Financial Interests, Personal, Expert Testimony: Medpace Japan K.K.; Financial Interests, Personal and Institutional, Funding: Amgen Inc., Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta,Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., LTD., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical ＆ Biological Laboratories Co., LTD., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics,Inc., Amgen Astellas BioPharma K.K., Bayer Yakuhin, Ltd., Blueprint Medicines Corporation., Life Technologies Japan Ltd., NEC Corporation., Novartis Pharma K.K., Craif Inc., Pfizer R&D Japan G.K., Turning Point Therapeutics,Inc.; Non-Financial Interests, Personal, Member: American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. P. Peterson, S. Barker, K. Liming, B. Frimodt-Moller: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. K. Park: Financial Interests, Personal, Advisory Board: JNJ, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Other, DMC member: BeiGene, Incyte; Financial Interests, Personal, Other, Advisor/Consultant: Genius, IMBdx; Financial Interests, Personal, Other, Advisor: Abion; Financial Interests, Personal, Stocks/Shares, Stock option: IMBDx, Genius.

Background

Selpercatinib, a highly selective RET kinase inhibitor with CNS activity, is approved in multiple countries for patients (pts) with RET fusion-positive NSCLC. In other oncogene-addicted NSCLC settings, targeted treatment beyond RECIST progression (PD) in the case of oligo-progression (oligoPD) is commonly utilized and endorsed by guidelines. We hypothesized that the pattern of PD would be associated with outcomes on post-PD therapy.

Methods

NSCLC pts were treated on the phase I/II LIBRETTO-001 trial (NCT03157128) and were permitted to continue selpercatinib beyond investigator (INV) assessed PD if the pt derived ongoing benefit according to the INV and with sponsor approval. Data of pts with PD confirmed by Blinded Independent Central Review (BICR) were used for this analysis (n=80; data cut of 13JAN2023). OligoPD was defined as up to 5 progressing lesions (1-2 [limited] versus 3-5).

Results

80 pts had BICR-confirmed PD and continued selpercatinib per INV assessment; 23 had widespread progression and 57 pts had oligoPD, including 20 pts with 1-2 progressing lesions and 37 pts with 3-5 progressing lesions. At study entry 11 pts out of 80 pts had CNS metastases. Median duration of treatment (mDoT) post-PD (Table) was longest in pts with limited oligoPD and shortest in pts with widespread PD. Post progression mDoT appeared comparable between pts who progressed in CNS only (n=8) versus pts with extracranial (n=68) PD. Of 80 pts with PD, 33 pts received local radiotherapy upon BICR confirmed progression, further analysis for whom is ongoing. No new safety signals were identified in this population. Table: 36P

Conclusions

Continuing selpercatinib beyond progression may be considered based on INV assessed benefit, particularly for pts with limited oligoPD, including pts with CNS progression. Clinical judgement of ongoing benefit together with radiological imaging should be used to make the most appropriate decision for pts in the setting of PD.

Clinical trial identification

NCT03157128.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Loxo Oncology.

Disclosure

M.J. De Miguel Luken: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Personal, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, Biontech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, Beigene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi aventis, Springer Healthcare Ltd, 4D Pharma; Financial Interests, Institutional, Expert Testimony: AbbVie, Da voltera, Eli Lilly, Ellipse pharma Ltd, F-Star, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Socar research, Taiho oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD, AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi Sankyo, GSK, Janssen, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Turning Point Therapeutics, Genmab, Taiho, Nuvalent, Enliven, Prelude therapeutics; Financial Interests, Institutional, Funding: Cristal Therapeutics. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics. P. Peterson, S. Szymczak, T. Puri: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. D.S.W. Tan: Financial Interests, Personal, Advisory Board: Amgen, Novartis, Boehringer Ingelheim, C4 Therapeutics, AstraZeneca, GSK, Takeda, Eisai, Guardant, Merck, Pfizer, Roche; Financial Interests, Institutional, Research Grant: AstraZeneca, Amgen, Pfizer, ACM Biolabs; Financial Interests, Personal, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.

Background

Alectinib is a preferred first-line treatment for pts with advanced ALK+ NSCLC and the sequence of post-alectinib treatments used in the real-world is not well characterised. ReAlec (NCT04764188) is a real-world, observational, multicentre, cohort study of the clinical management and outcomes of pts treated with alectinib. We report results from the primary interim analysis of cohort 1 (pts treated with first-line alectinib).

Methods

Eligible pts were ≥18 years old with advanced ALK+ NSCLC and initiated on-label, first-line alectinib after (arm A) or before (arm B) enrolment. Pts will be followed for up to 6 years. Retrospective medical history was collected at enrolment and additional data were recorded during routine visits. Co-primary objectives were progression-free survival and next line of therapy post-alectinib. Key secondary objectives were demographics, disease characteristics and safety.

Results

In total 745 pts were enrolled; demographics and disease characteristics are reported in the table. At data cutoff (10 May 2023), median treatment duration on the study was 8.3 months (arm A) and 13.8 months (arm B). Rates of alectinib discontinuation were 21.9% (arm A) and 15.3% (arm B); 73.2% (arm A) and 86.7% (arm B) of these pts discontinued alectinib due to progressive disease. The most common next line of therapy was lorlatinib (arm A: 60.5%; arm B: 67.7%). Treatment-related adverse events (TRAE) occurred in 26.3% of pts and were mostly Grade 1–2 and non-serious. TRAEs leading to dose modification/interruptions and treatment discontinuation occurred in 6.4% and 0.9% of pts, respectively. Grade 5 events unrelated to treatment occurred in 20 (2.7%) pts.

Table: 37P

Conclusions

Real-world demographics and disease characteristics of pts with advanced ALK+ NSCLC, and the safety profile of alectinib, were in line with clinical experience. Post-alectinib treatments and their effectiveness will continue to be evaluated.

Clinical trial identification

NCT04764188.

Editorial acknowledgement

Third-party medical writing assistance, under the direction of the authors, was provided by Neave Baldwin, BSc and Claire White, PhD of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

E. Bria: Financial Interests, Personal, Invited Speaker: AstraZeneca, F. Hoffmann-La Roche Ltd, Novartis, MSD, BMS; Financial Interests, Personal, Advisory Board: AstraZeneca, F. Hoffmann-La Roche Ltd, Novartis, Eli Lilly, MSD, BMS; Other, Personal, Research Grant: AstraZeneca, F. Hoffmann-La Roche Ltd, AstraZeneca; Financial Interests, Personal, Principal Investigator: AstraZeneca, F. Hoffmann-La Roche Ltd. J. Bar: Financial Interests, Personal, Invited Speaker: BMS, Medison, Pfizer; Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, MSD, Merck Serono, F. Hoffmann-La Roche Ltd, Takeda; Financial Interests, Institutional, Research Grant: Immunai, OncoHost, MSD, F. Hoffmann-La Roche Ltd, AbbVie; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Non-Financial Interests, Institutional, Principal Investigator: F. Hoffmann-La Roche Ltd, MSD, AbbVie, AstraZeneca, Merck, Bayer; Non-Financial Interests, Institutional, Leadership Role: Lung Ambition. M.J. Hochmair: Financial Interests, Personal, Speaker’s Bureau: F. Hoffmann-La Roche Ltd, BMS, MSD, Eli Lilly and Company, Amgen, Takeda; Financial Interests, Personal, Advisory Board: F. Hoffman-La Roche Ltd, BMS, MSD, Eli Lilly and Company, Amgen, Takeda. J. Fecker: Financial Interests, Personal, Full or part-time Employment: Roche Pharma AG; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Affiliate: Roche Pharma AG. J. Ojaimi, V. Smoljanovic: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann La-Roche Ltd; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. M. Itchins: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, F. Hoffmann-La Roche Ltd, Novartis, BMS, MSD; Financial Interests, Personal, Advisory Board: Pfizer, Takeda, Bayer, MSD, Amgen, Merck, F. Hoffmann-La Roche Ltd, BeiGene, Janssen, Gilead; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Advisory Role: F. Hoffmann-La Roche Ltd, Merck, Janssen; Financial Interests, Personal, Other: F. Hoffmann-La Roche Ltd. All other authors have declared no conflicts of interest.

Background

Brigatinib, an ALK tyrosine kinase inhibitor (TKI), showed superior clinical efficacy in 1L for ALK+ NSCLC compared to crizotinib in the phase III ALTA-1L trial. There is a lack of data on real-world treatment patterns and outcomes post-1L brigatinib.

Methods

This non-interventional, multicenter, retrospective chart review study included patients with ALK+ NSCLC previously enrolled in the brigatinib arm of ALTA-1L. Patients who discontinued 1L brigatinib (index event) were followed from the last dose of brigatinib. Time to treatment discontinuation (TTD), progression-free survival (PFS) for the 2L therapy, time from randomization of ALTA-1L to the date of disease progression on 2L therapy or death (PFS2), and overall survival (OS) were estimated using Kaplan-Meier methods.

Results

As of Oct 18, 2023, 48 patients (median age=58 years; male=45.8%; White=43.8%; Asian=54.2%) were enrolled with a median follow-up of 12.4 months. 40 (83.3%) had received subsequent systemic anticancer therapies. Of these, 30 (75%) had received 2L ALK TKIs: 16 (53%) had received lorlatinib, 8 (27%) had received alectinib, 6 (20%) had received crizotinib. Overall response rate and disease control rate for 2L ALK TKIs were 33.3% and 70.8%, respectively, and for 2L lorlatinib were 30.8% and 76.9%, respectively. Median PFS (95% CI) was 16.1 (4.4, NR) months with an estimated 24-month PFS of 47% (26.2, 65.3) for 2L ALK TKIs, while median PFS was 25.6 (3.8, NR) months with an estimated 24-month PFS of 53.4% (23.9, 76.0) for 2L lorlatinib. Please see Table for TTD, PFS, PFS2, and OS in 2L. Table: 38P

TTD, PFS, PFS2, and OS in patients with 2L ALK TKIs

Conclusions

Most patients started another ALK TKI after discontinuing 1L brigatinib. ALK TKIs offered clinical benefit after 1L brigatinib, suggesting brigatinib is an effective 1L treatment choice followed by other ALK TKIs, including lorlatinib.

Drs. A. Delmonte and M-J. Ahn have equally contributed to the study.

Editorial acknowledgement

Support for medical writing by Kalyani Bharadwaj, PhD (SNELL Medical Communication, Inc.), editing by Jane Kondejewski, PhD (SNELL Medical Communication, Inc.

Legal entity responsible for the study

Takeda Development Center Americas, Inc.

Funding

Takeda Development Center Americas, Inc.

Disclosure

A. Delmonte: Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim. M. Ahn: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Merck Sharp & Dohme, Roche, Bristol Myers Squibb, Merck KGaA, Alpha Pharmaceuticals. S. Ghosh: Financial Interests, Personal, Advisory Role: AstraZeneca, Chugai, Merck Sharp & Dohme, Pfizer, Roche, Takeda. M.J. Hochmair: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Takeda, Roche; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Roche. J.C. Yang: Financial Interests, Personal, Advisory Role, Honoraria: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astellas, Merck Sharp & Dohme, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceutical, Daiichi Sankyo, Takeda, AstraZeneca, Hansoh Pharmaceuticals. J. Han: Financial Interests, Personal, Research Grant: Hoffmann-La Roche Ltd, Ono, Pfizer, Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Takeda, MedPacto, Abion, Ono; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Hoffmann-La Roche Ltd., Merck Sharp & Dohme, Takeda. Y. Wu, Y. Wan, M. Lin, J. Kretz, B. Hupf, A.M. Kurec, E. Churchill, R. Fram: Financial Interests, Personal, Full or part-time Employment: Takeda. C.J. Cabasag: Financial Interests, Personal and Institutional, Full or part-time Employment: IQVIA. M.R. García Campelo: Financial Interests, Personal, Advisory Board: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda; Financial Interests, Personal, Advisory Role: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda; Financial Interests, Personal, Other, Speaker Honoraria: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda. All other authors have declared no conflicts of interest.

Background

Over 40% and 60% of patients (pts) with ALK-mNSCLC are alive and progression-free at 3 years with second (II)- and third (III)-generation (gen) aALK-TKIs. The side effects profile of aALK-TKIs is overall safe but their long-term effects in terms of BMC modifications are poorly studied. We conducted a retrospective analysis in this setting to study changes in multiparameter BMC.

Methods

BMC analysis was performed with a semiautomatic software to segment CT scans of the axial section passing through the midpoint of the vertebral body of L3. Specific tissues of interest radiodensities enable to identify and to quantify the skeletal muscle (SM) and total adipose tissue (TAT) composed of: visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and intramuscular adipose tissue (IMAT). Imaging was obtained before the initiation of each following line of aALK-TKIs.

Results

Between September 2015 and October 2023, 49 ALK-mNSCLC pts (M 20, F 29, median age 62) were sequentially treated. At baseline, 18% and 14% of pts had known dyslipidemia and mild obesity (BMI 25-38), respectively. First-line aALK-TKIs included crizotinib (C) (43%), alectinib (A) (55%), brigatinib (B) (2%). Nineteen progressing pts received second-line treatment with A (47%), ceritinib (CE) (16%) and lorlatinib (L) (37%) and third line treatment with B (50%) and L (50%) was given to 8 pts. Median progression-free survivals (PFS) were 22, 7 and 8 months with first-, second-and third-line TKIs, respectively. After I line treatment we observed a significant increase in VAT (+35.4%, p .003) and TAT (+15%, p .014) which maintains in following lines. This effect was larger with II gen aALK-TKIs for both VAT (p .007) and TAT (p .015) than with I gen TKIs. An association between baseline obesity or steroid use and TAT increase was also found (p .002 and p .003, respectively).

Conclusions

These preliminary results indicate that aALK-TKIs are associated with BMC changes in terms of adipose tissue disposition, in particular VAT. This effect occurs early at first-line treatment, is more pronounced with II gen TKIs and deserves further research to establish competing risks of comorbidity.

Legal entity responsible for the study

The authors.

Funding

University of Brescia.

Disclosure

S. Grisanti: Financial Interests, Personal, Advisory Board: Roche, Takeda, Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol-Myers; Financial Interests, Institutional, Funding: Roche, AstraZeneca. All other authors have declared no conflicts of interest.

Background

Lorlatinib is a third generation ALK inhibitor with marked efficacy in NSCLC. CTCAE-defined weight gain and dyslipidaemia has been reported in patients receiving lorlatinib in registrational trials. Lipid-lowering agents may interact with lorlatinib metabolism.

Methods

We conducted a single centre retrospective analysis of NSCLC patients receiving lorlatinib. The primary objective was to quantify weight gain and lipid profile changes in accordance with CTCAE v5.0. Extraction from electronic medical records was undertaken by authors. Mean relative dose intensity (RDI) was defined as % of full dose lorlatinib for duration of therapy. All analyses were descriptive. Patients without baseline weight recorded were excluded. The project was approved by the hospital service evaluation committee.

Results

43 patients were evaluable. 77% (n=33/43) were ALK+ and 23% (n=10/43) ROS1+. Mean duration of lorlatinib was 14.5 months. Mean RDI was 81%. Weight gain occurred in 81% (n=35/43) of patients, 44% (n=19/43) Grade≥1 and 9% (n=4/43) Grade≥3. Mean weight gain/BMI was 6.4kg/2.4kg/m² (range 0-30.1kg/11.4kg/m²). Dietitian referral occurred in 5% (n=2/43). Increase in total cholesterol (TChol) occurred in 51% (n=22/43) and triglyceride in 58% (n=25/43) of patients. 84% (n=36/43) were prescribed statins and 2% (n=1/43) ezetimibe/statin. 35% (n=15/43) patients had normal baseline TChol (<5mmol/L), 100% (n=15/15) of whom developed elevated TChol on lorlatinib, 73% (n=11/15) within 30 days of commencement. One patient with elevated TChol (8.3mmol/l) developed acute coronary syndrome 5 weeks after stopping lorlatinib.

Table: 40P

Baseline characteristics

Conclusions

Real world prevalence of weight gain was similar to that reported in landmark trials. Dyslipidaemia is frequent and requires active treatment which may impact metabolism of lorlatinib. Larger scale evaluation on quality of life impact and medical risk of weight gain/dyslipidaemia is required.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

D.J. McMahon: Non-Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Sponsor/Funding, Educational travel: Pfizer, Takeda. D.D. Chauhan: Financial Interests, Personal, Invited Speaker: BMS, MSD. M. Davidson: Financial Interests, Personal, Invited Speaker: Takeda. A.R. Minchom: Financial Interests, Personal, Other, Expenses: Amgen pharmaceuticals, LOXO oncology; Financial Interests, Personal, Invited Speaker: Bayer Pharmaceuticals, Chugai Pharmaceuticls, GSK, Janssen Pharmaceuticals, Merck pharmaceuticals; Financial Interests, Personal, Advisory Board: Faron pharmaceuticals, Janssen Pharmaceuticals, Merck pharmaceuticals, Takeda, Genmab; Financial Interests, Personal, Expert Testimony: GSK; Financial Interests, Institutional, Other, Research funding: MSD, Merck Pharmaceuticals; Financial Interests, Personal, Other, Honoraria: Novartis Oncology. S. Popat: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novartis, Amgen, Janssen, Daiichi Sankyo, AstraZeneca, Bayer, BMS, Blueprint, Guardant Health, BeiGene, Takeda, Lilly, Turning Point Therapeutics, GSK, MSD, Pfizer, Sanofi, EQRx; Financial Interests, Personal, Expert Testimony: Merck Serono, Roche; Financial Interests, Personal, Invited Speaker: Medscape, VJ Oncology; Financial Interests, Personal, Other, Journal Deputy Editor, Lung Cancer: Elsevier; Financial Interests, Institutional, Other, Sub-investigator: Amgen; Financial Interests, Institutional, Invited Speaker: Ariad, AstraZeneca, Roche, Boehringer Ingelheim, Celgene, Daiichi Sankyo, GSK, Takeda, Trizel, Turning Point Therapeutics, Roche, Janssen, BMS, Lilly; Financial Interests, Institutional, Other, Sub-Investigator: MSD, Blueprint; Financial Interests, Institutional, Research Grant: Guardant Health; Non-Financial Interests, Personal, Leadership Role, Chair of Steering Committee, Unpaid: British Thoracic Oncology Group; Non-Financial Interests, Personal, Officer, Thoracic Faculty, Unpaid: European Society of Medical Oncology; Non-Financial Interests, Personal, Leadership Role, Foundation Council Member, Unpaid: European Thoracic Oncology Platform; Non-Financial Interests, Personal, Advisory Role, Mesothelioma Task-force Member, Unpaid: International Association for the Study of Lung Cancer; Non-Financial Interests, Personal, Member of Board of Directors, Unpaid: Mesothelioma Applied Research Foundation; Non-Financial Interests, Personal, Advisory Role, Honorary Clinical Advisor, Unpaid: ALK Positive UK; Non-Financial Interests, Personal, Advisory Role, Research Advisory Group Member, Unpaid: Ruth Strauss Foundation; Non-Financial Interests, Personal, Advisory Role, Scientific Adivsory Board Member, Unpaid: Lung Cancer Europe. All other authors have declared no conflicts of interest.

