Background

In FLAURA2 (NCT04035486), osi, a 3rd gen CNS-active EGFR-TKI, combined with platinum-pemetrexed (osi-CTx) showed a statistically significant improvement vs osi-monotherapy (osi-mono) in PFS per investigator (HR 0.62 [95% CI 0.49–0.79], p<0.001) with a manageable and tolerable safety profile. Addition of CTx did not affect osi exposure. 76% of pts completed 4 CTx cycles; median duration of pemetrexed exposure was 8.3 mos. 40% of FLAURA2 pts had baseline CNS metastases (mets); we report exploratory analyses of CNS efficacy by CNS blinded independent central review (BICR; conducted by neuroradiologist). Updated safety data will be reported.

Methods

Eligible pts (≥18 y [Japan: ≥20] with EGFRm advanced NSCLC, no prior tx for advanced NSCLC; asymptomatic CNS mets not requiring steroids or stable >2 wks after definitive tx/steroids allowed) were randomised 1:1 to 1L osi-CTx or osi-mono until progression/discontinuation. Brain imaging (MRI preferred) was performed in all pts at baseline + progression, and at scheduled assessments until progression for pts with baseline CNS mets. CNS endpoints (modified RECIST 1.1) included CNS PFS, CNS response and CNS DoR by CNS BICR. Safety was assessed by CTCAE v5. Data cutoff: 3 Apr 2023.

Results

Of 557 pts randomised, 118/279 (osi-CTx) and 104/278 (osi-mono) were included in the CNS BICR full analysis set (cFAS; pts with ≥1 measurable and/or non-measurable lesion); 40/118 (osi-CTx) and 38/104 (osi-mono) were included in the CNS evaluable for response set (cEFR; pts with ≥1 measurable lesion). Demographics were balanced across tx arms. CNS efficacy is shown (table). Safety profile was similar in the cFAS and overall population. The safety and tolerability profile during the course of tx will be described.

Conclusions

In FLAURA2, pts with CNS mets in the osi-CTx arm had a clinically meaningful reduction in the risk of CNS progression, with high CNS ORR (and high CR) and durable responses, with a manageable and tolerable safety profile. Table: 512MO

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 in accordance with Good Publications Practice (GPP) guidelines (https://www.ismpp.org/gpp-2022).

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, AbbVie, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen; Non-Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, AbbVie, Janssen, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Mirati Therapeutics, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly and Company, Ignyta, Takeda Oncology, Novartis, Voronoi, SFJ Pharmaceuticals, Biocartis, LOXO Oncology, PUMA, Sanofi, Transcenta, Daiichi Sa; Financial Interests, Personal, Other, Dr. Jänne is a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Takeda Oncology, PUMA, Astellas Pharmaceuticals, Daiichi Sankyo ; Financial Interests, Personal, Royalties, Post marketing royalties from DFCI owned intellectual property on EGFR mutations licensed to Lab Corp: Lab Corp. C.K. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Takeda, Pfizer, Novartis, GSK, Merck KGA, Roche, Janssen, and MSD; Financial Interests, Personal, Research Grant: AstraZeneca, Amgen, Roche, Merck KGaA. K. Laktionov: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad, Pfizer; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Other: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad. T. Kato: Financial Interests, Personal, Full or part-time Employment: Lilly (family member); Financial Interests, Institutional, Funding: AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Chugai Pharma, Daiichi Sankyo, Haihe Biopharma, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Takeda, Turning Point Therapeutics; Financial Interests, Personal, Advisory Role: AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer; Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, GSK, Janssen, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Takeda, Taiho Pharmaceutical. L. Jiang: Non-Financial Interests, Personal, Local PI: Shanghai Chest Hospital, Shanghai Jiao Tong University, PR China. B. Chewaskulyong: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Honoraria: AstraZeneca. S. Lucien Geater: Financial Interests, Personal, Advisory Board: Pfizer, MSD; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Roche, Novartis, MSD; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim. F.A. Shepherd: Financial Interests, Personal, Invited Speaker, Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Lilly; Financial Interests, Institutional, Funding: AstraZeneca/MedImmune, Squibbb, Lilly, Roche Canada, Pfizer; Financial Interests, Personal, Advisory Role, Honoraria: AstraZeneca. K. Tanaka: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, BMS, MSD, Merck; Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca. D. Ghiorghiu, E. Armenteros Monterroso, X. Huang: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J.C. Yang: Financial Interests, Personal, Other, Personal fees: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb; Financial Interests, Personal, Research Grant: AstraZeneca, Roche/Genentech; Financial Interests, Personal, Other: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, MSD, Novartis, Ono Pharmaceuticals, Pfizer, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, Janssen Pharmaceuticals, Puma Technology, Gi. All other authors have declared no conflicts of interest.