Background

ROS1+ is a distinct molecular subset of NSCLC with a therapeutically druggable target. Information regarding the potential effect of ROS1+ fusion partners and resistance mechanisms on clinical characteristics and outcomes of TKI treatment in the real-world and in vitro remain limited.

Methods

In this multicenter study, we identified 55 ROS1+ patients in the past 10 years. Fusion partners were identified for 25 patients using Archer analysis. Clinical data were retrieved retrospectively for 48 patients. In vitro experiments with Ba/F3 cells expressing SLC34A2-ROS1 fusion were performed to investigate on-target resistance mechanisms.

Results

The median age was 62 years, 54% was female, and 33% were never smokers. ROS1 fusion partners were EZR (n=7), CD74 (n=9), SDC4 (n=6), SLC34A2 (n=1), LDLR (n=1) and HLA (n=1). Nine patients were not treated with TKI due to localized disease (n=6) or ECOG PS >3 (n=3). Thirty-nine patients received TKI (crizotinib; n= 36, non-crizotinib; n=3), of which 12 received it as 2^nd line treatment after 1 - 4 lines of chemotherapy. The response rate of crizotinib was 56% with a median progression-free survival (mPFS) of 5 months (95% CI 2.8–7.3). Second line TKI treatment with lorlatinib in 15 patients resulted in an ORR of 40% and a mPFS 3.7 months [95% CI 2.2–5.2]. The median overall survival in the total cohort (n=48) was 24 months (95% CI 20.2–28.2). Univariate analysis showed no statistical correlation between fusion partners and survival on TKI treatment. 7/15 patients underwent a tumour biopsy before 2^nd line TKI lorlatinib treatment, which revealed on-target resistance mutations in 3 patients (L2026M (n=1) and G2032R (n=2)). These patients showed no response to lorlatinib. Additionally, in vitro studies showed that SLC34A2-ROS1 BaF3 cells with L2026M or G2032R are more resistant to lorlatinib compared to unmutated SLC34A2-ROS1 BaF3 cells.

Conclusions

No associations were observed in this real-world ROS1+ population of the fusion partners in relation to TKI outcome. Second line treatment with lorlatinib was ineffective in patients with on-target resistance mutations. Consistent with these findings, lorlatinib was unable to suppress downstream signaling of SLC34A2-ROS1 G2032R or L2026M in vitro.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

W. Timens: Financial Interests, Institutional, Other, Consultancy payments: Merck Sharp & Dohme, Bristol Myers Squibb. J.T.J.N. Hiltermann: Financial Interests, Institutional, Advisory Board: BMS, AZD, Roche, Boehringer, Pfizer; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Roche; Non-Financial Interests, Personal, Principal Investigator: BMS, AstraZeneca, Roche, Novartis, Merck, GSK, Amgen. A.J. van der Wekken: Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Pfizer, Roche, Takeda, Janssen Cilag, Lilly, Amgen, Merck. All other authors have declared no conflicts of interest.

Background

Repotrectinib is a novel ROS1/TRK tyrosine kinase inhibitor that was recently approved by the United States Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic ROS1-positive non-small cell lung cancer. As the incidence of venous thromboembolism is estimated to be 3- to 5-fold higher in patients harbouring ROS1-rearrangement (Chiari et al. Clin Lung Cancer 2020), we reviewed all possible drug-drug interactions (DDIs) between antithrombotic agents and repotrectinib.

Methods

Data from FDA Product Information of repotrectinib (Augtyro®) was used to assess the DDI potential with antithrombotic agents (ATC code B01A). Repotrectinib acts as a moderate CYP3A inducer (midazolam AUC and C_max decreased by 69% and 48%, resp.). Although data are currently lacking, we hypothesize that repotrectinib is also a moderate P-gp inducer, analogous to sotorasib. Recommendations for DDI management were constructed using a modified “traffic light” system developed by the University of Liverpool to classify DDIs. These were either “no or minimal interaction expected; no action” (green); “clinically relevant interaction expected; action needed” (orange); or “severe interaction expected, do not co-administer” (red).

Results

FDA’s Product Information does not contain specific recommendations for combining repotrectinib with antithrombotic agents. We, therefore, applied extrapolations based on the known DDI potential of repotrectinib. A clinically relevant interaction is expected with apixaban, betrixaban, dabigatran, edoxaban, phenprocoumon, rivaroxaban, ticagrelor and warfarin. These patients should be closely monitored for reduced efficacy of the antithrombotic agent. The remaining 18 antithrombotic agents are not expected to be involved in a DDI. All DDI pairs, as well as DDIs between repotrectinib and other co-medications, will be included in an online tool (www.DDIManager.co).

Conclusions

Repotrectinib may be involved in a DDI with a number of widely-used antithrombotic agents, including all directly-acting oral anticoagulants (DOACs). An online tool can guide clinicians to manage DDIs between repotrectinib and relevant co-medications.

Legal entity responsible for the study

The authors.

Funding

RadboudUMC.

Disclosure

D. Burger: Non-Financial Interests, Personal, Member of Board of Directors: Global DDI Solutions; Financial Interests, Institutional, Funding, GlobalDDISolutions: AstraZeneca, Pfizer. J. Leentjens: Financial Interests, Institutional, Research Grant: BMS-Pfizer, Viatris, and AstraZeneca. A.J. van der Wekken: Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Takeda; Financial Interests, Institutional, Advisory Board: AstraZeneca, Janssen, Lilly, Roche, and Takeda; Financial Interests, Institutional, Funding: from AstraZeneca, BMS, Lilly, Pfizer, and Roche. R. ter Heine: Financial Interests, Institutional, Research Grant: Amgen. All other authors have declared no conflicts of interest.

Background

NTRK gene fusions are oncogenic drivers in various cancers, including lung cancer. Laro is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for use in pts with tumours harbouring an NTRK gene fusion. We report efficacy and safety with ctDNA analysis in pts with TRK fusion lung cancer treated with laro.

Methods

Pts treated with laro in two clinical trials (NCT02122913, NCT02576431) were analysed. NTRK gene fusions were determined by local testing before enrolment. Laro was administered at 100 mg twice daily. Response was assessed by an independent review committee (IRC) per RECIST v1.1. ctDNA was analysed using Guardant360 and GuardantOMNI.

Results

As of 20 July 2022, 30 pts (12 pts with CNS metastases) were enrolled. Pts received a median of two prior lines of systemic therapy, with 20 pts (67%) receiving two or more. Among 27 IRC-eligible pts, overall response rate was 74% (95% CI 54–89; three complete response [CR], 17 partial response [PR], four stable disease [SD], two progressive disease [PD] and one not evaluable). Median duration of response was 33.9 months (95% CI 9.5–not estimable [NE]); median follow-up was 22.9 months. Median progression-free survival was 33.0 months (95% CI 11.3–NE); median follow-up was 24.7 months. Median overall survival was 39.3 months (95% CI 17.2–NE); median follow-up was 23.1 months. Treatment-related adverse events were mostly Grade 1/2. ctDNA data were available for 14 pts. ctDNA analysis detected NTRK gene fusions in six of the 14 pts at treatment start. Baseline mutations were identified in nine pts. Eleven pts had prior immunotherapy. Best response to prior immunotherapy was one CR, one SD, two PD, two not evaluable and five unknown. The best responses to laro in these 11 pts were eight PR, two SD, and one PD.

Conclusions

Laro demonstrated durable responses, extended survival benefit and a favourable safety profile in pts with advanced lung cancer harbouring NTRK gene fusions. These results support the adoption of ctDNA next-generation sequencing panels that include NTRK gene fusions in clinical practice.

Clinical trial identification

NCT02122913, NCT02576431.

Editorial acknowledgement

Editorial assistance was provided by Anastasija Pesevska, PharmD, and Mel Ward, BA, both of Scion (London UK), supported by Bayer according to Good Publication Practice guidelines.

Legal entity responsible for the study

Bayer HealthCare Pharmaceuticals, Inc. and Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly and Company.

Funding

These studies were funded by Bayer HealthCare Pharmaceuticals, Inc. and Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly and Company.

Disclosure

A. Drilon: Financial Interests, Personal, Other, Received honoraria from/participated in advisory boards: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, Turning Point Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd, ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Merus, Chugai Pharmaceutical, Nuvalent, mBrace, AXIS, EPG Health, Harborside Nexus, Liberum, RV More, Ology; Financial Interests, Institutional, Funding: Pfizer, Exelixis, GSK, Teva, Taiho, PharmaMar; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, Expenses: Merck, Puma, Merus, Boehringer Ingelheim; Financial Interests, Personal, Other, CME honoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, AXIS, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, EPG Health, JNCC/Harborside. J.J. Lin: Financial Interests, Personal, Other, Compensated consultant: Genentech; Financial Interests, Personal, Invited Speaker, Compensated consultant: C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Novartis, Mirati Therapeutics, Turning Point Therapeutics, Elevation Oncology, Regeneron; Financial Interests, Personal, Invited Speaker, Honoraria and travel support: Pfizer; Financial Interests, Institutional, Sponsor/Funding, Institutional research funding: Roche/Genentech, Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Linnaeus Therapeutics, Nuvalent, Novartis; Financial Interests, Personal, Other, CME funding: OncLive, MedStar Health, PeerView Institute, Northwell Health. D.S.W. Tan: Financial Interests, Personal, Other, Consultancy: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer; Financial Interests, Personal, Other, Travel expenses: Pfizer, Boehringer Ingelheim, Roche; Financial Interests, Personal, Other, Honorarium: BMS, Takeda, Novartis, Roche, Pfizer; Financial Interests, Personal, Funding: Novartis, GSK, AstraZeneca. S. Kummar: Financial Interests, Personal, Other, Consulting/Advisory: Boehringer Ingelheim, SpringWorks Therapeutics, Gilead, EcoR1, Seagen, Mundibiopharma Ltd, Bayer, Mirati Therapeutics, Genome Insight, Genome & Company, Harbour Biomed; Financial Interests, Personal and Institutional, Leadership Role, Co-founder and equity holder: PathomlQ; Other, Personal, Advisory Role, Their spouse is scientific advisor: Cadila Pharmaceuticals Ltd; Other, Personal, Leadership Role, Their spouse is founder: Arxeon Inc. J.D. Patel: Financial Interests, Personal, Advisory Role: AbbVie, AstraZeneca, Takeda, Lilly. U.N. Lassen: Financial Interests, Personal, Advisory Board: Bayer, Pfizer, Novartis; Financial Interests, Personal, Funding: BMS, GSK, Pfizer, Roche. S. Leyvraz: Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Other, Travel grant support: Bayer. V. Moreno Garcia: Financial Interests, Personal, Other, Consultancy: Bayer, Pieris, BMS, Janssen; Financial Interests, Personal, Other, Travel support: Regeneron/Sanofi, BMS, Bayer; Financial Interests, Personal, Speaker’s Bureau: Nanobiotix, BMS, Bayer; Financial Interests, Personal, Other, Educational grant: Bayer, Medscape. L.S. Rosen: Financial Interests, Institutional, Funding: Bayer. B. Solomon: Financial Interests, Personal, Other, honoraria from or participated in advisory boards: AstraZeneca, Bayer. N. Neu: Financial Interests, Personal, Other, External employee: Bayer. D. Burcoveanu: Financial Interests, Personal, Full or part-time Employment: Bayer. C.E. Mussi: Financial Interests, Personal, Full or part-time Employment: Bayer. L. Shen: Financial Interests, Personal, Research Grant: Beijing Xiantong Biomedical Technology Co., Ltd, Qilu Pharmaceutical Co., Ltd, Zaiding Pharmaceutical (Shanghai) Co., Ltd, Jacobio Pharmaceuticals Co., Ltd, Beihai Kangcheng (Beijing) Medical Technology Co., Ltd; Financial Interests, Personal, Other, Consultancy:MSD, Merck, Boehringer Ingelheim, Harbour; Financial Interests, Personal, Invited Speaker: Hutchison Whampoa, Hengrui Therapeutics, Zai Lab, CStone Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

Supernatant from cytological samples, including body cavity effusion, sputum, bronchoalveolar lavage fluid (BALF) and needle aspiration, which has been validated for detecting genetic alternations based on cell free DNA (cfDNA) in patients with non-small cell lung cancer (NSCLC). But the sensitivity of fusions variations test is still problematic. And crucial technique is to protect and obtain stable cell free RNA (cfRNA) for genotyping.

Methods

This study provided a solution to protect supernatant cfRNA from various cytological samples, and established a reliable protocol to detect gene changes using both cfDNA and cfRNA simultaneously. 111 cytological samples were assessed to estimate the efficiency of cfRNA protective solution by cycle threshold (CT) values of RT-qPCR. An additional set of cytological samples (eg, malignant pleural effusion, sputum, BALF, needle aspiration) diagnosed with cancerous cells and matched tumor samples, were collected from 84 NSCLC patients. The clinical performance of supernatant cfDNA and cfRNA in detecting driver gene mutations was validated using the Multi-Gene Mutations Detection Kit by Amoy Diagnostics.

Results

91.89% (102/111) cfRNA were protected effectively, by estimating their CT values. In the 84 NSCLC patient samples, seven cytological samples failed the tests. Compared with tumor samples, the overall sensitivity and specificity of supernatant cfDNA and cfRNA in detection driver genes were 93.75% (74/77) and 100% (77/77), respectively. When the analysis was limited to patients with fusion gene changes, the sensitivity and specificity were both 100% (11/11) for EML4-ALK, ROS1, RET fusions, and MET gene 14 exon skipping.

Conclusions

These results suggest that the improved method enables the detection of mutations and fusions using cfDNA and cfRNA derived from supernatant samples of cytology. This finding is particularly relevant for fusion testing in NSCLC.

Legal entity responsible for the study

The authors.

Funding

National High Level Hospital Clinical Research Funding (121).

Disclosure

All authors have declared no conflicts of interest.

Background

Sufficient tumour tissue at diagnosis and recurrence is often suboptimal for comprehensive genomic profiling (CGP) in non-small cell lung cancer (NSCLC). Furthermore, the turnaround time for tumour tissue CGP may impact timely treatment decision-making. However, liquid biopsies may compensate for this shortfall in terms of sample size and turnaround time. Given the limitations of liquid biopsies in detecting actionable alterations, due to insufficient circulating tumour DNA (ctDNA), we, therefore, investigated the accuracy and concordance of ctDNA CGP.

Methods

Patients were recruited as part of an ongoing multi-centre prospective Precision Oncology Programme in advanced NSCLC, in Hong Kong starting from July 2021. CGP was performed using FDA-approved Foundation One CDx and Foundation One Liquid CDx. The diagnostic accuracy of liquid biopsy was investigated by positive percentage agreement (PPA). The correlation of tumour mutational burden (TMB) was calculated with Pearson correlation.

Results

72 patients with matched liquid and tissue CGPs were analysed. In our cohort, the median age at biopsy was 69. 71% of the ctDNA samples had a tumour fraction score of <1%. Additionally, the average ctDNA TMB and tumour tissue TMB was 5.5 muts/Mb and 6.1 muts/Mb, respectively. 47% (n=35) of patients harboured ESCAT level I actionable mutations. The actionable mutations reported were: ALK fusions (n=1), BRAF V600E (n=2), EGFR L858R (n=17), EGFR Exon 19 deletion (n=13), KRAS G12C (n=1), and MET exon 14 splice site (n=1). The PPA of the reported actionable mutations in our paired cohort was 71%. Conversely, the correlation of TMB between liquid and tumour tissue was 0.56 with a PPA of 60%.

Conclusions

Importantly, our study highlights the potential of ctDNA in detecting clinically actionable mutations when tumour biopsies are unavailable. Conversely, ctDNA alone is not adequate in reporting TMB.

Legal entity responsible for the study

University of Hong Kong.

Funding

Roche Hong Kong Limited.

Disclosure

All authors have declared no conflicts of interest.

Background

The role of driver mutations and PDL-1 status in the treatment of NSCLC is increasing. Biomarker evaluation is performed in almost all of the patients and treatments are applied according to this evaluation. In this study, the frequency and testing rates of biomarkers in patients with NSCLC were investigated.

Methods

In the "Registurk-Lung" study (NCT05254119) conducted in our country, histopathological, molecular, and clinical data of more than 5865 patients from 42 centers were collected. Biomarkers (EGFR, ALK, ROS-1, BRAF, MET, RET, KRAS^G12C, PDL-1, Her-2, TP53, and NTRK gene fusions) were evaluated in terms of the rates of testing and detected alteration rates.

Results

The median age was 64 (26-97) years and 18,2% of the patients were female. 63,2% of the patients had non-squamous and 36,8% had squamous histology. In this study, data of 1380 non-squamous lung cancer patients were evaluated. We found the test performing rates of biomarkers in these patients as EGFR mutation in 77,1%, ALK rearrangement in 73,3%, ROS-1 in 58,2%, BRAF mutation in 24,7%, MET alteration in 7,5%, RET fusion in 8,3%, KRAS^G12C mutation in 7,6%, HER-2 mutation in 5,1%, PDL-1 expression in 59,4%, and NTRK gene fusions in 6,1% of the patients. When we examined the alteration rates, EGFR mutation was found as 10,4%, ALK rearrangement 3,2%, ROS-1 1.2%, BRAF mutation 1,7%, MET alteration 1,2%, RET fusion 0,5%, KRAS^G12C mutation 18,9%, HER-2 mutation 0,4%, TP53 mutation 23,6% and NTRK gene fusions 0,14%. The PDL-1 expression was negative (<1%) in 40,4% of the patients. The rate of patients with PDL-1 expression greater than 50% was 24,0%, while the rate of PDL-1 expression 1-49% was 35,6% of the patients. While single biomarker targeted tests (IHC, PCR, FISH.) were applied as a main method, comprehensive genomic analysis (CGA, NGS) was performed in only 7,8% of the patients. As a result of comprehensive genomic analysis, a druggable result was detected in 14% of the patients.

Conclusions

An awareness has been raised about the use of biomarkers in the treatment of lung cancer. This awareness and the identification of biomarkers and directing the treatment will benefit our patients in terms of survival and treatment adherence.

Clinical trial identification

NCT05254119.

Legal entity responsible for the study

The authors.

Funding

Oncological Clinical Research Association.

Disclosure

M. Artac: Financial Interests, Personal, Invited Speaker, satellite symposium speaker: BMS. S. Sezgin Goksu: Financial Interests, Personal, Advisory Board: Novartis, MSD; Financial Interests, Personal, Invited Speaker: Novartis, Roche, Pfizer, BMS, MSD; Financial Interests, Personal and Institutional, Invited Speaker: BMS, MSD, Lilly, Roche, Jounce Therapatics. M.A.N. Sendur: Financial Interests, Personal, Advisory Board: BMS, Pfizer, Takeda, Roche, Astellas; Financial Interests, Personal, Invited Speaker: Astellas, Pfizer, BMS, MSD, Roche. C. Arslan: Financial Interests, Institutional, Invited Speaker: BMS, Bayer, Amgen, Teva, Lilly, Johnson &Johnson, Roche, Novartis, BMS, Merck, AstraZeneca, Nektar, Johnson & Johnson, Lilly, Amgen, Bayer, Incyte; Financial Interests, Institutional, Advisory Board: Novartis, Merck, AstraZeneca, Johnson & Johnson, Lilly, Astellas, Teva, BMS. M. Gumus: Financial Interests, Institutional, Invited Speaker: Pfizer, Gen Pharmaceuticals, Novartis, Bayer, Amgen, Jounce Therapeutics; Financial Interests, Institutional, Advisory Board: Amgen, Roche, BMS, AstraZeneca. All other authors have declared no conflicts of interest.

Background

Next-generation sequencing (NGS) analysis is considered standard for lung cancer diagnosis in clinical practice. Little is known about the feasibility of NGS using tumor tissue sampled with a 1.1 mm-diameter cryoprobe. We aimed to investigate the suitability of specimens obtained by transbronchial cryobiopsy (TBC) using a 1.1 mm-diameter cryoprobe for NGS analysis.

Methods

Patients with lung cancer who underwent TBC using a 1.1 mm-diameter cryoprobe for NGS testing between October 2020 and April 2023 were enrolled. A 4.0 mm- or 3.0 mm-diameter bronchoscope with radial probe endobronchial ultrasound and virtual bronchoscopic navigation was used to detect peripheral lung lesions. All procedures were performed under fluoroscopic guidance. Data was analyzed retrospectively.

Results

A total of 56 patients underwent TBC using a 1.1-mm cryoprobe for NGS testing during the study period. Most patients (98%) were in the advanced stage of lung cancer (recurrent or inoperable disease of stages III or IV). The diagnostic yield of NGS for DNA and RNA sequencing was 95% each (53 of 56). Of the 53 patients with positive NGS results, 29 (55%) harbored actionable mutations. Details of the reported mutations are shown in the table. Moderate bleeding was found in three patients (5%), and none of the study patients developed life-threatening complications, including pneumothorax or lung infection. Table: 47P

Conclusions

TBC using a 1.1 mm-diameter cryoprobe is a useful and safe tool for NGS analysis, for both DNA and RNA sequencing.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) can identify a wide spectrum of genomic alterations (GAs), guiding treatment decisions in patients (pts) with non-small cell lung cancer (NSCLC), especially with adenocarcinoma histology. However, the clinical utility of NGS in pts with lung squamous cell carcinoma (L-SCC) remains controversial. We report the clinical utility of ctDNA-based NGS in a cohort of advanced L-SCC, according to the ESMO ESCAT scale of actionability.

Methods

This was a multicenter retrospective study including treatment-naïve pts with advanced L-SCC with plasma ctDNA NGS performed (InVisionFirst-Lung®) between Feb 2018 and Dec 2022. Clinical actionability was classified according to the ESCAT scale; Tier I (ready for clinical implementation), Tier II (alteration-drug match with antitumor activity), Tier III (supported in other tumor types/similar alterations), and Tier IV (preclinical evidence). We defined clinically informative results as ESCAT tier I/II/III.

Results

A total of 131 pts with advanced L-SCC underwent NGS-ctDNA at 13 institutions in the United States, Canada, France, and Spain. Median age was 73 (range, 45-97), and 2/3 were male. Smoking history data was not available. At diagnosis, ≥1 ctDNA GA was detected in 68% (87/128; 3 failed); TP53 mutation (mut) was the most frequent GA (48%). NGS-ctDNA provided clinically informative results for 33 pts (26%); 5 (4%) were ESCAT tier I (2 BRAFV600E mut, 1 ALK fusion, 1 EGFR exon (ex) 19 deletion, 1 MET ex14 skipping mut), 3 (2%) ESCAT tier IIB (1 KRASG12D mut, 1 KRASG12V mut, 1 KRASG12R mut) and 25 (20%) ESCAT tier III (9 PIK3CA mut, 6 FGFR1 amplifications, 5 EGFR amplifications, 2 KRASG12A mut, 1 IDH1 mut, 1 HRAS mut, 1 NRAS mut). Additionally, NGS-ctDNA detected GAs classified as ESCAT IV (7 CDKN2A mut, 4 PTEN mut, 2 KRAS G13C mut, 1 KRAS G61K mut) in 14 pts (11%).

Conclusions

NGS-ctDNA provided clinically informative results for 26% of pts with advanced lung SCC, including 6% for whom targeted therapies are available in routine practice or clinical trials (4% ESMO ESCAT tier I and 2% ESMO ESCAT tier IIB). These results suggest that molecular profiling, including plasma NGS testing, should be considered in this population.

Legal entity responsible for the study

Neogenomics.

Funding

Has not received any funding.

Disclosure

M. García Pardo de Santayana: Financial Interests, Personal and Institutional, Research Grant, SEOM "Retorno de Investigadores" Grant: SEOM; Financial Interests, Personal and Institutional, Research Grant, AECC "Ayuda Clinico Junior 2023" Grant: AECC. M. Nahorski: Financial Interests, Personal and Institutional, Full or part-time Employment: Neogenomics. K. Howarth: Financial Interests, Personal, Full or part-time Employment: SAGA diagnostics. P. Garrido Lopez: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BMS, GSK, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Daiichi Sankyo, Sanofi; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal, Advisory Board, Spouse: Boehringer Ingelheim, Gebro, Janssen, Nordic; Financial Interests, Personal, Invited Speaker, Spouse: Boehringer Ingelheim, Janssen; Financial Interests, Personal, Other, Data monitoring committee for INC280I12201 trial in 2020: Novartis; Financial Interests, Personal, Invited Speaker, CACZ885V2201C_CANOPY-N trial: Novartis; Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen; Financial Interests, Institutional, Invited Speaker: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma; Financial Interests, Personal, Invited Speaker, IO102-012/KN-764 trial: IO Biotech; Financial Interests, Personal, Invited Speaker, JNJ-61186372 (JNJ-372) Clinical Development Program: Janssen; Non-Financial Interests, Personal, Leadership Role, Council member as Women for Oncology Committee ChairPast Fellowship and Award Committee and Press CommitteeFaculty for lung and other thoracic tumours: ESMO; Non-Financial Interests, Personal, Leadership Role, President of the Spanish Federation of Medical Societies (FACME) 2020-2022Past President 2023-2024: FACME; Non-Financial Interests, Personal, Leadership Role, Former President of Spanish Medical Oncology Society: SEOM; Non-Financial Interests, Personal, Leadership Role, Member of the Scientific Committee of the Spanish Against Cancer Research Foundation (aecc) and also Board member: AECC; Non-Financial Interests, Personal, Leadership Role, IASLC Women in Thoracic Oncology Working Group Member: IASLC; Non-Financial Interests, Personal, Advisory Role, Member of the Spanish National Health Advisory Board: Spanish Minister of Health; Non-Financial Interests, Personal, Advisory Role, Assesmment for lung cancer screening evaluation: EUnetHTA; Non-Financial Interests, Personal, Advisory Role: Spanish National Evaluation network (RedETS); Non-Financial Interests, Personal, Advisory Role, scientific advisory group member for clinical immunological, oncology and lung cancer areas: EMA; Non-Financial Interests, Personal, Other, Educational Committee Member: IASLC; Other, Personal, Other, My son is working in the pharma company TEVA as an engineer. I do not have any kind of relationship with TEVA: TEVA. C. Teixido: Financial Interests, Personal, Invited Speaker: AstraZeneca, Merck Sharp & Dohme, Roche Farma, Diaceutics, Pfizer, Janssen Oncology; Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis; Financial Interests, Institutional, Research Grant: Novartis. N. Reguart Aransay: Financial Interests, Personal, Advisory Board: Roche, MSD, Takeda, Bayer, Boehringer, Pfizer, Novartis, Sanofi, Janssen, AstraZeneca, Amgen, Novartis, AbbVie; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, BMS, Amgen, Novartis, Sanofi, Merck; Financial Interests, Personal, Expert Testimony: Merck, Janssen; Non-Financial Interests, Personal, Principal Investigator, PI of Investigator Initiated Trial (PEERS) sponsored by MSD. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen, Seagen, Gilead, Pierre Fabre; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen; Non-Financial Interests, Personal, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre; Non-Financial Interests, Personal, Principal Investigator: AbbVie, Sanofi, Janssen. B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, Beigene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi Aventis, Springer Healthcare Ltd, 4D Pharma; Financial Interests, Institutional, Expert Testimony: AbbVie, Da voltera, Eli Lilly, Ellipse pharma Ltd, F-Star, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Socar research, Taiho oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD, AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi Sankyo, GSK, Janssen, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Turning Point Therapeutics, Genmab, Taiho, Nuvalent, Enliven, Prelude therapeutics; Financial Interests, Institutional, Funding: Cristal Therapeutics. N. Leighl: Financial Interests, Personal, Other, CME/independent lectures: MSD, BMS, Hoffmann LaRoche, EMD Serono; Financial Interests, Personal, Invited Speaker, independent lectures: Novartis, Takeda; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Array, Bayer, EMD Serono, Guardant Health, Lilly, MSD, Pfizer, Roche, Takeda, Janssen. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, Roche, AstraZeneca, MSD, Janssen; Financial Interests, Personal, Invited Speaker: Takeda, Roche, BMS, AstraZeneca, Janssen; Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI; Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS; Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen; Financial Interests, Institutional, Invited Speaker, Cover cost of molecular test.: INIVATA; Financial Interests, Institutional, Invited Speaker: GILEAD; Financial Interests, Institutional, Invited Speaker, Beca SEOM Grupo Emergente 2022: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Substantial heterogeneity exists in the benefits from local treatments for oligometastatic non-small cell lung cancer (NSCLC). We propose that circulating tumor DNA (ctDNA) can molecularly redefine populations with induced oligopersistence disease and those more likely to benefit from surgery in NSCLC.

Methods

In this prospective, observational study, we enrolled patients with oligometastatic NSCLC identified through ¹⁸F-FDG-PET/CT following systemic therapy. Patients underwent resection targeting residual lesions. Comprehensive ctDNA monitoring was conducted perioperatively. Tumor tissues were pathologically assessed per the IASLC multidisciplinary recommendations for neoadjuvant therapy assessment, and multi-region sampling and whole-exome sequencing (WES) were performed.

Results

A total of 68 patients with induced oligometastases were enrolled, predominantly with adenocarcinoma (n=63, 92.6%), EGFR mutations (n=44, 64.7%), and oligopersistence (n=58, 85.3%). Patients who achieved major pathological response had better prognosis compared to those who did not (HR=4.57, 95% CI 2.16-9.65, p<0.05). Patients with preoperative ctDNA negative status had significantly better outcomes than those with positive status (HR=3.42, 95% CI 1.19-9.87, p=0.001). Patients who maintained or transitioned to negative ctDNA 1 month after surgery exhibited better outcomes than those who maintained or transitioned to positive ctDNA (maintaining negative vs. transition to positive: HR=3.22, p=0.041; transition to negative vs. maintaining positive HR=4.57, p=0.03). Thus, patients who maintained or transitioned to ctDNA negative status may represent a subgroup with molecular-level oligometastases who were more likely to benefit from surgery. Moreover, WES of tumors revealed resistant clones to systemic therapy in a subset of patients, emphasizing the importance of surgery. Collectively, patients without acquired resistance mutations detected in tumor tissue had a better prognosis than those with detection (HR=3.67, 95% CI 0.92-14.7, p=0.006).

Conclusions

We redefine oligopersistence disease and identify a pre-respondent subgroup more likely to benefit from surgery in NSCLC through ctDNA at the molecular level.

Legal entity responsible for the study

W-Z. Zhong.

Funding

This research was supported by funding from the National Natural Science Foundation of China Major Joint Project on Key Scientific Issues of Lung Cancer(No.82241235), National Natural Science Foundation of China (81872510), Guangdong Provincial People's Hospital Young Talent Project (GDPPHYTP201902), Guangdong Basic and Applied Basic Research Foundation (No.2019B1515130002), High-level Hospital Construction Project (DFJH201801), and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120).

Disclosure

Y. Xiong, M. Cai, F. Li, R. Chen: Financial Interests, Personal, Full or part-time Employment: Geneplus-Beijing. Y. Wu: Financial Interests, Personal, Advisory Role: AstraZeneca, Roche Holdings AG; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, AstraZeneca, Eli Lilly, Roche Holdings AG, Pfizer, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Boehringer Ingelheim (Inst), Roche Holdings AG (Inst). W. Zhong: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Pfizer, Roche Holdings AG, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

Metastatic nodules, particularly lymph node (LN) metastases, share biological and histological characteristics with primary lung nodules. However, most radiomics studies on lung cancer have focused only on primary nodules, and little is known about the prognostic value of radiomic features from metastatic nodules. We hypothesize that LN contains independent prognostic value, and a combination of both primary lung nodules and metastatic LN nodules on chest CT can predict patient outcomes more accurately.

Methods

De-identified chest CT scans from 79 advanced NSCLC patients receiving first-line immunotherapy at Memorial Sloan Kettering Cancer Center (MSKCC) were analyzed. Radiologists annotated primary lung nodules and LN metastases, extracting textural radiomic features. The study's primary endpoint was progression-free survival (PFS). Three models, utilizing a cross-validation approach, were developed based on a) primary nodules, b) metastatic lymph nodes, and c) a combination of both. The least absolute shrinkage and selection operator (LASSO) Cox regression built the radiomic signature for PFS, yielding a radiomic risk score (RRS). High- and low-risk groups, defined by median RRS, were compared using a statistical Student t test for hazard ratios across different models.

Results

The RRS, computed from the top six selected features with corresponding coefficients, demonstrated a significant association with PFS (HR = 2.11, 95% CI: [1.54 – 3.43], P = 0.002) when derived from both primary nodules and LN metastases. In contrast, radiomic features from either primary nodules or LN metastases alone exhibited lower HRs for PFS (HR=1.95 vs HR=1.37). Notably, a statistically significant difference in HRs was observed between the LN+PN model and LN alone, while no difference was found in HRs between LN+PN and PN alone.

Conclusions

The study findings suggest that combining radiomic features from both primary lung nodules and lymph node metastases provides complementary information that improves the prediction of progression-free survival in advanced non-small cell lung cancer patients.

Legal entity responsible for the study

The authors.

Funding

NIH.

Disclosure

A. Madabhushi: Financial Interests, Personal, Advisory Board, Serve on SAB and consult: SimbioSys; Financial Interests, Personal, Advisory Board: Aiforia, Picture Health; Financial Interests, Personal, Full or part-time Employment: Picture Health; Financial Interests, Personal, Ownership Interest: Picture Health, Elucid Bioimaging, Inspirata Inc; Financial Interests, Personal, Royalties: Picture Health, Elucid Bioimaging; Financial Interests, Institutional, Funding: AstraZeneca, Bristol Myers-Squibb, Boehringer Ingelheim, Eli Lilly. All other authors have declared no conflicts of interest.

Background

TP53 is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC) and has been associated with a worse prognosis. However, in the era of precision oncology, the prognostic value of TP53 co-mutation with other oncogenic genes remains controversial. Our study aimed to investigate the prognostic value of TP53 mutations in patients with advanced NSCLC.

Methods

Patients diagnosed with advanced NSCLC after March 2021 from seven public oncology centres in Hong Kong were enrolled and underwent FoundationOne next-generation sequencing prior to treatment. Relationship between TP53 mutation status and progression-free survival (PFS) or overall survival (OS) were analysed using survival analyses. Patients were further subdivided according to the presence of “druggable” or “non-druggable” co-mutations. The impact of using precision oncology-guided first-line treatment in the druggable population on survival was also assessed.

Results

A total of 426 patients with advanced NSCLC were included in this study. 244 (57%) harboured TP53 mutations (TP53 mt+) and 182 (42%) were TP53 wild-type (TP53WT). TP53 mt+ had a statistically significant worse PFS (hazard ratio (HR) 1.36; p=0.05) and OS (HR 1.47; p=0.04) when compared with TP53WT cohort. Furthermore, TP53mut+ with non-druggable targets had the worst survival outcomes, compared to TP53mut+ with druggable targets and TP53WT groups: 2-year PFS rate (18.3%, 35.1% and 37.8% respectively; p=0.033) and 3-year OS rate (12.5%, 66.7% and 57.1% respectively; p<0.001). Nevertheless, patients with TP53mt+ and druggable targets who received precision-oncology guided treatments had significantly better PFS (HR 0.50; p=0.01) and OS (HR 0.15; p<0.001) than those who did not. Patients who had EGFR or KRAS mutations receiving targeted first-line therapy had no significant difference in PFS or OS irrespective of TP53 status.

Conclusions

TP53mt+ imposes a negative impact on survival in patients with advanced NSCLC. However, this poor prognostic factor becomes negated in patients with druggable targets who receive targeted first-line therapy. Our study further highlights the importance of using precision-directed oncology treatment from the outset.

Legal entity responsible for the study

The University of Hong Kong.

Funding

Roche Hong Kong Limited.

Disclosure

All authors have declared no conflicts of interest.

Background

Dabrafenib plus trametinib (D+T) is the standard first-line (1L) treatment of advanced BRAF V600E mutated (mut) non-small cell lung cancer (NSCLC). To date, the role of liquid biopsy (LB) as a tool for predicting outcomes of 1L D+T in advanced BRAF V600E mut NSCLC has not been assessed.

Methods

We conducted a prospective multicentric study in 25 Italian Centers aimed at exploring the role of LB in advanced BRAF V600E mut NSCLC patients treated with 1L D+T. Plasma samples were collected before treatment start (t0), after 4 weeks (t1), every 4 weeks during the first 16 weeks of treatment and every 8 weeks until progression (PD). Digital droplet PCR (ddPCR) was performed to monitor BRAF V600E in plasma samples. Next-Generation Sequencing (NGS) analysis was conducted on circulating tumor DNA positive t0 and PD plasma samples.