Background

Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell–directing activity. In the global, phase 3 PAPILLON study (NCT04538664), ami and carboplatin-pemetrexed (ami-chemo) significantly improved progression-free survival (PFS) vs chemo (data submitted to ESMO 2023) in treatment naïve patients (pts) with Ex20ins advanced NSCLC. The incidence of EGFR mutations is higher among Asian pts than other races. Thus, we evaluated ami-chemo vs chemo in Asian pts by race from PAPILLON.

Methods

Pts were randomized 1:1 to ami-chemo or chemo. The primary endpoint was PFS by blinded independent central review. Secondary endpoints included objective response rate (ORR), PFS after first subsequent therapy (PFS2), overall survival (OS), and safety. Crossover to ami monotherapy was allowed for pts in the chemo arm who progressed.

Results

186/308 randomized pts were Asian (ami-chemo, 97; chemo, 89); median age was 57/62 years, 56%/58% female, and 21%/25% had a history of brain metastases for ami-chemo/chemo, respectively. At a median follow up of 16.6 months, the median PFS for Asian pts was 11.5 months (95% CI, 9.8–13.7) for ami-chemo vs 5.6 months (95% CI, 4.9–7.0) for chemo (HR, 0.34; 95% CI, 0.23–0.49; P<0.001); this was comparable to the overall population. The 18-month PFS rate was 31% for ami-chemo vs 3% for chemo. ORR was 70% (95% CI, 60–79) for ami-chemo vs 51% (95% CI, 40–62) for chemo (odds ratio, 2.16; 95% CI, 1.19–3.93; P=0.012). Median PFS2 was not estimable for ami-chemo vs 18.8 months for chemo (HR, 0.46; 95% CI, 0.26–0.83; P=0.008). Median interim OS was not estimable vs 24.4 months for ami-chemo vs chemo (HR, 0.65; 95% CI, 0.34–1.24; P=0.189) despite crossover among chemo-randomized pts who had progressed. AE rates in Asian pts were similar to the overall PAPILLON population. Most common ami-chemo TEAEs (>50%) were paronychia, neutropenia, rash, anemia, and leukopenia; no new safey signals. Discontinuation of ami due to treatment-related AEs was 8%.

Conclusions

Ami-chemo demonstrated superior PFS vs chemo in Asian pts with a tolerable safety profile. These results were consistent with those of the overall population.

Clinical trial identification

NCT04538664.

Editorial acknowledgement

Claire E. Brady of Lumanity Communications Inc.

Legal entity responsible for the study

Janssen Pharmaceuticals.

Funding

Janssen Pharmaceuticals.

Disclosure

C. Zhou: Financial Interests, Personal, Invited Speaker, Honoraria: Eli Lily, 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. Kitazono: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Ono Pharmaceutical Co, Chugai Pharmaceutical Co., Ltd. A. Ono: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Local PI: Janssen Research&Development. M. Thiagarajan: Non-Financial Interests, Personal, Leadership Role, President: Malaysian Oncological Society. J. Hung: Financial Interests, Personal, Financially compensated role: AstraZeneca, Roche, Ono Pharma, Eli Lilly, Takeda, BI, Pfizer, Chugai, Novartis, Janssen. M. Boyer: Financial Interests, Personal, Research Funding: Janssen, Amgen, AstraZeneca, Pfizer, Roche/Genentech, Merck Sharpe and Dohme, Eli Lilly, Imugene, Daiichi Sankyo, Dizal. J. Xie, A. Bhattacharya, M. Baig, T. Agrawal, R.E. Knoblauch: Financial Interests, Personal, Full or part-time Employment: Janssen. 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, Janssen; Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc, Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc; Financial Interests, Personal, Other, Advisory role: Medpacto, Blueprint medicines, RandBio, Hanmi; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; 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; Financial Interests, Institutional, Research Grant: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, 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, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center; Other, Personal, Other, Founder: DAAN Biotherapeutics. All other authors have declared no conflicts of interest.