Results

We enrolled 41 BRAF V600E mut NSCLC patients treated with 1L D+T. Overall, 25 (61%) patients were male, median age was 71 years (range, 40–82), and 29 (71%) patients were smokers. D+T achieved an Overall Response Rate of 44% and a Disease Control Rate of 79% among 34 evaluable patients. After a median follow-up of 7.9 months (95% Confidence Interval [CI], 6.8–11.7), median progression-free survival (mPFS) was 8.2 months (95% CI, 4.3–NR) and median Overall Survival (mOS) was 18.2 months (95% CI, 16.5–Not Reached [NR]). At ddPCR, t0 plasma sample was positive for BRAF V600E in 14/38 (37%) evaluable patients (shedders), with a median variant allele frequency of 4.2%, while the presence of co-mutations was observed in NGS analysis in 12 (86%) cases. Among 13 baseline shedders, clearance of BRAF V600E at t1 was observed in 10 (77%) patients. Baseline shedders had a shorter mOS than non-shedders (mOS 6.1 months vs NR, p=0.014). TP53 co-mutation at t0 was a poor predictive factor of D+T efficacy (mPFS TP53 mut vs TP53 wild type 2.3 months vs NR, p=0.014). A trend towards a better mPFS and mOS for patients who had a clearance of BRAF V600E at t1 was observed.

Conclusions

Liquid biopsy might be a promising approach to predict the outcomes of 1L D+T in advanced BRAF-V600E mut NSCLC patients. NGS analyses on putative resistance mechanisms to 1L D+T are ongoing.

Clinical trial identification

GOIRC-03-2020.

Legal entity responsible for the study

Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).

Funding

Novartis Pharma.

Disclosure

A. Leonetti: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Takeda, Roche, Ely Lilly, Sanofi; Financial Interests, Personal, Advisory Board: Sanofi, BeiGene, Novartis; Financial Interests, Personal, Other, Travel Support: MSD, Novartis. A. Sartore Bianchi: Financial Interests, Personal, Advisory Board: Amgen, Servier, Novartis; Financial Interests, Personal, Invited Speaker: Bayer, Guardant Health, Pierre Fabre. D.L. Cortinovis: Financial Interests, Personal, Advisory Board, fee for consulting activity: MSD, BMS, Roche, Sanofi Genzyme, Amgen, AstraZeneca, Novartis. S. Pilotto: Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, AstraZeneca, MSD, Roche, Amgen, Novartis, Takeda, Sanofi; Financial Interests, Personal, Advisory Board: MSD, Amgen, AstraZeneca, Novartis, Eli Lilly, Sanofi; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb, AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, Roche, BMS. F. Mazzoni: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, MSD; Financial Interests, Personal, Invited Speaker: Takeda. E. Bria: Financial Interests, Personal, Advisory Board: AZ, Roche, BMS, MSD, Eli Lilly, Amgen, Pfizer, Novartis; Financial Interests, Personal, Invited Speaker: AZ, Roche, BMS, MSD, Eli Lilly, Pfizer, Novartis; Financial Interests, Institutional, Research Grant: AZ, Roche. M. Tiseo: Financial Interests, Personal, Other, Speakers' and Consultants' fees: AstraZeneca, Pfizer, Eli Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background

MET exon 14 skipping mutation (METex14) is a rare alteration in non-small cell lung cancer (NSCLC). Here we report disease and patients characteristics, efficacy and tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS.

Methods

Clinical, pathological and molecular data, treatment efficacy/tolerability outcomes were retrospectively collected from patients’ medical charts and electronic healthcare records from the ATLAS registry.

Results

From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years old (range 46-92). Most patients were male (52%), with ECOG- PS <2 (72%) and adenocarcinoma subtype (83%). 24% had brain metastases. Overall, 56 (38%) patients were treated with capmatinib and 34 (23%) with tepotinib. Among patients treated with MET inhibitors, 29% and 52% of them received targeted treatment in 1^st and 2^nd line, respectively. Response rate (RR) was 37% (33% in previously treated and 46% in treatment-naïve patients) with a disease control rate of 62%. With a median follow up of 10.8 months, progression free survival (PFS) was 6.6 months (95% CI: 4.3-8.3). In patients receiving MET inhibitor in 1^st, 2^nd and further lines, PFS was 7.2 (95% CI: 4.3-10.4), 6.6 months (95% CI: 5.1-11.2) and 3.9 months (95% CI: 2.7-8.7), respectively. Overall survival was 10.7 months (95% CI: 7.2-19.3). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases.

Conclusions

Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with MET exon 14 skipping mutation. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. MET inhibitor activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in the METex14 therapeutic strategy management.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Passiglia: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Novartis, Roche, MSD, Amgen, Janssen, Sanofi, BeiGene, Thermo Fisher Scientific. M. Occhipinti: Financial Interests, Personal, Other: Eli Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD. S. Pilotto: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Novartis, Amgen, Takeda, Sanofi, Bristol-Myers Squibb, MSD, Roche. E. Bria: Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Roche; Financial Interests, Personal, Invited Speaker: MSD, Pfizer, Eli Lilly, BMS, Novartis, Takeda. S. Novello: Financial Interests, Personal, Invited Speaker: Eli Lilly, MSD, Roche, BMS, Takeda, Pfizer, AstraZeneca, Boehringer Ingelheim. M. Tiseo: Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Eli Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim. G. Pasello: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Roche, Lilly, MSD, Novartis, Amgen, Janssen. All other authors have declared no conflicts of interest.

Background

METΔ14ex is the driver alteration for approximately 3% of non-small cell lung cancers (NSCLC) and associated with a higher PD-L1 expression, but unclear benefit from immunotherapy (IO).

Methods

Seventy-eight consecutive patients with metastatic NSCLC harboring METΔex14 who received first-line IO as monotherapy or chemoimmunotherapy (CHT+IO) in 10 German academic lung cancer centers were analyzed.

Results

The median age was 72 years (range 49-86), 34 patients (44%) were female, 47 (60%) were active or former smokers, and 23 (29%) presented with brain metastases. The Eastern Cooperative Group (ECOG) performance status was 0, 1, 2 and 3 in 27 (35%), 28 (36%), 18 (23%) and 4 (5%) cases, respectively. The most common histology was adenocarcinoma (n=61, 78%). IO was given to 43 (55%) patients as monotherapy, and to 35 (45%) combined with CHT. For patients with PD-L1 tumor proportion score (TPS) ≥50% (n=52, 67%), 1-49% (n=14, 18%) and <1% (n=12, 15%), disease control rates (DCR) were 56%, 57% and 100% (p=0.015), respectively. Other efficacy parameters including overall response rate (ORR), median progression-free survival (mPFS) and median overall survival (mOS) by PD-L1 tumor proportion score (TPS) and type of treatment are summarized in the table. Primary progressive disease/early death (before radiologic reassessment) under IO monotherapy, but not under CHT+IO, was significantly associated with never-smoker status (p=0.041). No significant correlations were found between smoking status and PD-L1 TPS (p=0.595).

Table: 54P

Conclusions

Our exploratory analysis suggests an association between higher PD-L1 TPS and worse clinical outcomes under IO in patients with NSCLC harboring METΔ14ex. Although these results should be interpreted with caution, they contrast the favorable effect of PD-L1 expression for IO efficacy in other NSCLC and underline the need for alternative biomarkers for IO in this patient population.

Legal entity responsible for the study

Thoraxklinik Heidelberg.

Funding

Deutsches Zentrum für Lungenforschung; Merck.

Disclosure

J.B. Kuon: Financial Interests, Personal, Invited Speaker: BMS, AstraZeneca, Pfizer. D. Misch: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi, Takeda. D. Kauffmann-Guerrero: Financial Interests, Personal, Advisory Board: BMS, Boehringer Ingelheim, MSD, Roche, Pfizer, AstraZeneca; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Other: Novartis. M. Hilbrandt: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim. B. Hackanson: Financial Interests, Personal, Invited Speaker: BMS, MSD, Boehringer Ingelheim, Pfizer, Roche, AstraZeneca. M. Faehling: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, BMS, MSD; Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, Gilead, Roche, Daiichi Sankyo, Mirati, Revolution Medicines. M. Kirchner: Financial Interests, Personal, Invited Speaker: Veracyte Inc. M. Allgäuer: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim. C. Grohe: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Takeda, MSD, Novartis, Pfizer, Roche, AbbVie, Tesaro/GSK, Blueprint Medicines. A. Tufman: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Roche, Pfizer, BMS, MSD, Sanofi, Lilly, Novartis. M. Reck: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Merck, Novartis, Regeneron, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS, Biontech, Boehringer Ingelheim, Daiichi Sankyo, Gilead, MSD, Mirati, Pfizer, Regeneron, Roche, Sanofi; Financial Interests, Personal, Other, Member of DMSB: Daiichi Sankyo. N. Frost: Financial Interests, Institutional, Funding: Roche; Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, BeiGene, Berlinchemie, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Sharp&Dohme, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda. A. Stenzinger: Financial Interests, Personal, Advisory Board: Aignostics, AstraZeneca, Janssen, Bayer, Seattle Genetics, Pfizer, MSD, Eli Lilly, Illumina, Thermo Fisher, Amgen; Financial Interests, Institutional, Advisory Board: BMS, Takeda, Novartis; Financial Interests, Personal, Invited Speaker: Roche, Incyte; Financial Interests, Institutional, Research Grant: Bayer, Chugai, BMS, Incyte. M. Thomas: Financial Interests, Personal, Advisory Board: Sanofi, Lilly, BMS, MSD, Roche, Boehringer, Janssen, AstraZeneca, Amgen, Novartis; Financial Interests, Personal, Invited Speaker: Sanofi, Lilly, MSD, Roche, GSK, Pfizer, Janssen, AstraZeneca, Amgen, Novartis; Financial Interests, Institutional, Advisory Board: Takeda; Financial Interests, Institutional, Invited Speaker: Takeda; Financial Interests, Institutional, Funding: Roche, Takeda, BMS, AstraZeneca, Amgen. P. Christopoulos: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, MSD, Takeda, Roche, Daiichi Sankyo; Financial Interests, Personal, Expert Testimony: Chugai; Financial Interests, Personal, Invited Speaker: Gilead, Thermo Fisher; Financial Interests, Institutional, Funding: AstraZeneca, Boehringer Ingelheim, Amgen, Novartis, Roche; Financial Interests, Personal, Funding: Takeda. All other authors have declared no conflicts of interest.

Background

Non-small cell lung cancer (NSCLC) can harbor different KRAS mutations. Although targeted therapy is available for KRAS G12C-mutant (mt) NSCLC, immune checkpoint inhibitors (ICIs) are still the first line treatment (tx) for these patients (pts). Here we aimed to assess the outcomes on ICIs for KRAS G12C compared to KRAS non-G12C-mt pts.

Methods

This is an updated observational, retrospective, multicenter study of pts with KRAS-mt NSCLC treated with ICIs between January 2017 and October 2023. 14 pts received anti-KRAS G12C tx. Targeted sequencing was performed in 59% cases and polymerase chain reaction in the rest. Clinicopathological and molecular data were collected. We evaluated the characteristics, tx response and survival outcomes on ICIs of pts with KRAS G12C vs non-G12C-mt tumors.

Results

189 pts were included with a median follow-up of 34.3 months (m). STK11 and TP53 were the most frequent co-mutated genes present in 4.3%/18.5% G12C/non-G12C and 21.3%/44.7% G12C/non-G12C, respectively. In all KRAS mt tumors, harboring a TP53 co-mutation was associated to a positive PD-L1 and a better ECOG (p < 0.001 and p=0.006, respectively). In addition, a trend to a better overall survival (OS) was seen in TP53 vs STK11 tumors (14.7 vs 6.1m, respectively, p = 0.195). No differences were seen in the median duration of response or progression free survival between G12C/non-G12C (10.7 vs 9.5m p=0.202 and 8 vs 5m p= 0.554, respectively). KRAS G12C tumors were associated with a better median OS compared with non-G12C tumors (16.2 vs 9.2m p=0.024). In the multivariate analysis for OS, PD-L1 negative tumors and ECOG ≥1 were independently associated with worse OS (p=0.004 and p<0.001, respectively). Table: 55P

Conclusions

Our work shows that pts with KRAS G12C tumors are associated with better OS on ICIs tx when compared with pts with KRAS non-G12C tumors. Harboring a TP53 co-mutation associated to a KRAS mutation might determine a different tumor microenvironment and therefore a better response to ICI tx.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

N. Castro Unanua: Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Travel: Roche; Financial Interests, Personal, Other, Travel:MSD, Lilly. P.F. Simoes Da Rocha: Financial Interests, Personal, Other, Travel Support: AstraZeneca; Financial Interests, Personal, Other, Travel Suport: MSD, BMS, Kiowa Kirin. A. Taus Garcia: Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, MSD, Pfizer, GSK, Takeda; Financial Interests, Personal, Advisory Board: Sanofi, GSK; Financial Interests, Personal, Other, Travel Suport: GSK, MSD, AstraZeneca. B. Bellosillo Paricio: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Merck-Serono, Novartis, Roche, Thermo Fisher, Pfizer, BMS; Financial Interests, Personal, Other, Research Grants: Thermo Fisher, Roche Diagnostics, Roche Farma. H. Arasanz: Financial Interests, Personal, Other, Clinical Trial Coordinator: Ferrer; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Takeda, MSD; Financial Interests, Personal, Other, Travel Support: BMS, Angelini Pharma, Roche. E. Arriola: Financial Interests, Personal, Advisory Board: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda; Financial Interests, Personal, Speaker’s Bureau: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda; Financial Interests, Personal, Other, Cofounder: Trialing Health S.L. All other authors have declared no conflicts of interest.

Background

Lung adenocarcinoma is a complex and heterogeneous disease characterized by diverse molecular alterations. Programmed death-ligand 1 (PD-L1) expression is a crucial biomarker in treatment algorithms, yet its clinico-pathological correlations with other mutations remain unclear. This study aims to investigate the impact of PD-L1 expression on outcomes in patients with KRAS mutations.

Methods

A single-center retrospective cohort study included patients diagnosed with non-squamous NSCLC between January 2018 and July 2022. A targeted next-generation sequencing (NGS) analysis by Ion Torrent® (ThermoFisher Scientific) (Ion AmpliSeq CLv2 panel) was performed. PD-L1 expression was assessed by Immunohistochemistry (ab SP263), and patients were categorized into PD-L1 <1% (negative), 1-49% (intermediate), and ≥ 50% (high).

Results

Clinical data from 464 patients were collected, revealing KRAS mutations in 179 patients (38.6%). 77 (43%) had a co-mutation, most frequently TP53 (74%) and STK11 (14.3%). Others co-mutations (24.7%) include MET, BRAF, FGFR2, SMAD4, ERBB4, PTEN, CTNNB1, PIK3CA, FBXW7. PD-L1 expression in KRAS mut cohort was negative in 59 (33,7%), intermediate in 61 (34.8%) and high in 55 pts (31,4%); in KRAS WildType: negative in 109 (39.9%), intermediate in 105 (38.4%) and high in 59 pts (21,6%); in patients with KRAS and a co-mutation was: negative in 22 (29%), intermediate in 22 (29%) and high in 33 pts (43,4%). Our data shows a higher incidence of PD-L1 expression in KRAS-mutated patients compared to KRAS wild-type (p=0.02), especially when presenting a co-mutation (p=0.003). Analysis of progression-free survival (PFS) after the first line of treatment with immune checkpoint inhibitors (ICIs) in 30 pts with stage IV KRAS-mutated NSCLC and high PD-L1 showed a trend favoring patients presenting a co-mutation (mPFS 13.7mo KRAS co-mutated vs. 3.6mo in KRAS only; HR 0.26; CI 95% 0.09-0.070; p=0.19).

Conclusions

These findings emphasize the importance of further exploring PD-L1 role in KRAS mutated patients, especially by taking into account accompanying mutations in other genes evaluated by NGS.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Activating mutations of KRAS are described in 25% of patients affected by metastatic non-small cell lung cancer (mNSCLC) and represent a biochemically heterogeneous group. The predictive role of KRAS subtypes is still unclear, since different amino acids substitutions lead to the activation of different downstream pathways that could influence response to immunotherapy (IO).

Methods

We retrospectively evaluated 323 mNSCLC patients harbouring a missense mutation in 1 out of 3 hotspots in the guanosine triphosphatase domain of RAS (279 in codon G12, 26 in G13 and 18 in Q61); among G12 variants, the most frequent were: G12C (39.3%), G12V (21.4%) and G12D (13.3%). We analyzed overall survival (OS) in whole population, comparing different codons, different G12 variants or KRAS G12C mutation versus all the others. Then we analyzed progression-free survival (PFS) and OS in patients with a PD-L1≥50% treated with first-line (1L) IO and in PD-L1<50% cases receiving 1L chemoimmunotherapy (CT-IO), comparing the same populations above mentioned. Median follow up was 30 months.

Results

No differences in OS were evidenced in different codons (p = 0,37) or in different G12 variants (p = 0,26); only KRAS G12C mutations showed a slightly longer median OS when compared to all other mutations even if not statistically significant (17,99 vs 11,0 months; p=0,09). In patients with a PD-L1≥50% treated with 1L IO, no differences in PFS and OS were evidenced among different codons (p=0,95 and p=0,77, respectively), or G12 variants (p= 0,76 and p=0,70, respectively), or in KRAS G12C versus all other mutations (p=0,78 and p=0,89, respectively). By the contrary, in patients treated with CT-IO due to a PD-L1<50%, PFS was significantly longer in KRAS G12C mutated cases (14,6 vs 5,6 months; HR 0,53 95%CI: 0,31-0,89; p=0,02) as well as OS (not reached vs 15,8 months; HR 0,39; 95%CI: 0,21-0,74; p=0,01). No differences in PFS and OS among different codons (p=0,19 and p=0,13, respectively) or G12C variants (p=0,27 and p=0,11, respectively) were revealed.

Conclusions

The KRAS G12C mutation seems a positive predictive indicator of response to 1L CT-IO in patients with a PD-L1<50%. Different KRAS mutations did not show a prognostic role in mNSCLC patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The clinical significance of HRD in breast cancer, ovarian cancer and prostate cancer has been established, but the value of HRD in NSCLC has not been fully and thoroughly investigated.

Methods

FFPE samples from 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assesses through AmoyDx Genomic Scar Score (GSS), cases with a GSS score > 50 were considered as HRD-positive. Differences in genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed.

Results

Of the 355 patients, 89 (25.1%) were HRD-positive. Compared with HRD-negative patients, HRD-positive patients were likely to have more somatic pathogenic HRR mutations, higher TMB (p < 0.001) and less driver gene mutations (p < 0.001). Further, in EGFR/ALK mutant patients, HRD positive NSCLC harbored more amplification in oncogenic genes, like MYC, MET, RICTOR, and CDK6. In EGFR/ALK wild type patients, more amplifications in PI3K pathway genes, like PIK3CA, AKT3 and cell cycle genes, AURAK, CCND1 were occurred in HRD positive NSCLC. Regardless of EGFR/ALK mutation status, HRD-positive NSCLC displayed higher activity of tumor proliferation and enrichment of “Type 2 T helper cell”. HRD-negative NSCLC showed pro-inflammatory and anti-tumor immunity characteristics, “MHC Ⅱ”, and “Effector memory CD8 T cell”. The PFS of HRD-positive patients who received target therapy were significantly shorter than HRD-negative patients (mPFS: 12 vs 16 months, p = 0.042), and 3rd-generation TKI showed limited improvement of efficacy in HRD-positive patients. HRD-positive, EGFR/ALK wild-type patients responded poorly to platinum-free immune combination regimens (mPFS, HRD-positive, Plt+ vs HRD-positive, Plt-, 18.0 vs 5.0 months, p = 0.09).

Conclusions

Unique genomic and transcriptional characteristics were disclosed in HRD positive NSCLC. Unfavored prognosis and poor response to EGFR-TKIs, immunotherapy was revealed in HRD-positive NSCLC. This study suggested a potential strategy combining PARP inhibitors with targeted or immuno-therapy.

Legal entity responsible for the study

The authors.

Funding

National High Level Hospital Clinical Research Funding, Grant/ Award Number: BJ-2019-195.

Disclosure

All authors have declared no conflicts of interest.

Background

The phase III TROPION-Lung01 trial (NCT04656652) evaluated Dato-DXd, a TROP2-directed antibody-drug conjugate, in patients with previously treated advanced NSCLC. The study met its dual primary endpoint of progression-free survival (PFS) in the intent-to-treat population with a significant improvement vs docetaxel (hazard ratio [HR] 0.75; 95% CI, 0.62-0.91; p = 0.004). Interim overall survival (OS) was not mature nor statistically significant, however favored Dato-DXd. Efficacy was primarily attributed to patients with NSQ histology. We report efficacy and safety in the NSQ subgroup from TROPION-Lung01.

Methods

Patients were randomized 1:1 to Dato-DXd 6 mg/kg or docetaxel 75 mg/m² every 3 weeks, and histology was a stratification factor. PFS and OS by histology were prespecified subgroup analyses; NSQ safety analysis was post hoc. PFS and tumor response were assessed per RECIST 1.1 by blinded independent central review (BICR).

Results

Among 299 patients randomized to Dato-DXd and 305 randomized to docetaxel, 234 in each arm had NSQ histology. At data cutoff (March 29, 2023) median study follow-up was 12.9 months (Dato-DXd) and 12.7 months (docetaxel). In the NSQ subgroup, improved PFS was seen with Dato-DXd vs docetaxel (HR [95% CI], 0.63 [0.51-0.79]); median 5.5 vs 3.6 months. Additional efficacy is shown in the table. In the NSQ subgroup, any grade treatment-related adverse events (TRAEs) occurred in 88% of patients in each treatment arm, with Grade ≥3 events in 22% treated with Dato-DXd and 41% treated with docetaxel. TRAEs associated with dose reduction occurred in 21% and 30% of patients, respectively; TRAEs led to discontinuation in 9% and 12% of patients, respectively. Table: 59P

Efficacy of Dato-DXd in NSQ NSCLC

Conclusions

In TROPION-Lung01, Dato-DXd demonstrated clinically meaningful PFS benefit vs docetaxel in the subgroup of patients with NSQ NSCLC. Safety profile was manageable. OS assessment continues to final analysis.

Editorial acknowledgement

Editorial support was provided by Isobel Markham of Core Medica, London.

Legal entity responsible for the study

Daiichi Sankyo.

Funding

Daiichi Sankyo and AstraZeneca.

Disclosure

N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati, Amgen, Novartis, Sanofi, gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Pfizer, Janssen, Boehringer, Novartis, Sanofi, AbbVie, Amgen, Lilly, Grunenthal, Takeda, Owkin, Leo Pharma, Daiichi Sankyo, Ipsen; Financial Interests, Institutional, Research Grant, Local: Roche, Sivan, Janssen; Financial Interests, Institutional, Funding: BMS, Leo Pharma; Financial Interests, Institutional, Research Grant:MSD; Other, Personal, Other, Family member is an employee: AstraZeneca. I. Okamoto: Financial Interests, Personal, Advisory Role: Daiichi Sankyo, AstraZeneca; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Chugai Pharma, Lilly, Bristol Myers Squibb, MSD Oncology, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical; Financial Interests, Personal, Other, Honoraria: Chugai Pharma, Lilly, Bristol Myers Squibb, MSD Oncology, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical. A.E. Lisberg: Financial Interests, Personal, Full or part-time Employment: Boston Scientific; Financial Interests, Personal, Stocks/Shares: Boston Scientific; Financial Interests, Personal, Research Grant: Daiichi Sankyo, Calithera Biosciences, AstraZeneca, Dracen Pharmaceuticals, WindMIL, eFFECTOR Therapeutics, Duality Biologics; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Leica Biosystems, Jazz Pharmaceuticals, Novocure, Pfizer, MorphoSys, Eli Lilly, Oncocyte, Novartis, Regeneron, Janssen oncology, Sanofi group of companies, G1 Therapeutics, Molecular Axiom, Amgen, IQVIA, Bayer, Daiichi Sankyo. E. Pons-Tostivint: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Sanofi, Takeda; Non-Financial Interests, Institutional, Principal Investigator, Local: Amgen, Bristol Myers Squibb, Daiichi Sankyo, PDC line, Sanofi, Takeda. R. Cornelissen: Financial Interests, Personal, Advisory Board: Spectrum, Janssen; Financial Interests, Personal, Invited Speaker: Ad Liberum, MSD; Financial Interests, Personal, Advisory Role: MSD. L. Paz-Ares: Financial Interests, Personal, Other, Consultory fees: Lilly, MSD, Roche, PharmaMar, Merck KGaA (Darmstadt, Germany), AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, Daiichi Sankyo; Financial Interests, Personal, Other, Payment for honoraria for lectures, presentations, speakers bureaus, educational events: AstraZeneca, Janssen, Merck; Financial Interests, Personal, Other, Payment for honoraria for lectures, presentations, speakers bureaus, educational events: Mirati; Financial Interests, Personal, Member of Board of Directors: Altum sequencing, Stab Therapeutics. D. Vicente Baz: Financial Interests, Personal, Advisory Role: Merck KGaA, Darmstadt, Germany, AstraZeneca, Roche, Pfizer, MSD, Bristol Myers Squibb, Novartis, Takeda; Financial Interests, Personal, Other, payment or honoraria: AstraZeneca, Pfizer, MSD, BMS, Gilead; Financial Interests, Personal, Other, Travel support for attending meetings: AstraZeneca, Pfizer, BMS; Financial Interests, Personal, Advisory Board: Gilead, MSD. S. Sugawara: Financial Interests, Personal, Speaker’s Bureau: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Kyowa Kirin, Lilly, Merck, MSD K.K, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono Pharmaceutical, Otsuka, Pfizer, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific, TOWA PHARMACEUTICAL; Financial Interests, Personal, Principal Investigator, Local: AnHeart, AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, MSD K.K, Nippon Boehringer Ingelheim, Ono Pharmaceutical. M. Pérol: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, MSD, Boehringer Ingelheim, Takeda, Illumina, Pfizer, MEDSCAPE; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, ESAI, IPSEN; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, AstraZeneca, Roche, Takeda; Financial Interests, Personal, Other, Steering Committee Member: Roche; Financial Interests, Personal, Other, Data Monitoring Safety Board: Roche. C. Mascaux: Financial Interests, Institutional, Principal Investigator, Coordinating: GSK; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, MSD, Sanofi, Takeda, Amgen, Janssens; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Kephren, Bristol Myers Squibb, Pfizer, MSD, Sanofi, Takeda, Amgen, Janssens; Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, Kephren, Bristol Myers Squibb, Pfizer, MSD, Sanofi, Takeda, Amgen, Janssens. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Personal, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Personal, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Personal, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. Y. Le Guen: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca. J. Sands: Financial Interests, Personal, Invited Speaker: Arcus, AstraZeneca, Daiichi Sankyo, PharmaMar, Amgen, Boehringer Ingelheim, Curadev; Financial Interests, Personal, Advisory Role: Arcus, AstraZeneca, Daiichi Sankyo, PharmaMar, Amgen, Boehringer Ingelheim, Curadev; Non-Financial Interests, Institutional, Principal Investigator, Local: AstraZeneca, Daiichi Sankyo, PharmaMar, Amgen, Boehringer Ingelheim, Phanes, Legend, Genentech. M. Chargualaf: Other, Personal, Full or part-time Employment: Daiichi Sankyo. Y. Zhang: Financial Interests, Personal, Stocks/Shares, I’m an employee of DSI and have stocks of DS.: Daiichi Sankyo, Inc. P. Howarth: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. D. Uema: Other, Personal, Sponsor/Funding: Daiichi Sankyo. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Yuhan, MSD, Merck, Amgen, Daiichi Sankyo, Alpha pharmaceuticals, Pfizer, Roche, BMS. All other authors have declared no conflicts of interest.

Background

SG, a Trop-2–directed antibody-drug conjugate, has demonstrated activity and manageable safety in heavily pretreated patients with mNSCLC. EVOKE-02 (NCT05186974) is an open-label, multicohort phase II study evaluating SG + pembro ± a platinum agent in 1L mNSCLC. Here we report results by histology (squamous vs nonsquamous) in patients treated with SG + pembro in Cohorts A and B of EVOKE-02.

Methods

Patients aged ≥ 18 years, with no prior systemic treatment for mNSCLC, no actionable genomic alterations, and an ECOG PS of ≤ 1 were enrolled into Cohort A (programmed death [ligand] 1 [PD-L1] tumor proportion score [TPS] ≥ 50%) or B (PD-L1 TPS < 50%). PD-L1 status, if not already known, was determined locally or at the central laboratory using the 22C3 assay prior to enrollment. Patients received SG 10 mg/kg on Days 1 and 8 + pembro 200 mg on Day 1 of a 21-day cycle. The primary end point is objective response rate (ORR; per RECIST v1.1); secondary end points include progression-free survival, overall survival, duration of response (DOR), disease control rate (DCR), and safety.

Results

As of June 16, 2023, 30 patients in Cohort A and 33 in Cohort B were enrolled. In Cohort A (PD-L1 TPS ≥ 50%), the ORR by investigator assessment was 73% (8/11) in efficacy-evaluable patients (those with ≥ 13 weeks of follow-up) with squamous mNSCLC and 67% (12/18) in patients with nonsquamous mNSCLC; in Cohort B (PD-L1 TPS < 50%), it was 54% (7/13) and 37% (7/19), respectively (Table). Median DOR was not reached in either cohort. In the safety population (N = 63), any-grade treatment-emergent adverse events (TEAEs) were reported in 63 patients (100%; grade ≥ 3, 70%). Table: 60P

Conclusions

In EVOKE-02, SG + pembro showed promising activity regardless of histology (squamous and nonsquamous) in previously untreated mNSCLC. The safety profile was manageable and consistent with the known safety profile of each agent.

Clinical trial identification

NCT05186974.

Editorial acknowledgement

Medical writing and editorial support was provided by Sonal Joshi, PhD, of Parexel, and funded by Gilead Sciences, Inc. This study is in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Gilead Sciences, Inc.

Funding

Gilead Sciences, Inc.

Disclosure

F. Cappuzzo: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Mirati, PharmaMar, Novocure, OSE, GALECTO and MSD; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Mirati, Novocure, OSE, andMSD. J. Patel: Financial Interests, Personal, Advisory Board: AbbVie, AnHeart, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Guardant, Sanofi, Takeda; Financial Interests, Personal, Other, travel: Tempus; Financial Interests, Personal, Invited Speaker, travel: Daiichi Sankyo. B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Medpacto, Blueprint medicines, RandBio, Hanmi, GC Cell, Gilead, Ridgeline Discovery GmbH; Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc, Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, Amgen, AstraZeneca, Regeneron, Seagen, Samsung Bioepis; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: CHA Bundang Medical Center, MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, Gradiant Bioconvergence, Therapex, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, JINTSbio, Hanmi, Daewoong Pharmaceutical Co., Ltd., Vertical Bio AG, Korea Institute of Oriental Medicine, National Research Foundation of Korea, KHIDI; Other, Personal, Other, Founder: DAAN Biotherapeutics; Other, Personal, : ASCO. D. Vicente Baz: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD Oncology, Pfizer, Roche/Genentech. J. Fuentes Pradera: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, Takeda, Sanofi; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Gilead, Roche, Daiichi, Bioatla. J. Neal: Financial Interests, Personal, Other, Honoraria: CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, HMP Education; Financial Interests, Personal, Advisory Role: AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, Anheart Therapeutics; Financial Interests, Institutional, Research Grant: Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GSK, Janssen, AbbVie, Novocure; Financial Interests, Personal, Other, Royalties: Up to date - Royalties . E.B. Garon: Financial Interests, Personal, Advisory Board: Novartis, BMS, EMD Serono, Regeneron, Sanofi, Gilead, Eli Lilly, Zymeworks, AstraZeneca, AbbVie, Sensei, Seagan, Arcus, Summit, Synthekine, BridgeBio, Atreca, Sumitomo, Merus, Hookipa, LianBio; Financial Interests, Personal, Other, DSMB: Nuvalent; Financial Interests, Personal, Other, Independent Medical Education: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Novartis, Merck, EMD Serono, Eli Lilly, Genentech, Iovance, Mirati, AstraZeneca, BMS, ABL Bio, Daiichi Sankyo Sanko, Prelude, Arrivent, Regeneron, Synthekine, Gilead; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board: Lungevity. S. Mekan: Financial Interests, Institutional, Full or part-time Employment: Gilead Sciences. F. Safavi: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc. N. Fernando: Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Inc.; Non-Financial Interests, Personal, Advisory Board, Safety Review Meetings: Gilead Sciences, Inc. M. Chisamore: Financial Interests, Institutional, Stocks/Shares: Merck & Co. Inc; Financial Interests, Institutional, Full or part-time Employment: Merck & Co. Inc. M. Reck: Financial Interests, Personal, Other, Consulting: Amgen, AstraZeneca, Boehringer Ingelheim, BeiGene, Daiichi Sankyo, Lilly, Merck, Mirati Therapeutics, MSD Oncology, Novartis, Pfizer, Roche, Regeneron, Sanofi, Janssen, Bristol Myers Squibb, Regeneron; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Amgen, Celgene, Lilly, Merck Serono, Mirati Therapeutics, MSD Oncology, Novartis, Pfizer, Roche, Sanofi, Janssen; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Jannsen, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Lilly, Merck, MSD, Mirati, Novartis, GSK, Pfizer, Roche, Regeneron, Sanofi, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Sanofi. All other authors have declared no conflicts of interest.

Background

In the CameL phase III study (NCT03134872), Camre + Carbo-Pem was superior to Carbo-Pem for PFS in patients (pts) with previously untreated, advanced non-squamous NSCLC without EGFR/ALK alterations. Here, we present the updated outcomes after a follow-up of approximately 5 yrs.

Methods

Pts were randomized (1:1) and received 4–6 cycles of Camre (200 mg) plus Carbo-Pem (n=205) or Carbo-Pem (n=207) Q3W, followed by maintenance Camre + Pem or Pem only. Crossover from Carbo-Pem group to Camre monotherapy was permitted after disease progression. Total Camre exposure was up to 2 yrs.

Results

As of May 28, 2023, with a median follow-up duration (i.e., time from randomization to data cutoff) of 65.2 mo (range, 59.7‒72.2), there were 139 (67.8%) deaths in the Camre + Carbo-Pem group and 157 (75.8%) in the Carbo-Pem group. Median OS was 27.1 mo (95% CI, 21.9‒31.5) with Camre + Carbo-Pem vs. 19.8 mo (95% CI, 15.9‒23.7) with Carbo-Pem (HR, 0.74 [95% CI, 0.58–0.93]; 1-sided p=0.0043). The 5-yr OS rate was also higher with Camre + Carbo-Pem compared with Carbo-Pem (31.2% [95% CI, 24.7%‒37.9%] vs. 19.3% [95% CI, 13.9%‒25.3%]). Totally, 95 (45.9%) pts crossed over from the Carbo-Pem group to receive Camre monotherapy. After adjustment for crossover, the OS benefit with Camre + Carbo-Pem was more pronounced (adjusted HR, 0.62 [95% CI, 0.49–0.79]; 1-sided p<0.0001). Among the 33 pts in the Camre + Carbo-Pem group who completed 2 yrs of Camre, ORR was 97.0%; median DoR was 59.6 mo (95% CI, 31.3–not reached); and 5-yr OS rate was 84.3% (95% CI, 66.4%–93.2%). No new safety signals were noted, and no obvious evidence of cumulative toxicity was found with long exposure to Camre.

Conclusions

Camre + Carbo-Pem as first-line therapy continued to exhibit a clinically meaningful improvement in OS over Carbo-Pem, with manageable toxicity. Pts who completed 2 yrs of Camre had durable response and remarkable OS benefit. The 5-yr updated analysis further supports Camre + Carbo-Pem as a standard-of-care for previously untreated, advanced non-squamous NSCLC without EGFR/ALK alterations.

Clinical trial identification

NCT03134872.

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals.

Funding

Jiangsu Hengrui Pharmaceuticals.

Disclosure

C. Zhou: Financial Interests, Personal, Other, lectures, presentations, speakers’ bureaus, manuscript writing, or educational events: Amoy Diagnostics, Boehringer Ingelheim, C-Stone, Hengrui, Innovent Biologics, Lilly China, LUYE Pharma, Merck Sharp & Dohme, Qilu, Roche, Sanofi, and TopAlliance Biosciences Inc; Financial Interests, Personal, Other, on data safety monitoring boards or advisory boards: Hengrui, Innovent Biologics, Qilu, and TopAlliance Biosciences Inc. Z. Wang, X. Ma: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

In the phase III CameL-sq trial, camrelizumab + chemo as 1L treatment significantly extended PFS vs placebo + chemo in patients (pts) with advanced sqNSCLC. Here we report the outcomes 4 yrs after enrollment of the last pt.

Methods

Eligible pts with previously untreated advanced sqNSCLC were randomized 1:1 to receive camrelizumab (200 mg) or placebo plus carboplatin (AUC 5) and paclitaxel (175 mg/m²) Q3W for 4-6 cycles, followed by maintenance therapy with camrelizumab or placebo. Pts allocated to the placebo arm were allowed to cross over to camrelizumab upon disease progression.

Results

389 pts were randomized and treated (camrelizumab + chemo, n=193; placebo + chemo, n=196). As of Dec. 15, 2023, median time from randomization to data cutoff was 53.5 mo (range 47.5-61.0). Median OS was substantially prolonged with camrelizumab + chemo vs placebo + chemo (27.4 mo vs 15.5 mo; HR 0.56 [95% CI 0.45-0.72]); the OS benefit with camrelizumab + chemo was sustained, with a consistent improvement in OS rate of ∼20% at 2, 3, and 4 yrs (Table). 97 (49.5%) pts in the placebo + chemo arm crossed over to camrelizumab; analyses adjusted for cross-over effect with the Rank Preserving Structural Failure Time model further confirmed the OS benefits with camrelizumab + chemo (HR 0.35, 95% CI 0.27-0.47). Improvement in OS with camrelizumab + chemo vs placebo + chemo was seen regardless of baseline demographic and clinical characteristics; median OS was 19.8 mo vs 14.4 mo (HR 0.62, 95% CI 0.45-0.86) in the PD-L1 TPS <1% subgroup and 38.4 mo vs 20.1 mo (HR 0.56, 95% CI 0.40-0.81) in the PD-L1 TPS ≥1% subgroup. No new safety signals were identified. Table: 62P

OS outcomes

Conclusions

The addition of camrelizumab to chemo continued to demonstrate clinically meaningful survival benefits with manageable toxicities after long-term follow-up; 4-yr OS rate was ∼20% higher in pts receiving camrelizumab + chemo, further supporting this regimen as a standard of care 1L treatment for advanced sqNSCLC.