Background

Osimertinib (osi) is the preferred 1L treatment (tx) for patients (pts) with EGFRm advanced NSCLC; however, most pts will develop progressive disease (PD) due to tx resistance. The phase III, open-label, randomised FLAURA2 (NCT04035486) study demonstrated a significant PFS benefit with 1L osi + CT vs osi monotherapy in EGFRm advanced NSCLC. A safety run-in (SRI) assessed safety of the combination prior to the randomised phase. We report preliminary results for the pre-specified, exploratory analysis of acquired mechanisms of resistance to osi ± CT in pts.

Methods

Pts with treatment-naïve, EGFRm advanced NSCLC received osi + CT (osi 80 mg once daily [QD] + pemetrexed 500 mg/m² + cisplatin 75 mg/m² or carboplatin AUC5 every 3 weeks [Q3W] for 4 cycles, followed by osi 80 mg QD + pemetrexed 500 mg/m² Q3W) or osi monotherapy (80 mg QD) until PD/discontinuation criterion. Plasma ctDNA samples collected at baseline and PD up to 15 Dec 2022 were analysed using next-generation sequencing (Guardant Health, GuardantOMNI™).

Results

138 matched baseline and PD plasma samples were evaluable for analysis (10 from the SRI [osi + CT] and 128 from the randomised part [osi + CT, n=51; osi, n=77]). Of these, 126 had EGFRm ctDNA detected at baseline (osi + CT, n=53; osi, n=73). Resistance mechanisms were broadly similar across tx arms, although numerically fewer pts with acquired EGFR C797S and MET amplification were detected in the osi + CT arm than the osi monotherapy arm (Table). No novel resistance mechanisms were detected specifically in pts on the osi + CT arm.

Conclusions

Acquired resistance mechanisms to 1L osi monotherapy were consistent with previous data (Chmielecki Nat Commun. 2023). Osi + CT resulted in similar resistance mechanisms to osi monotherapy, and should not impact subsequent targeted second-line tx options. This analysis was enriched with pts who had early progression; further follow-up is required. Table: 514MO

Clinical trial identification

FLAURA2, NCT04035486.

Editorial acknowledgement

The authors would like to acknowledge Donna Tillotson of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice (GPP) guidelines (https://www.ismpp.org/gpp-2022).