Clinical trial identification

NCT03668496.

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Disclosure

C. Zhou: Financial Interests, Personal, Speaker’s Bureau: Amoy Diagnostics, Boehringer Ingelheim, C-stone, Eli Lilly China, Hengrui, Innovent Biologics, LUYE Pharma, Merck Sharp & Dohme, Qilu, Roche, Sanofi, TopAlliance Biosciences Inc; Financial Interests, Personal, Advisory Role: Hengrui; Financial Interests, Personal, Invited Speaker: Innovent Biologics, Qilu, TopAlliance Biosciences Inc. Z. Wang, X. Lu: Financial Interests, Personal, Full or part-time Employment: Hengrui. All other authors have declared no conflicts of interest.

Background

TFS, a novel endpoint that can capture time periods of disease control and durability of clinical benefit following treatment (tx) discontinuation. TFS may be particularly appropriate in immunotherapy where some pts have shown continued benefit following a defined course of tx. Here we present TFS analysis with 4 y of follow-up in pts with mNSCLC treated with 1L NIVO + IPI + chemo or chemo alone in CM 9LA. As previously reported, CM 9LA significantly improved OS with NIVO + IPI + chemo vs chemo (HR 0.69 [96.71% CI 0.55-0.87]).

Methods

Analysis included all randomized pts who received NIVO + IPI (up to 2 y) + chemo (2 cycles; n = 361) or chemo (4 cycles; n = 358) up to 48 mo. TFS was defined as the restricted mean (r-mean) between Kaplan-Meier (KM) curves for time to tx cessation and time to subsequent tx/death. TFS was also divided into periods with/without ongoing grade ≥ 3 tx-related adverse events and estimated over 24-, and 48-mo periods from randomization.

Results

At 4 y, an estimated 21% of pts treated with NIVO + IPI + chemo were alive, and an estimated 17% were alive without any subsequent systemic tx. Of pts treated with chemo, OS rate of 16% was observed at 4 y, and 8% for those that were alive without any subsequent tx. Over the 48-mo period since randomization, for pts treated with NIVO + IPI + chemo vs chemo, r-mean OS was 22.2 vs 17.6 mo (difference 4.6 mo; 95% CI 2.19-7.01), and r-mean TFS was 7.5 vs 5.0 mo (difference 2.6 mo; 95% CI 1.05-4.16), which was 16% vs 10% of 48-mo period spent in TFS. Mean TFS with toxicity constituted a small proportion of the 48-mo period for both tx arms, resulting in r-mean TFS without toxicity of 6.8 vs 4.5 mo (difference 2.3 mo; 95% CI 0.76-3.79). Similar results were shown by tumor PD-L1 expression levels and will be presented. The proportion of mean time spent in TFS increased from 11% of 24-mo to 16% of 48-mo period in the NIVO + IPI + chemo arm, while decreased from 14% to 10% in the chemo arm.

Conclusions

In this CM 9LA analysis, 1L NIVO + IPI + chemo demonstrated an improvement in TFS with and without toxicity, regardless of tumor PD-L1 expression level, over 48 mo compared with chemo. These data reflect durable clinical benefit of NIVO + IPI + chemo following tx cessation.

Clinical trial identification

NCT03215706.

Legal entity responsible for the study

BristolMyers Squibb.

Funding

BristolMyers Squibb.

Disclosure

M. Reck: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Merck, Novartis, Regeneron, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS, Biontech, Boehringer Ingelheim, Daiichi Sankyo, Gilead, MSD, Mirati, Pfizer, Regeneron, Roche, Sanofi; Financial Interests, Personal, Other, Member of DMSB: Daiichi Sankyo. M. Regan: Financial Interests, Personal, Advisory Board, Also invited speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Includes consulting.: Tolmar Pharmaceuticals; Financial Interests, Personal, Advisory Board: AstraZeneca, Tersera Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Bayer; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial supported by company: Novartis; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported by company: Pfizer, Ipsen, TerSera; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial drug supply from company: Roche; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported or drug supply from company: AstraZeneca; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials with funding from company: Debiopharm; Financial Interests, Institutional, Funding, IBCSG translational research collaboration: Biotheranostics; Non-Financial Interests, Personal, Advisory Role: Bristol Myers Squibb. D.P. Carbone: Financial Interests, Personal and Institutional, Research Grant, Grants or contracts from any entity: Merck to OSU.; Financial Interests, Personal and Institutional, Other, Consulting Fees: AbbVie, Arcus Biosciences, BMS, BMS Brazil, BMS Israel, BMS KK, Boehringer Ingelheim, Curio Science, Daiichi Sankyo Inc, Flame Biosciences, Genentech/Roche, GI Therapeutics (Intellisphere), GSK, InThought, Iovance Biotherapeutics, Janssen, JNJ, Merck, Mer; Financial Interests, Personal and Institutional, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Other, DSMBs: EORTC, AbbVie, Lilly; Financial Interests, Personal, Other, Adv Boards: AbbVie, Amgen, Arcus Biosciences, AstraZeneca, Cantargia (PPD), Daiichi Sankyo Inc, EMD Serono, Flame Biosciences, Iovance Biotherapeutics, Genentech, G1 Therapeutics, GSK, Gritstone Oncology, Janssen/JNJ, Jazz, Lilly, Merck, Merck KGgA, MSD, Mirati, Novo. S. Lu: Financial Interests, Institutional, Invited Speaker: Hansoh, AstraZeneca, Roche, Hengrui; Financial Interests, Institutional, Advisory Board: AdtraZeneca, Prizer, Boehringerlngelheim, Hutchison MediPharma, ZaiLab, GenomiCare, Yuhan Corporation, Menarini, InventisBio Co.Ltd, Roche, Simcere Zaiming Pharmaceutical Co., Ltd.; Financial Interests, Personal, Research Grant: AstraZeneca, Hutchison, BMS, Heng Rui, Roche, Hansoh, BeiGene, Lilly Suzhou Pharmaceutical Co.Ltd; Financial Interests, Personal, Invited Speaker: FibroGen. T. John: Financial Interests, Personal, Invited Speaker, Speaker tour Vietnam: AstraZeneca; Financial Interests, Personal, Invited Speaker, CTIO: Merck Sharp Dohme; Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Bayer, Specialised Therapeutics; Financial Interests, Institutional, Advisory Board: Roche, Novartis, Pfizer, Amgen, Takeda, PharmaMar; Financial Interests, Personal, Other, Speaker/Chair: ACE Oncology. J. Penrod: Financial Interests, Personal and Institutional, Stocks/Shares: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Full or part-time Employment: Bristol Myers Squibb. J. Li: Financial Interests, Personal and Institutional, Full or part-time Employment, BMS GBDS Market Access biostatistician: Bristol-Myers Squibb. Y. Yuan, J. Mahmood: Financial Interests, Personal and Institutional, Full or part-time Employment: Bristol Myers Squibb. A. Lee, L. Eccles, S. Ray: Financial Interests, Personal and Institutional, Stocks/Shares: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Full or part-time Employment: Bristol Myers Squibb. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, President. ASEICA (Spanish Association of Cancer Research): ASEICA; Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group.

Background

In EMPOWER-Lung 3 (NCT03409614) Part 1, patients with aNSCLC and PD-L1 <50% were randomized to 3 treatment arms: CHEMO, CEMI+CHEMO or CEMI+IPI+CHEMO. Clinical outcomes for CEMI+IPI+CHEMO vs CHEMO (including OS [HR: 0.615 (95% CI, 0.441–0.857)]) were previously reported; safety profile was generally consistent with the known safety for CEMI, CHEMO and IPI. PROs were evaluated and reported here.

Methods

PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks) for the first 6 doses, and then the start of every 3 cycles, using the EORTC QLQ-C30 and QLQ-LC13 questionnaires. Time to definitive clinically meaningful deterioration (TTD) analysis was conducted and between-arm (CEMI+IPI+CHEMO [n=109] vs CHEMO [n=106]) TTD comparisons were made per stratified log-rank test and proportional hazards model for global health status (GHS)/quality of life (QoL). A mixed-effect model for repeated measures compared overall differences in score changes from baseline between arms. No adjustments for multiplicity were conducted.

Results

Significant delay in TTD in GHS/QoL favouring CEMI+IPI+CHEMO vs CHEMO [HR: 0.45 (95% CI, 0.23–0.86); P=0.014] was observed; significant TTD delays favouring CEMI+IPI+CHEMO were also observed in functions: physical, role, emotional and social; and symptoms: fatigue, nausea/vomiting, pain, dyspnoea (QLQ-C30), insomnia, appetite loss, diarrhoea, sore mouth, peripheral neuropathy, alopecia, pain in arm or shoulder, pain in chest, and pain in other parts. Significant overall differences in score changes favouring CEMI+IPI+CHEMO vs CHEMO was observed in fatigue, nausea/vomiting, appetite loss and alopecia. When comparing between arms, no analyses yielded statistically significant PRO results favouring CHEMO for any scale.

Conclusions

In patients with PD-L1 <50% aNSCLC, CEMI+IPI+CHEMO vs CHEMO resulted in significant overall improvement and delayed TTD in multiple cancer-related and lung cancer-specific PROs. Positive PROs further support the favourable benefit–risk profile of CEMI+IPI+CHEMO in 1L aNSCLC with PD-L1 <50%.

Clinical trial identification

NCT03409614.

Editorial acknowledgement

The study was funded by Regeneron Pharmaceuticals, Inc., and Sanofi. Editorial support was provided by Rachel McGrandle, MSc, of Alpha (a division of Prime, Knutsford, UK) funded by Regeneron Pharmaceuticals, Inc. Responsibility for all opinions, conclusions, and data interpretation lies with the authors.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc.

Disclosure

A. Baramidze: Financial Interests, Personal, Other, Travel support: Regeneron Pharmaceuticals, Inc. C. Gessner: Financial Interests, Personal, Advisory Board: AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, GSK, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Sanofi. K. Dunnigan, X. He, P. Rietschel, R. Quek: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background

Immunotherapy plus chemotherapy is the standard of care for metastatic non-small cell lung cancer (NSCLC). Radiotherapy (RT) achieved prolonged progression-free survival (PFS) and overall survival (OS) in well selected oligometastatic NSCLC patients. However, the value of additional RT to immuno-chemotherapy remains unclear.

Methods

SABRcure is a multi-center phase II study evaluating the efficacy and safety of durvalumab combined with chemotherapy and RT in patients with oligometastatic EGFR/ALKwt NSCLC. Patients received durvalumab and chemotherapy for 4 cycles, followed by RT to all lesion, and durvalumab monotherapy until disease progression, or intolerance, or up to 24 months(m). Stereotactic ablative body RT (SABR) and definitive RT was performed if feasible. The primary endpoint was PFS per RECIST v1.1. Secondary end points were objective response rate (ORR), OS and safety.

Results

Between Sep 2021 and Apr 2023, 35 patients from 5 hospitals were enrolled (median age 65 years, 57.1% adenocarcinoma). There were 28 (80%) patients received RT and 23 (65.7%) received SABR. As of December 10^th, 2023, 11 patients were still on treatment with durvalumab. With median follow up of 15.7 m, median PFS was 10.4 m (95% CI 4.4, NE). One-year OS rate was 73.6% (95% CI 55.3%, 85.3%). ORR was 71.9%. Median PFS was 18.69 m (7.23, NE) and 24.3 m (7.6, NE) in patients with RT and SABR, respectively. More subgroup analyses were described in the table. Adverse events (AE) ≥grade 3 were reported in 57.1% (20/35). SAE was reported in 45.7% (16/35) and imAE occurred in 34.3% (12/35). Table: 65P

Conclusions

In oligometastatic NSCLC, the combination of durvalumab, chemotherapy and RT is effective and tolerable. Patients without disease progression after upfront systematic therapy and receive RT/SABR have longer PFS, indicating that RT/SABR may be the key to improve efficacy.

Clinical trial identification

NCT04255836.

Legal entity responsible for the study

Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital).

Funding

AstraZeneca China.

Disclosure

All authors have declared no conflicts of interest.

Background

The abscopal effect (AbE) is a systemic immune response mediated by the effects of radiotherapy (RT) on the immune system. The AbE in patients with metastatic cancer treated with RT alone has been seen rarely, however, in the era of immune checkpoint inhibition (ICI) AbE has been recognized more commonly. The actual frequency in the RT-ICI setting is unclear.

Methods

We retrospectively screened metastatic cancer patients receiving RT for progressive disease during ICI between 2015- 2021. Patients switching systemic treatment within radiological response assessment (RA) were excluded. Eligible patients had ≥1 NIL outside the 10% RT isodose and a maximum of 5 NIL were measured. According to iRECIST, size reduction ≥30% was rated abscopal response (AR), increase by ≥20% abscopal progression (AP), every change of size in between was classified as “control” (abscopal control, AC). Hereby, we report the subgroup of non-small cell lung cancer (NSCLC).

Results

We analyzed preliminary data from 8 participating centers in Germany. 3381 cases were screened to identify 33 eligible NSCLC patients with a total number of 39 lesion irradiated and 85 non-irradiated lesions (NIL). Median age was 63.50 years (interquartile range (IQR): [56.00;67.25]). Patients were treated either with stereotactic (n=3; 9%) or stereotactic fractionated (n=5, 15%), hypofractionated (n=19; 58%) or normofractionated (n=4; 12%) RT or a combination of different fractionations (n=2, 6%). ICI consisted of either pembrolizumab (n=20; 61%) or nivolumab (n=12; 36%). AR as well as AC was found in 9 (27%) patients, respectively. AP and other was seen in 11 (33%) patients. In addition, at least one AR was seen in 4 (12%) patients.

Conclusions

We present the NSCLC subgroup analysis of AbE following concurrent RT for progressive disease during ICI treatment in a large multicenter cohort (ARTIC/ARO 2022-10). We report an AR rate of 27% which is similar to earlier reports ranging between 18-52%. In addition, 12% of the identified NSCLC patients showed at least one AR of the measured NIL. Subgroup analyses, predictors of AbE and survival outcomes from our data are underway.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Ivo is a bispecific antibody with cooperative binding to enhance binding affinity to PD-1 by >18 fold and VEGF by >4 fold with the potential to drive synergistic anti-tumor activity. Ivo has a mean T_1/2 of 6-7 days. We aimed to assess the efficacy and safety of ivo combined with chemotherapy as first line treatment of advanced Sq-NSCLC.

Methods

Updated data from an open-label, multi-center phase II study, previously reported at ASCO 2023, assessing the efficacy and safety of ivo+chemo, in pts receiving first line therapy for advanced Sq-NSCLC. Pts were treated with 10 mg/kg (n=10) or 20 mg/kg(n=53) ivo q3wks combined with carboplatin and pemetrexed (non-Sq) or carboplatin and paclitaxel (Sq). Pts were excluded if they had tumor encircling blood vessels, necrosis and cavitation, or had central, cavitary sq NSCLC, or risk of hemorrhage. The primary endpoint was ORR per RECISTv1.1 by investigator.

Results

63 pts with advanced Sq-NSCLC received ivo plus chemotherapy. Median age was 59 yrs. 3% and 97% pts had ECOG PS 0 and 1, respectively, and 8% of pts had baseline brain metastasis. Median follow-up was 21.0 mo. Pts with Sq-NSCLC experienced a 71.4% ORR with median DOR 12.7 mo, 90.5% DCR, the median PFS 11.1 mo, and 21-mo OS rate was 69.5%. The table lists the most common treatment related adverse events (TRAEs) ≥ 10%. Grade ≥3 TRAEs occurred in 44.4%, TRAEs leading to discontinuation occurred in 11.1% of pts. Overall incidence of bleeding events was 46% (grade 1-2) with one grade ≥3 event (hemoptysis) at 10mg/kg dose. Table: 68P

Conclusions

Ivonescimab plus chemotherapy has promising anti-tumor activity in pts with advanced NSCLC and was administered safely in combination with platinum doublet chemotherapy to pts with Sq histology.

Clinical trial identification

NCT04736823.

Legal entity responsible for the study

Akeso.

Funding

Akeso.

Disclosure

L. Zhang: Financial Interests, Institutional, Research Grant: Hengrui, BeiGene, Xiansheng, Eli Lilly, Novartis, Roche, Hansoh, Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: MSD, BeiGene, Xiansheng. Y. Xia: Financial Interests, Institutional, Full or part-time Employment: Akeso. All other authors have declared no conflicts of interest.

Background

Two phase III trials (SAPPHIRE and CONTACT-01) have evaluated the combination of TAM receptor tyrosine kinase inhibitors (TYRO3, AXL, MERTK, TAMi) and immune checkpoint inhibitors (ICB) in NSCLC patients who were resistant to previous ICB plus chemotherapy (Chemo). Although there is substantial preclinical evidence supporting the inhibition of TAM RTKs to enhance ICB efficacy, both trials failed to improve outcomes over docetaxel. We hypothesized that 1) moving TAMi plus ICB to the first-line setting may be more appropriate; 2) TAMi would be beneficial for tumors with high TAM RTK expression.

Methods

To preliminarily explore optimal biomarker and scenario for employing TAMi plus ICB, we assessed the association between TAM RTK mRNA expression and ICB efficacy and tumor microenvironment in our in-house phase III randomized controlled trials (ORIENT-11, NCT03607539) that compared PD-1 inhibitor Sintilimab plus Chemo (n=113) versus Chemo (n=58) in treatment-naïve non-squamous NSCLC. The 75th percentile of a gene was selected as cutoff for high expression.

Results

Among the three RTKs, high TYRO3 expression defined a subset of patients with no overall survival (OS; HR=0.92, P=0.8) and progression-free survival (PFS; HR=0.86, P=0.7) from ICB+Chemo over Chemo, while the advantage of OS (HR=0.59, P=0.02) and PFS (HR=0.29, P= 2.00E-08) both remained in patients with low TYRO3 expression. These reduced benefits were independently of PD-L1 expression and other clinical variables (P interaction=0.01). These findings suggested that TYRO3 could serve as a biomarker for identifying patients who may benefit from incorporation of TAMi in the first-line setting. Conversely, high AXL and MERTK expression did not curtail ICB+Chemo efficacy. High TYRO3 but not AXL and MERTK expression was associated with elevated T regulatory cell infiltration.

Conclusions

Future trials investigating TAMi plus ICB should in a biomarker-driven approach (high TAM RTK expression) in the first-line setting. Importantly, most TAMi developed to date are pan-TAM inhibitors, leading to significant off-target toxicities. Our findings emphasize the urgency of developing highly selective agents specifically targeting TYRO3.

Clinical trial identification

NCT03607539.

Legal entity responsible for the study

A. Li.

Funding

This study was supported by the National Natural Science Foundation of China (81972898, 82172713, and 81972556), the Guangdong Basic and Applied Basic Research Foundation (2023B1515020008), and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (22ykqb15).

Disclosure

All authors have declared no conflicts of interest.

Background

Envafolimab has been used as the first subcutaneously injected PD-L1 inhibitor for the treatment of solid tumors. Therefore, this study aims to investigate the efficacy and safety of envafolimab in combination with recombinant human endostatin (Rh-endostatin) as a first-line treatment modality and chemotherapy in patients with driver-negative advanced NSCLC.

Methods

This was a single-arm, single-center, prospective, phase II clinical study. Between April 2022 and August 2023, consecutive eligible patients with histologically or cytologically confirmed with untreated stage IV NSCLC (excluding driver mutations) were enrolled. Patients received 4-6 cycles of envafolimab and Rh-endostatin combined with platinum-based dual-agent chemotherapy, followed by maintenance therapy with envafolimab and Rh-endostatin until disease progression or intolerable toxicity. The primary endpoints were the objective response rate (ORR) and disease control rate (DCR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and tolerability.

Results

As of December 1, 2023, the median follow-up was 11.8 months (95% CI, 9.4-12.6). 29 patients with advanced NSCLC were enrolled at Shandong Cancer Hospital, 14/29 were squamous cell carcinoma, and 15/29 were non-squamous non-small cell lung cancer. The ORR was 72.4% (95% CI, 54.3% - 85.3%), and the DCR was 93.1% (95% CI, 78.0%- 98.1%), showing statistically significant differences compared with data from previous results. Median PFS and OS were not reached yet. Safety was manageable with no ≥ grade 3 treatment-related adverse events (TRAEs) or immune-related adverse events (irAEs).

Conclusions

Envafolimab in combination with Rh-endostatin and chemotherapy as a first-line treatment for lung cancer exhibits favorable therapeutic efficacy with a manageable safety profile, which might represent a promising treatment regimen and warrant further investigation.

Legal entity responsible for the study

S. Yuan.

Funding

Simcere Pharmaceuticals Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

MEK inhibition combined with blocking the PD-1 axis may achieve a greater clinical response than either inhibitor alone due to increased T cell infiltration of tumours. We combined binimetinib with pembrolizumab in patients with stage IV advanced non-small cell lung cancer (NSCLC) and PD-L1 tumor proportion score>=50%.

Methods

A 3 + 3 dose escalation design was used. Binimetinib at dose level 1 (DL1; 45 mg) or dose level -1 (DL-1; 30 mg) twice daily orally continuously was given with pembrolizumab 200 mg IV q 21 days. The primary objective was to define the recommended phase II dose (RP2D). Secondary outcomes included safety of the combination and response (RECIST 1.1) with a planned phase Ib expansion in patients with RAS/RAF/MEK dysregulated tumours via next generation gene sequencing. Genomic markers are being explored in tissue and plasma.

Results

Eleven patients (3 DL1= 45 mg, 8 DL-1= 30 mg) were enrolled: 7 with KRAS, 2 BRAF and 1 STK11 alteration which acts as a tumor suppressor gene encoding for LKB1. Two of 3 patients at DL1 experienced dose limiting toxicity (DLT) including grade 3 elevated amylase and diarrhea, grade 4 elevated lipase and a grade 2 rash requiring dose reduction. Of 8 patients treated at DL-1, 2 were not evaluable for DLT as 1 progressed in cycle 1 and another was noncompliant with treatment. Of the remaining 6 patients, 1 experienced a DLT with grade 3 rash. Common toxicities across all cycles were rash (100%), diarrhea (45%), pruritis (45%) and lower extremity edema (36%). A partial response was noted in 4 (36%), stable disease in 4 (36%) and progressive disease in 3 (27%) with an overall response rate of 36% and a disease control rate of 73%. All 4 responding patients had either a RAS or RAF alterations while 2 of the 3 patients with early disease progression had no RAS or RAF mutation.

Conclusions

The RP2D of the combination in patients with advanced NSCLC is binimetinib 30 mg BID plus pembrolizumab 200 mg IV q21 days. There appears to be an early trend of patients responding to combination treatment who harbor a KRAS or BRAF mutation. Updated data including circulating tumor DNA variant allele frequency associated with response and final analysis of primary endpoints will be presented.

Clinical trial identification

NCT03991819.

Legal entity responsible for the study

Princess Margarette Cancer Centre.

Funding

Pfizer grant (drug supply), MSD (drug supply), Princess Margaret Cancer Foundation.

Disclosure

N. Leighl: Financial Interests, Personal, Other, CME/independent lectures: MSD, BMS, Hoffmann LaRoche, EMD Serono; Financial Interests, Personal, Invited Speaker, independent lectures: Novartis, Takeda; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Array, Bayer, EMD Serono, Guardant Health, Lilly, MSD, Pfizer, Roche, Takeda, Janssen. All other authors have declared no conflicts of interest.

Background

Immune checkpoint blockade has increased survival for lung cancer patients. Unfortunately, many patients’ tumors do not respond. Recent evidence suggests that the gut microbiome is critical in response to ICB. The microbiome is malleable; therefore, it holds promise as both a biomarker of response to ICB and a therapeutic target. While several methods of modifying the microbiome are under investigation in clinical trials globally, lifestyle-based interventions are arguably the safest and most patient-empowering strategies. Here, we describe the use of a small dietary intervention designed to increase the abundance of microbes that promote response to ICB.

Methods

The BEWELL Study (Black raspberry nEctar Working to prEvent Lung cancer NCT04267874) was a randomized, cross-over trial that tested 2x 80 mL black raspberry (BRB) nectar drink boxes per day for 4 weeks versus a taste and texture-matched placebo control. Surveys were collected before the intervention (physical activity, eating patterns), and blood, stool, and urine were collected at four time-points: pre- and post-BRB, and pre- and post-placebo. Plasma cytokines, urine polyphenols, and gut microbes were assessed. Stool from participants before and after the intervention was transferred into tumor-bearing (mc38, CMT167) C57BL/6 mouse models, which were then treated with anti-PD1 (RMP1-14) or control (IgG, clone 2A3), and tumor volumes assessed by caliper. Individual microbes were cultured from stool samples and added to pre-BRB samples at 1e7 CFU to recapitulate the post-BRB response to ICB.

Results

Participants in the BEWELL Study showed a significantly greater abundance of several taxa in the family Lachnospiraceae following BRB. Less physically active participants were more likely to experience a significant increase in Lachnospiraceae. In mouse models, a change in Lachnospiraceae was associated with smaller tumor volumes. Further, a Lachnospiraceae isolate promoted smaller tumor volumes when supplemented into a pre-BRB stool gavage.

Conclusions

These results suggest that a BRB dietary intervention may alter the human gut microbiome to support improved response to ICB.

Clinical trial identification

NCT04267874.

Legal entity responsible for the study

D. Spakowicz.

Funding

Pelotonia, Lung Cancer Foundation of America.

Disclosure

All authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (ICI) dramatically improved outcomes of patients with non-small cell lung cancer (NSCLC). The gut microbiome has emerged as a biomarker of response to ICI in NSCLC and a potential therapeutic target. High fiber and Mediterranean diets were associated with prolonged response in patients with melanoma treated with ICI. The objective of this study was to assess the effect of diet on outcome and microbiome composition.

Methods

Prospective collection of clinical and dietary data were assessed in 102 patients with NSCLC amenable to ICI. We employed a standardize food frequency questionnaire (FFQ) specific to the NSCLC population designed by a clinical nutritionist. FFQ answers were recorded electronically and analyzed using a calculation tool to estimate the median daily fiber (g/day), and surrogate markers of the Mediterranean diet; Monounsaturated fatty acids (MUFA) and Polyunsaturated fatty acids (PUFA) intake (g/1000kcal). Then correlated with progression-free survival (PFS) and overall survival (OS). Microbiome was profiled in a sub-group of 76 patients using shot-gun metagenomic, MetaPhlan4 pipeline was used to detect species, diversity index and LefSe were calculated.

Results

Among the 102 patients with NSCLC the median fiber intake was 16 g/day and did not correlate with outcome. However, Spearman correlation showed a significant association between increased PUFA or MUFA intake and longer OS (p<0,001 and p<0,001). Moreover, MUFA dietary intake correlated with a prolonged PFS (median PFS high MUFA intake: 20.0 months versus low MUFA intake: 9.1 months, p=0.02). Additionally, MUFA and PUFA intake correlated with the increase abundance of Eubacterium, Alistipes and Bifidobacterium.

Conclusions

In this cohort, patients had a very low fiber diet, however a high MUFA and PUFA intake was associated with beneficial response and an overrepresentation of known beneficial immunogenic bacteria. These results raise the possibility that evidence-based dietary recommendations counseling using educational tools may represent an important strategy to employ the gut microbiome as a potential therapeutic target in improving the response to ICI.

Legal entity responsible for the study

The authors.

Funding

Merck.

Disclosure

All authors have declared no conflicts of interest.

Background

In an open-label, single-arm, multicenter phase II study, camrelizumab demonstrated promising efficacy as a second-line treatment in pre-treated advanced/metastatic NSCLC, with those exhibiting positive PD-L1 expression deriving greater benefit from camrelizumab (Yang et al., Cancer Immunol Immunother, 2021). Here we present an updated analysis of efficacy and safety outcomes from this study with a follow-up period of approximately 5 years.

Methods

Eligible patients had advanced/metastatic NSCLC and had previously received platinum-based doublet chemotherapy. Patients with EGFR/ALK alterations who had progressed on at least one approved tyrosine kinase inhibitor and had a PD-L1 tumor proportion score (TPS) ≥50% were also eligible. Patients were assigned to 4 cohorts based on their PD-L1 TPS and received camrelizumab intravenously at a dose of 200 mg every 2 weeks. The primary endpoint was ORR.

Results

A total of 146 patients were enrolled between May 24, 2017 and Aug 1, 2018. As of the data cutoff on Aug 31, 2023, the median follow-up was 62.3 months (95% CI 57.7–65.3), and 111 (76.0%) death events occurred. The median OS was 14.8 months (95% CI 10.2–18.7), and the 5-year OS rate was 19.3% (95% CI 13.0–26.7). Patients with positive PD-L1 expression (TPS ≥1%) continued to derive a greater benefit in longer-term OS from camrelizumab (Table). No new safety signals with camrelizumab were identified. Table: 74P

OS results

Conclusions

The updated analysis demonstrates the long-term efficacy of camrelizumab as a second-line treatment in pre-treated advanced/metastatic NSCLC, especially in patients with positive PD-L1 expression. Our findings further consolidate camrelizumab as an established and efficacious therapeutic approach for this patient population.

Clinical trial identification

NCT03085069.

Legal entity responsible for the study

The authors.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Disclosure

X. Li, X. Ma, W. Shi: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Wu: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Hengrui, Merck, MSD, Pfizer, Roche, Sanofi, AstraZeneca, Boehringer Ingelheim, BMS, Hengrui, Merck, MSD, Pfizer, Roche, Sanofi, Yunhan, Eli Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Takeda; Non-Financial Interests, Personal, Leadership Role: Chinese Thoracic Oncology Group (CTONG); Non-Financial Interests, Personal, Other, WCLC 2020 Conference Chair: IASLC; Non-Financial Interests, Personal, Leadership Role, Past President: Chinese Society of Clinical Oncology (CSCO). All other authors have declared no conflicts of interest.

Background

The use of immune checkpoint inhibitors including PD-1 and PD-L1 inhibitors is recommended for the treatment of previously untreated advanced non-small cell lung cancer (NSCLC) patients. The immunohistochemical detection of PD-L1 expression on tumor cells has emerged as the most widely utilized biomarker in clinical practice. However, the predictive value of tumor mutation burden (TMB) remains controversial. Here, we reported the result of two cohorts of an umbrella trial, to evaluate the efficacy and safety of sintilimab monotherapy in untreated NSCLC with PD-L1 expression ≥50% (PD-L1^high, 14^th arm) or with TMB ≥10 mut/Mb & PD-L1 expression <50% (TMB^high, 15^th arm).

Methods

Patients received sintilimab monotherapy 200mg every 21 days. The primary objective was objective response rate (ORR). To determine whether sintilimab monotherapy has sufficient activity, we used Simon's minimax two-stage to calculate sample size for these two treatments cohorts.

Results

Between May 29, 2019 and January 6, 2022，831 untreated advanced NSCLC patients were screened with tumor tissue by next-generation sequencing. 63 patients were enrolled and received sintilimab monotherapy in PD-L1^high arm (n = 34) or TMB^high arm (n = 29). As the cutoff data of October 31, 2023, the median follow-up is 21.6 months. The primary endpoint was reached with a confirmed ORR of 47.1% (16/34) and 37.9% (11/29) in PD-L1^high and TMB^high arms, respectively. The median progression-free survival (PFS) was 6.9 months and 14.1 months; the median overall survival (OS) was NR and 37.8 months in PD-L1^high and TMB^high arms, respectively. Treatment-related adverse events with grade ≥3 occurred in 19% (12/63) patients, which was 14.7% (5/34) and 24.1% (7/29) patients in these two arms. The most common adverse events are rash and increased glutamic pyruvic transaminase.

Conclusions

In this prospective trial, PD-L1 high expression is a good biomarker for PD-1 inhibitor monotherapy for untreated advanced NSCLC; high TMB also seems to be a predictive marker for PD-1 inhibitor monotherapy, that could achieve long PFS and OS.

Clinical trial identification

NCT03574402.

Legal entity responsible for the study

Chinese Thoracic Oncology Group (CTONG).

Funding

This work was funded by Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (2017B030314120, Yi-Long Wu), Guangdong Provincial People's Hospital Scientific Research Funds for Leading Medical Talents in Guangdong Province (KJ012019426, Yi-Long Wu), National Natural Science Foundation of China (Grant No. 82072562, Qing Zhou), the High-Level Hospital Construction Project (DFJH201810, Qing Zhou), and the National Natural Science Foundation of China (82202997, Si-Yang Maggie Liu).

Disclosure

Q. Zhou: Financial Interests, Personal, Invited Speaker: BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. W. Zhong: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Eli Lilly and Pfizer. Y. Wu: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Pfizer; and personal fees from Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Sanofi, and Roche. All other authors have declared no conflicts of interest.

Background

Liquid biopsies of cell-free DNA (cfDNA), circulating tumour DNA (ctDNA), and circulating tumour cells (CTCs) can be used to monitor the efficacy of systemic therapy. We investigated the predictive value of CTCs and ctDNA in patients with advanced non-small cell lung cancer (NSCLC) treated with pembrolizumab.

Methods

cfDNA was evaluated in 127 patients’ plasma samples at baseline(t0), after 3-weeks(t1), 6-weeks(t2) and 9-weeks(t3) from 46 individuals and analysed by next-generation sequencing to identify and quantify somatic mutations. CTCs were detected in peripheral blood mononuclear cells and characterised according to PD-L1 and Ki67.

Results

Patients presenting an increase in cfDNA at t1/t2 had shorter progression-free survival (PFS) (2.05 vs 6.1 months, p=0.04) and overall-survival (OS) (8.35 vs 20.0 months, p=0.004) than those with decreased cfDNA. Somatic mutations were found in TP53, EGFR, KRAS, ALK, PI3KCA and MAP2K1 in 58.14% of patients. Carriers of KRAS mutations at t2 had a worse overall survival (OS) than non-carriers (Hazard ratio (HR)=3.2, p=0.03). Patients with >50% decrease or clearance in ctDNA from baseline to early treatment, had lower risk for progression (HR=0.14, p=0.03) and mortality (HR=0.29, p=0.03), respectively. In addition, a high Ki67 CTC-index (iKi67), negatively affected patient progression (HR=10.13, p=0.03) and survival (HR=6.1, p=0.01). We then layered the assessment of iKi67 and ctDNA markers to establish a sensitive and robust combinatorial risk classification approach for detecting patients with PD. Importantly, the combination of ctDNA and iKi67 was superior in identifying patients with disease progression.

Conclusions

Early assessment of these circulating markers provides predictive information regarding the efficacy of pembrolizumab immunotherapy in patients with metastatic NSCLC and may be used for treatment stratification.

Clinical trial identification

NCT02705820 (Our patients participated in the SWIPE SWItch maintenance pembrolizumab trial).

Legal entity responsible for the study

The authors.

Funding

The present work was financed by the European Regional Development Fund and the Republic of Cyprus (RESTART 2016-2020 (EXCELLENCE/0918/0358). This study was partly supported by the EU’s HORIZON 2020 Research and Innovation Program, CY-Biobank, Grant Agreement No. 857122. Funding was also provided by theMSD.

Disclosure

All authors have declared no conflicts of interest.

Background

Previous studies have investigated the potential clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) in various immunotherapy-treated solid tumors, including non-small cell lung cancer (NSCLC), with controversial results. We herein aimed to further clarify the prognostic and predictive value of baseline and post-treatment levels of sPD-1 and sPD-L1 in patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs).

Methods

55 patients with advanced NSCLC eligible to receive immunotherapy (as monotherapy or in combination with chemotherapy) were prospectively enrolled. A group of sex- and age-matched healthy controls (n=16) was also recruited, for determination of the optimal cut-off value of the examined biomarkers. Serum sPD-1 and sPD-L1 levels were measured in peripheral blood samples using ELISA, both at baseline and at the time of treatment response evaluation, and were correlated with prognosis (PFS, OS), treatment response and the remaining clinicopathological features of patients.

Results

Mean age of patients was 66.5 years (SD=8.0 years); 65,5% of patients received chemotherapy and pembrolizumab combination while the remaining patients received pembrolizumab monotherapy. Levels of sPD-1 after treatment were found to be significantly increased as compared to baseline (p<0,001). A minimal increase of mean sPD-L1 levels after treatment was also observed, albeit without reaching statistical significance. Univariate Cox regression analysis showed that increased pre-treatment values of sPD-1 (HR=10.96; p=0.037) and sPD-L1 (HR=1.68; p=0.040) were significantly associated with reduced OS. However, only sPD-L1 retained its prognostic significance in multivariate analysis (HR=2.10; p=0.014).

Conclusions

Increased pre-treatment values of sPD-L1 may independently predict a worse OS in advanced-stage NSCLC patients treated with ICIs.