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

C.K. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Takeda, Pfizer, Novartis, GSK, Merck KGA, Roche, Janssen, and MSD; Financial Interests, Personal, Research Grant: AstraZeneca, Amgen, Roche, Merck KGA. J.P. Robichaux: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Licencing Fees or royalty for IP, Inventor on patents held by UT MD Anderson Cancer Center licenced to SP for treatment of EGFR/HER2 exon 20 mutant cancers: UT MD Anderson Cancer Center and Spectrum Pharmaceuticals; Financial Interests, Personal, Other, Inventor on patent held by UT MDACC regarding EGFR mutation subtypes and methods of treatment (no monetary exchange): UT MD Anderson Cancer Center; Financial Interests, Personal, Stocks/Shares: AstraZeneca. 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, Trasncenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, 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. S. Kim: Non-Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Norvasc, Takeda, Terrapex, Yuhan; Non-Financial Interests, Personal, Funding: Yuhan; Non-Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim. T.M. Kim: Non-Financial Interests, Personal, Advisory Board: Boryung, Janssen, Novartis, Takeda, Regeneron; Financial Interests, Personal, Advisory Role: AstraZeneca, Boryung, Hanmi, IMBDx, Janssen, Novartis, Takeda, Sanofi, Regeneron, Roche/Genentech, Samsung Bioepis; Non-Financial Interests, Personal, Coordinating PI: Regeneron; Financial Interests, Personal, Local PI: ABBVIE, AstraZeneca, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, F. Hoffmann-La Roche Ltd/Genentech, Inc, Hanmi, Janssen, Novartis, Regeneron, Sanofi, Takeda, and Yuhan. K. Kobayashi: Financial Interests, Personal, Financially compensated role, Board Chairman: NPO North East Japan Study Group; Financial Interests, Personal, Speaker’s Bureau, Speaker Fees: AstraZeneca, Takeda Pharmaceutical Co., Daiichi Sanko Pharmaceutical Co., Boehringer Ingelheim. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, AbbVie, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Merck, Novartis, Janssen, Pfizer, Roche, Pierre Fabre, Takeda, ArriVent, Mirati, Seagen; Non-Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, AbbVie, Janssen, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre Fabre, Takeda, ArriVent, Mirati, Seagen. S. Sugawara: Financial Interests, Institutional, Local PI: AnHeart, AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, MSD K.K, Nippon Boehringer Ingelheim, Ono Pharmaceutical; 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 PHA. N. Yanagitani: Financial Interests, Personal, Advisory Board: Pfizer Inc.; Financial Interests, Personal, Speaker, Consultant, Advisor, Lecture Fees: Taiho, MSD, Ono, Bristol Myers Squibb, Novartis, Pfizer Inc.,Chugai co., Eli Lilly and Company, Boehringer Ingelheim, Bayer AG. A. Markovets, Y. Rukazenkov: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. P. Bhetaryia: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. L. Poole: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Lilly, Takeda. R.J. Hartmaier: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Other, Personal, Other: Inventor on patent: US11066709B2 (no fees or royalties); Financial Interests, Personal, Stocks/Shares: AstraZeneca. J.C. Yang: Financial Interests, Institutional, Advisory Board, My institute received fee for my role as advisory board: AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Takeda, Yuhan Pharmaceuticals, Janssen, Puma Technology, Gilead, GSK, Dizal Pharmaceutica; Financial Interests, Personal, Coordinating PI: AstraZeneca, MSD, Dizal Pharmaceutical; Non-Financial Interests, Personal, Member: ASCO, ESMO, IASLC; Financial Interests, Personal, Research Funding: AstraZeneca, Roche; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Takeda, Yuhan Pharmaceuticals, Janssen, Dizal Pharmaceutical. All other authors have declared no conflicts of interest.

Background

Befotertinib (D-0316), a novel third-generation EGFR-TKI, showed a favorable progression-free survival (PFS) benefit and manageable in pretreated patients (pts) with EGFR T790M-positive NSCLC.

Methods

Adult pts received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily until disease progression or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee; secondary endpoints included investigator-assessed ORR, disease control rate (DCR), PFS, duration of response (DOR), intracranial PFS (iPFS), iORR, OS and safety. Herein, we present the investigator-assessed final OS, PFS, ORR, iORR, iPFS and safety data.

Results

At data cutoff (May 31, 2023), 133 (76%) deaths occurred in cohort A while 161 (56%) death in cohort B. The median duration of follow-up for OS was 47.9 months (95% CI: 47.1–48.3) in cohort A and 36.7 months (35.9–37.9) in cohort B. The median OS was 23.9 months (95% CI: 21.1–27.2) in cohort A and 31.5 months (26.8–35.3) in cohort B. The ORR was 54.5% (95% CI 46.9%–62.1%) in the cohort A and 66.2% (95% CI 60.4%–71.6%) in the cohort B. The median PFS was 11.0 months (95% CI 9.6–12.5) in the cohort A and 12.5 months (11.1–14.0) in the cohort B. The median DOR was 12.5 months and 13.6 months, DCR was 93.2% and 94.8%, iPFS was 16.5 (95% CI 8.6–NE) and 34.5 months (13.8–NE), iORR was 26.7% and 57.1% for cohort A and cohort B, respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1% in the cohort A and 50.3% in the cohort B, in which 22.2% and 31.7% were related to the study drug.

Conclusions

Befotertinib exhibited notable efficacy in both dose cohorts, showing a comparable OS benefit with other 3^rd-generation EGFR TKIs in cohort A (50 mg), while even greater OS benefits in cohort B. Further, safety remained manageable and consistent with prior assessments. Overall, befotertinib maintained its remarkable efficacy with a manageable safety profile in pretreated pts with confirmed T790M mutation-positive NSCLC.