Legal entity responsible for the study

National & Kapodistrian University of Athens.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Early clinical trials and pharmacological studies show comparable pembrolizumab results with doses lower than the marketed 200 mg Q3W. Following a recommendation from the Dutch Society of Medical Oncology, many Dutch hospitals implemented an alternative, partially lower, weight-based dosing regimen for pembrolizumab. This analysis compares the overall survival (OS) of the alternative pembrolizumab dosing regimen to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients.

Methods

Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1996 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1^st, 2021 and Mar 31^st, 2023. 604 patients in 21 hospitals received alternative dosing and 1362 patients in 19 hospitals received standard dosing, as described in the table. A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing regimens. The non-inferiority margin was set at 1.2 for OS (Table).

Results

Distribution of age, gender and treatment combinations were similar for both groups, comorbidity score was higher in the standard dosing group. Median daily pembrolizumab dose in the alternative dosing group was 7.14 mg/day (interquartile range (IQR): 5.48-8.04 mg/day) vs. 9.15 mg/day (IQR: 8.33-9.52 mg/day) in the standard dosing group. The OS of the alternative dosing regimen was non-inferior compared to standard dosing (adjusted hazard ratio 0.833, 95% confidence interval: 0.692-1.003). Table: 79P

Reduced and standard pembrolizumab dose levels and OS

Conclusions

This real-world analysis on a nationwide registry showed that the OS of NSCLC patients after alternative partially lower pembrolizumab dosing was non-inferior to standard pembrolizumab dosing. Alternative pembrolizumab dosing regimens can lead to substantial cost reductions.

Legal entity responsible for the study

Dutch Institute for Clinical Auditing.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

LILRB2 is an immune checkpoint of leukocyte immunoglobulin-like receptor B family. The blockade of LILRB2 can reprogram the immunosuppressive phenotype of myeloid cells to enhance the efficacy of immune checkpoint inhibitor (ICB) in preclinical studies, which are undergoing early clinical testing in NSCLC. The single-cell-level resolution of LILRB2 and its impact on the PD-1/PD-L1 immunotherapy have not been fully explored.

Methods

The predictive value of LILRB2 mRNA expression for ICB was first evaluated in two independent phase III randomized controlled trials (RCTs), including ORIENT-11 [sintilimab plus chemotherapy, n = 113; chemotherapy, n = 58] and OAK (atezolizumab, n = 344; chemotherapy, n = 355). BayesPrism algorithm were used to deconvolute monocyte subsets from GSE123904, GSE127465 and GSE207422.

Results

Higher LILRB2 expression was significantly associated with significantly prolonged progression free survival with ICB (ORIENT-11: HR=0.57 p=0.027;OAK: HR=0.77, p=0.023). However, no trend was observed in chemotherapy arm in each study. These findings maintained in patients with PD-L1 expression≥1%. From the three single-cell RNA-seq datasets, we identified a monocyte subset with high LILRB2 expression, referred as LILRB2+monocyte. Deconvolution of LILRB2+ monocyte in the two RCTs demonstrated its predictiveness for ICB. Further, in a single-cell dataset, the transcriptional signatures of LILRB2+ monocytes were enriched in MPR patients treated with neoadjuvant PD-1 blockade. Functionally, LILRB2+ monocytes were positively correlated with immune-related interferon-ɑ (IFN-ɑ) and interferon-γ (IFN-γ) signaling. LILRB2+ monocytes were predicted to interact with GZMB+ and GZMK+ cytotoxic T lymphocyte, which thereby promotes anti-tumor immunity by enhancing CD8+ T cell effector functions.

Conclusions

LILRB2+ defines a monocyte subset that is positively associated with greater benefits from ICB, in contrast to most previously-revealed monocyte subsets with an immunosuppressive phenotype. The evaluation of LILRB2+ monocytes may help identify patients who could benefit from future co-inhibition of PD-1/PD-L1 and LILRB2 signaling.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Identifying robust biomarkers for predicting patient response remains a challenge in the field of tumor immunotherapy. Tumor-associated macrophages (TAMs), the most abundant cells in the innate immune system, significantly influence cancer prognosis and immunotherapy.We explored the potential association of a TAM molecular signature with prognosis and other relevant tumor characteristics to enhance prediction accuracy for patient response to immunotherapy.

Methods

We conducted a comprehensive analysis of single-cell RNA sequencing data from two cancer datasets to dissect the molecular characteristics of TAMs. Next, we investigated potential relationships between TAMs.Sig and prognosis across 33 different types of cancer. We compared it with other previously reported six ICI response signatures and developed an immune response prediction model based on TAMs.Sig. Finally, we performed functional and subtyping analyses in non-small cell lung cancer patients using TAMs.Sig.

Results

We identified seven novel TAM prognostic genes, namely CRYAB, SHC1, CCL3L3, CREG1, PCDHGC3, CCND1, and XAGE1A. Subsequently, these genes were utilized to construct a TAMs.Sig. The presence of TAMs.Sig exhibits a negative correlation with the tumor immune response. The predictive model developed using KNN regression demonstrated superior diagnostic capability compared to other algorithms with an AUC value of 0.703. In patients with lung adenocarcinoma (LUAD), there exists a significant relationship between TAMs.Sig and both mDFS(p=0.034) as well as mOS(p=0.0061). Two different subtypes of LUAD were identified by important tumor macrophage prognostic genes and Cluster B exhibited higher dysregulation scores along with elevated CD274 expression. However,TMB was found to be higher in patients belonging to Cluster A compared to those in Cluster B.

Conclusions

Our findings reveal that clustering patients based on TAMs.Sig predicts ICI outcomes with greater accuracy than other previously identified signatures across multiple types of cancer and is a promising approach for predicting ICI response in patients with lung adenocarcinoma.

Legal entity responsible for the study

Shanghai Chest Hospital.

Funding

Shanghai Municipal Health Commission (No. 2022YQ039 and No.201940084), Shanghai "Rising Stars of Medical Talents" Youth Development Program, Youth Medical Talents-Specialist Program and the Project of Science and Technology Development Fund of Shanghai Chest Hospital (No. 2021YNZYB02).

Disclosure

All authors have declared no conflicts of interest.

Background

Autoantibodies (AAbs) hold promise for monitoring treatment responses in cancer immunotherapy. We propose a comprehensive longitudinal analysis of an AAb panel to predict treatment responses in advanced NSCLC during immunotherapy. Furthermore, it explores the functional implications of HDAC3 on the immune microenvironment at the single-cell transcriptomics and protein level.

Methods

A total of 131 plasma samples were collected from 55 advanced NSCLC patients undergoing anti-PD1 monotherapy from 2016 to 2022. Utilizing the high-density HuProt^TM antigen microarray (21,000 proteins), predictive AAbs were identified by comparing responders and non-responders(n=22 with 53 plasma samples). Subsequently, an independent cohort (n=33 with 78 plasma samples) underwent validation for candidate AAbs. The prognostic value of HDAC3 was confirmed through immunohistochemistry (IHC). Employing single-cell transcriptomics and multiple immunohistochemistry (mIHC), analyses were conducted on cell communication between HDAC3+ and HDAC3- malignant lung cells.

Results

Five predictive AAbs (HDAC3, METTL21C, HSPB3, SPACA7, and SPPL2B) were selected and validated. The baseline AAbs predictive efficacy achieved an area under the curve (AUC) of 0.76, 0.76, 0.74, 0.77 and 0.75. After treatment, the AUC were 0.84, 0.78, 0.72, 0.76, and 0.76. HDAC3 AAb demonstrates the most robust prognostic capability. Employing the five AAbs as a risk score classifier, PFS could be accurately distinguished (P = 0.014 and P = 0.023). Compared with HDAC3- malignant lung cells, HDAC3+ malignant lung cells exhibited higher chromosome copy number variation, senescence and EMT scores (P < 0.0001) and were enriched in PI3K−AKT−MTOR, and P53 signaling (P < 0.05). Single-cell transcriptomics, IHC and mIHC confirmed that increased infiltration of HDAC3+ malignant lung cells correlated with decreased CD4⁺T and CD8⁺T cells and an increase in TGFβ signaling.

Conclusions

This study highlights AAb signatures as potential biomarkers for monitoring aNSCLC undergoing immunotherapy. HDAC3 emerges as a potent prognostic indicator and HDAC3+ lung malignant cells exhibited enhanced malignancy with immunosuppressive microenvironment.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Although PD-L1 is currently a widely accepted biomarker for predicting the efficacy of immunotherapy, relying solely on PD-L1 as a single biomarker may not be sufficient to identify the suitable treatment population for immunotherapy due to the highly complex tumor microenvironment.

Methods

All samples were assayed using time-of-flight mass spectrometry. Two cohorts were combined for analysis. 43 gene characteristic modules obtained from the WGCNA network were analyzed. The relationship between gene expression and gene mutations was verified. An Individualized PPI network was constructed to demonstrate the differences between DCB and non-durable clinical response (NDB) cohorts.

Results

In this study, data were obtained from 50 patients with NSCLC who were treated with anti-PD-1/PD-L1 monotherapy and were subjected to high-throughput proteomic/transcriptomic profiling. Among them, the data of 23 NSCLC patients were from our institution, and their primary lung lesions were examined by protein mass spectrometry (SHFK cohort). Data for the remaining 27 patients were from GSE135222 with the RNA-seq analysis data (GSE135222 cohort). By combining differential gene screening and weighted correlation network analysis (WGCNA), a total of 43 gene modules positively correlated to efficacy were screened. Secondly, the elastic network, a machine learning model, was used to screen the input variables and three key gene modules were obtained. By using gene expression-mutation association analysis, 59 mutated genes coexisting with our selected genes were located. Finally, investigation of the MSKCC ICI cohort confirmed that patients with this gene signature had prolonged progression-free survival (PFS), indicating a durable clinical response (DCB). Moreover, our patient-specific protein network further confirmed the practically significant protein-protein interaction (PPI) of selected gene panels.

Conclusions

Our proteomic gene signature-based prediction model using machine learning algorithms could estimate the prognosis of patients treated with ICI. Our results provided a rationale for using proteomic gene to develop ICI-specific proteomic gene signatures for immunotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Recent studies suggest immune infiltrates in primary tumors and metastases can serve as independent prognostic biomarkers and predict efficacy of platinum-based anticancer drugs in patients with non-small cell lung cancer patients (NSCLC).The study of subsets of (TILs) is crucial, as they exhibit distinct physiological and pathological implications within the tumour microenvironment.

Methods

From January 2016 to December 2018, we conducted a prospective study on 50 chemotherapy naive patients with advanced stage NSCLC. CD3, CD4, CD8 and FOXP3 lymphocytes were detected in paraffin embedded tumor tissues by stained slides (H&E). We studied the average density of TILs subgroups using the median values as cut-off, which was categorized on whether they above or below the median value. All patients received gemcitabine and platinum agents. Assessment of (TILs), correlation with overall response rate (ORR), TTP and OS were done. Tumor response was assessed by RECIST v1.1.

Results

A significant association was seen between the density of CD4 and CD8 (TILs) and the clinical benefit response to chemotherapy, with (p- 0.048 and 0.034, respectively) but no correlation with FOXP3 and CD3. Low FOXP3 levels resulted in longer OS and TTP in patients (p = 0.016 and p = 0.006 respectively) while decreased FOXP3/CD4 ratio was associated with prolonged OS and TTP (P-0.026 and 0.016 respectively). In multivariate analysis, a statistically significant link was found between FOXP3 level and the presence of a lung nodule. This showed a high hazard ratio (HR) for OS (p-0.001 and 0.036, respectively) and a higher risk of progression for FOXP3 level. Moreover, there is a correlation between performance status and TTP.

Conclusions

Platinum treatments predict prognosis and treatment response by assessing high CD8, low FOXP3/CD4 ratio, and FOXP3 TIL infiltration in tumor environments. Understanding micro-environmental immune milieu significance is crucial for prognosis and treatment response.

Legal entity responsible for the study

M. Eissa.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (ICIs) have revamped the clinical outcomes of patients (pts) affected by advanced non-oncogene addicted non-small cell lung cancer (NSCLC). The aim of our study is to develop an ensemble clustering algorithm (Clust) integrated with a logistic regression model (Pro) to prognostically stratify NSCLC pts treated with ICIs (NSCLC-Pro ClustAI).

Methods

Data extraction involved, retrospectively, all consecutive pts with advanced NSCLC treated with ICIs at Department of Medical Oncology, Ancona, Italy. Baseline features included clinicopathological variables and comorbidities commonly available in daily clinical practice. An unsupervised clustering analysis was used to identify groups within the dataset that hold prognostic significance. Clust was built by stacking both the K-means algorithm and the Gaussian Mixture Model. Subsequently, Pro was used to predict clusters’ label. The metrics used to evaluate the average performance of Pro on test sets were ACCuracy (ACC) and Area Under the Curve (AUC). The model was developed in Python on-cloud using the Google Colab service.

Results

A total of 89 NSCLC pts with complete data available were included in the final analysis. The two generated clusters were: cluster 1 (n=54) and cluster 2 (n=35) (Table). Considering clinical outcomes, median progression free survival was 9.96 months for cluster 1 and 3.78 months for cluster 2 (p = 0.007), and median overall survival was 14.25 months for cluster 1 and 9.14 months for cluster 2 (p=0.05). The average ACC and AUC across all splits achieved by Pro model for pts classification into clusters were 0.978 and 0.981, respectively. From the feature ranking, it emerged that the one with higher importance was CONUT score.

Table: 85P

Dataset stratification

Conclusions

By using easy to obtain and reproducible clinicopathological features, we demonstrated that NSCLC-Pro ClustAI is a promising and accurate prognostic model for stratifying NSCLC pts receiving ICIs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L. Cantini: Financial Interests, Institutional, Ownership Interest: Fortrea Inc.; Financial Interests, Institutional, Stocks/Shares: Fortrea Inc. R. Berardi: Financial Interests, Institutional, Advisory Role: AstraZeneca, Boehringer Ingelheim, Novartis, Merck, Otsuka, Eli Lilly, Roche. All other authors have declared no conflicts of interest.

Background

Immunotherapy (IO) alone or in combination with chemotherapy (CT-IO) has become the standard of care for most patients with metastatic Non-Small Cell Lung Cancer (NSCLC). Nevertheless, 20-30% of patients do not benefit from these treatments facing a negative risk-benefit balance and the identification of reliable predictive factors for a better patients’ selection is an important unmet need.

Methods

In this retrospective single-centre analysis, patients with metastatic NSCLC treated with first line (CT)-IO between 2015 and 2021 were eligible. Clinical, pathological and laboratory data were retrieved. Primary aim was to identify the features predicting early progression (radiological progression or death within 3 months from treatment start) by artificial intelligence (AI) models.

Results

201 patients were included: 121 IO (all PD-L1 ≥50%), 80 CT-IO (all PD-L1 <50%). 46% in IO group and 36% in CT-IO group were early progressors. Early progression correlated with poor performance status, elevated neutrophil percentage (>80%) and neutrophil/lymphocyte ratio (≥8), lower-range PD-L1 status (50%-75%, in IO only), use of steroids (in IO only), bone and liver metastases (in CT-IO) by a statistical exploratory data analysis. In IO only population, black-box models (Automated Machine Learning, AutoML) encompassing clinical, laboratory and pathological data reached an AUC of 0.82 in predicting early progression (best model: Voting Ensemble). White box tools (SHapley Additive exPlanations) paired with AutoML generated models increased the interpretability of the results despite slightly lower precision scores. Dimensionality reduction algorithms such as t-SNE (t-distributed stochastic neighbor embedding) and SVM (Support Vector Machine) were applied on our dataset to rebalance sample size with feature list, obtaining a reliable pattern of cases distribution.

Conclusions

Artificial intelligence models can predict trustworthy patterns of early progression in IO-treated patients. Pairing black box and white box methods is feasible and could increase robustness and interpretability of the results.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F.R. Ogliari: Financial Interests, Personal, Invited Speaker: Roche, Sanofi. A. Traverso: Financial Interests, Personal, Advisory Board: IQVIA, Illumina, Varian. V. Gregorc: Financial Interests, Personal, Advisory Board: Eli Lilly SPA; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Sanofi, BMS, MSD; Financial Interests, Personal, Expert Testimony: Novartis, Eli Lilly, BMS, MSD. L. Hendriks: Financial Interests, Institutional, Advisory Board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, Merck, Janssen, MSD, Anheart; Financial Interests, Institutional, Invited Speaker, for educational webinar: AstraZeneca, Lilly; Financial Interests, Institutional, Invited Speaker, educational webinar/interview: Bayer; Financial Interests, Institutional, Invited Speaker, educationals:MSD; Financial Interests, Personal, Invited Speaker, for webinars: Medtalks; Financial Interests, Personal, Invited Speaker, payment for post ASCO round table discussion: VJOncology; Financial Interests, Personal, Invited Speaker, payment for post ASCO/ESMO/WCLC presentations, educational committee member: benecke; Financial Interests, Institutional, Invited Speaker, payment for post ESMO/ASCO discussion: high5oncology; Financial Interests, Institutional, Other, podcast on brain metastases: Takeda; Financial Interests, Institutional, Other, educational webinar: Janssen; Financial Interests, Institutional, Invited Speaker, satellite symposium at conference: GSK, sanofi; Financial Interests, Personal, Invited Speaker, presentation guideline: medimix; Financial Interests, Institutional, Invited Speaker, podcast and educational: Pfizer; Financial Interests, Personal, Other, member of the committee that revised these guidelines: Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases; Financial Interests, Institutional, Research Grant, for IIS: Roche, Boehringer Ingelheim, AstraZeneca, Takeda, Novartis; Financial Interests, Institutional, Research Grant, donation for health care improvement project: Merck; Financial Interests, Institutional, Research Grant, funding for healthcare improvement project: Pfizer; Financial Interests, Institutional, Research Grant, for IIS, under negotiation: gilead; Financial Interests, Institutional, Invited Speaker: AstraZeneca, GSK, Novartis, Merck Serono, Roche, Takeda, Blueprint Medicines, Mirati, AbbVie, MSD, Gilead; Non-Financial Interests, Personal, Other, Chair metastatic NSCLC for lung cancer group: EORTC; Non-Financial Interests, Personal, Other, secretary NVALT studies foundation: NVALT; Non-Financial Interests, Personal, Other, vice chair scientific committee: Dutch Thoracic Group. A. Bulotta: Financial Interests, Personal, Advisory Board: Roche, BMS, AstraZeneca; Financial Interests, Personal, Invited Speaker: BMS, MSD, AstraZeneca, Eli Lilly. R. Ferrara: Financial Interests, Personal, Advisory Board, In April 2022:MSD; Financial Interests, Personal, Advisory Board: BeiGene; Financial Interests, Institutional, Invited Speaker: MSD, Pfizer, AstraZeneca, Roche, Sanofi, Novartis, BMS, IPSEN, Daiichi Sankyo Company. All other authors have declared no conflicts of interest.