Clinical trial identification

NCT03861156.

Legal entity responsible for the study

Betta Pharmaceuticals Co., Ltd.

Funding

Betta Pharmaceuticals Co., Ltd.

Disclosure

S. Lu: Financial Interests, Institutional, Invited Speaker: Hansoh, AstraZeneca, Roche, Hengrui; Financial Interests, Institutional, Advisory Board: AstraZeneca, Prizer, Boehringer Ingelheim, 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, Coordinating PI: FibroGen. All other authors have declared no conflicts of interest.

Background

Clinical evidence supports c-Met as a target in pts with advanced EGFR-mut NSCLC after progression on osimertinib (O; third-generation EGFR-TKI). Here we report the final results of the Teliso-V (T; first-in-class c-Met–targeting ADC) + O combination arm of the phase 1b study (NCT02099058) in pts with advanced/metastatic EGFR-mut, c-Met OE NSCLC with progression on prior O.

Methods

Pts (≥18 yr) with advanced/metastatic EGFR-mut, c-Met OE (centrally assessed by IHC [Clinical Trial Assay]: 3+ in ≥25% tumor cells) NSCLC with progression on O received T (IV Q2W 1.6 or 1.9 mg/kg) + O (oral 80 mg QD). Pts in expansion phases had ≤2 prior lines (L) of therapy, including O.

Results

As of March 23, 2023, 41 pts were enrolled. Data for 38 pts with sufficient follow-up are shown (T [1.6 mg/kg, n=20; 1.9 mg/kg, n=18] + O); median age was 60 yr; 40/42/18% of pts received 1/2/>2 prior L for metastatic NSCLC, including platinum-based therapy in 47%. Median number of T cycles (28 d/cycle) was 6 (range, 1–30). No DLTs were observed in safety evaluation cohorts. AEs possibly related to T occurred in 37 (97%; any grade [G]) pts; most common (≥20%) were peripheral sensory neuropathy (50%), peripheral edema (21%), and nausea (21%). Of these, G ≥3 were reported in 12 (32%) pts; most common (≥5%) were anemia (11%), and peripheral motor and sensory neuropathy (5% each). AEs leading to T discontinuation/interruption/reduction occurred in 24/58/37% of pts. No deaths related to T or O were reported. Overall T + O efficacy is shown in the table. Table: 515MO

Conclusions

T + O showed tolerable safety and encouraging efficacy in pts with EGFR-mut, c-Met OE NSCLC with progression on O, regardless of MET amplification status or number of prior L, with an ORR of 53/50% and DCR of 71/76% as per investigators/ICR. T + O may be a potential option for these pts and warrants further clinical investigation.

Clinical trial identification

NCT02099058.

Editorial acknowledgement

Medical writing support was provided by Iratxe Abarrategui, PhD, CMPP, of Aptitude Health, the Netherlands, and funded by AbbVie.

Legal entity responsible for the study

AbbVie Inc.

Funding

AbbVie.

Disclosure

H. Horinouchi: Financial Interests, Institutional, Research Funding: AbbVie, MSD, Chugai/Roche, Daiichi Sankyo, Janssen, Genomic Health; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, MSD, Lilly, BMS, Ono, Janssen, Kyowa Kirin, Nihonkayaku. B.C. Cho: Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen; Financial Interests, Institutional, Research Funding: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp., GI Innovation, GI Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Ja; Financial Interests, Personal, Advisory 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, Janssen, MedPa; Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal, Advisory Board: KANAPH Therapeutics Inc, BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc; Financial Interests, Personal, Speaker’s Bureau: ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer; Financial Interests, Personal, Stocks/Shares: TherCanVac Inc, Gencurix Inc, Bridgebio Therapeutics, KANAPH Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence Corp., J INTS Bio; founder of DAAN Biotherapeutics; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS Bio. D.R. Camidge: Financial Interests, Personal, Advisory Role: AbbVie, Apollomics, AstraZeneca, Daiichi Sankyo, Elevation, Kestrel, Nuvalent, Seattle Genetics, Takeda, Turning Point, Amgen, Anchiano, Bio-Thera, BMS, Eisai, EMD Serono, Eli Lilly, GSK, Helsinn, Janssen, OnKure, Mersana, Pfizer, Qilu, Roche, Sanofi, CBT; Financial Interests, Personal, Research Funding: Inivata; Financial Interests, Institutional, Research Funding: AbbVie, AstraZeneca, Dizal, Inhibrx, Karyopharm, Pfizer, Phosplatin, PsiOxus, Rain, Roche/Genentech, Seattle Genetics, Takeda, Turning Point. P. Tomasini: Financial Interests, Institutional, Research Funding: Roche, Janssen; Financial Interests, Personal, Expert Testimony: AstraZeneca, Roche, BMS, AbbVie, Johnson & Johnson, Takeda. Y. Li, A. Vasilopoulos, P. Brunsdon, D. Hoffman, W. Shi, V. Blot: Financial Interests, Personal, Full or part-time Employment: AbbVie ; Financial Interests, Personal, Stocks/Shares: AbbVie. J.W. Goldman: Financial Interests, Institutional, Research Funding: AbbVie, AstraZeneca; Financial Interests, Personal, Speaker, Consultant, Advisor: AbbVie, AstraZeneca. All other authors have declared no conflicts of interest.

Background

Epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET) are dysregulated in many tumors, including NSCLC. Osimertinib is a third generation EGFR tyrosine kinase inhibitor approved as first-line (1L) therapy for EGFRmut NSCLC. MCLA-129 is a bispecific antibody targeting EGFR and c-MET with enhanced antibody-dependent cellular cytotoxicity. In a phase 1/2 trial (NCT04868877), MCLA-129 combined with osimertinib is explored in NSCLC, either as 1L therapy or after progression on osimertinib (2L+).

Methods

Patients (pts) with advanced/metastatic EGFRmut NSCLC who were treatment-naïve or progressed on osimertinib were included. Pts received MCLA-129 1500 mg IV Q2W with 28 day cycles and osimertinib 80 mg QD PO, until disease progression or unacceptable toxicity. Tumor imaging was conducted Q8W. Primary endpoint: investigator-assessed ORR (RECIST 1.1), in pts with measurable disease, ≥2 MCLA-129 cycles and ≥1 post-baseline scan. Secondary endpoints: DCR and safety. Biomarker analyses of EGFR/c-MET expression and ctDNA mutation status are planned.

Results

As of 10 May 2023, 48 pts were treated (14/1L, 34/2L+). Median age was 56 y (range 40-80) and 61 y (35-81) respectively. All 2L+ pts received osimertinib in 1L/2L, 71% as the most recent therapy; 24% had prior chemotherapy. Median exposure duration was 10 wks (range 2-26) and 10 wks (range 2-38), with 13 (93%) and 23 pts (68%) continuing treatment at data cutoff for 1L and 2L+ respectively. In 1L, 8/10 evaluable pts had partial response (PR) (80%; 95% CI 44-98), 2 confirmed; all were ongoing. DCR was 90% (95% CI 56-100). In 2L+, 11/22 evaluable pts had PR (50%; 95% CI 28-72), 6 confirmed. 9/11 PRs were ongoing. DCR was 82% (95% CI 60-95). In 48 pts treated, the most common AEs regardless of causality were IRRs (composite term) in 85% of pts (6% ≥G3). Skin toxicity was common (75%; 4% G3). 5 pts (10%) had treatment-related interstitial lung disease (ILD)/pneumonitis (2 G2, 2 G3, 1 G5), 1 progressed to G5 after data cutoff.

Conclusions

MCLA-129 plus osimertinib showed promising clinical efficacy in EGFRmut NSCLC, in 1L and 2L+. IRRs and ILD/pneumonitis were observed.

Clinical trial identification

Protocol number: MCLA-129-CL01, release date: 27-Jan-2021; NCT04868877, EudraCT 2021-000203-20.

Editorial acknowledgement

Medical writing was provided by Lama Yamani of Veristat.

Legal entity responsible for the study

Merus N.V.

Funding

Merus N.V.

Disclosure

F. Cappuzzo: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Pharmamar, Mirati, Novocure, OSE, and MSD; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Mirati, Pharmamar, Novocure, OSE, GALECTO and MSD. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daiichi Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.: Multiple. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer, Roche; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology, AnHeart Therapeutics; Financial Interests, Personal, Ownership Interest: MBrace Therapeutics, BlossomHill Therapeutics; Financial Interests, Institutional, Local PI: Pfizer, Mirati, JNJ/jassen, Merus, Revolution Medicine, Nuvalent. M. Brandão: Financial Interests, Personal, Invited Speaker, Speaker at a symposium at the AORTIC Conference 2019: Roche; Financial Interests, Institutional, Invited Speaker, December 2021: Janssen; Financial Interests, Institutional, Advisory Board, 03/2023: Sanofi; Financial Interests, Institutional, Invited Speaker, 01/2023: Takeda; Financial Interests, Institutional, Invited Speaker, 05/2023: Pfizer; Financial Interests, Institutional, Local PI: AstraZeneca, Roche, Boehringer, Sanofi; Non-Financial Interests, Personal, Leadership Role, EORTC Lung Cancer Group - Young and Early Career group Chair (since January 2022): EORTC. M.F. Sanmamed: Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Speaker, Consultant, Advisor: Pieris, Numab, MSD. C. Helissey: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Astellas, MSD, Ipsen, Viatris, AstraZeneca, Bayer. S. Grisanti: Financial Interests, Personal, Advisory Board: Roche, Takeda, Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol-Myers; Financial Interests, Institutional, Funding: Roche, 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, Pyramid Biosciences, Molecular Axiom, Novartis, Oncorus, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics; Financial Interests, Institutional, Research Grant: Acerta, AbbVie, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, Boehringer Ingelheim, BerGenBio, BioAtla, Black Diamond, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Curis, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, EMD Serono, Dynavax, Lilly, Elicio Therapeutics, 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, Kartos Therapeutics, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Rain Therapeutics, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rubius Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Tempest Therapeutics, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tizona Therapeutics, Vyriad, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, WindMIL Therapeutics, Y-mAbs Therapeutics. V. Boni: Financial Interests, Personal, Speaker, Consultant, Advisor: Oncoart, Guidepoint, Eli Lilly, MSD, SOLTI, TACTICS, Getthi, Gedefo; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Bayer; Financial Interests, Personal, Advisory Board: Puma Biotechnology, Ideaya Biosciences, Loxo Therapeutics, CytomX Therapeutics, Janssen, Nanobiotix /Novartis. P. Jamme: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Pierre Fabre; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Pierre Fabre. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, BMS, Checkmab, Daiichi Sankyo, GSK, Novartis, Seagen, T-One-Therapeutics. C. Yan, B. Barasa, B. Richard, A.K. Joe, G. Laus: Financial Interests, Personal, Full or part-time Employment: Merus N.V. 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, Local PI, 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 Scientiffic Advisory Committee: CAC Hospital Universitari Parc Taulí. All other authors have declared no conflicts of interest.

Background

Selpercatinib, a highly selective and potent CNS penetrant RET inhibitor has been approved for treatment of advanced RET fusion+ non-small-cell lung cancer (NSCLC). LIBRETTO-431 (NCT04194944), is a randomized, phase 3 trial comparing first-line selpercatinib to platinum-based chemotherapy +/- pembrolizumab (pembro). This analysis describes the patient-reported outcomes (PROs) from LIBRETTO-431.

Methods

PRO data (data cut-off: 01 May 2023) were evaluated for the intent-to-treat (ITT) population and the subgroup of patients that received pembro (ITT-pembro). Time to confirmed deterioration (TTCD) of pulmonary symptoms (using NSCLC-Symptom Assessment Questionnaire [SAQ]) and physical function (using EORTC QLQ-C30 Physical Function scale [QLQ-C30 PF]) was time from randomization to the first ≥2 point increase of NSCLC-SAQ total score or ≥5 point decrease in QLQ-C30 PF, confirmed at next assessment. TTCD was compared between treatment groups using log rank test and Cox proportional hazards model. Symptomatic adverse events (using PRO version of the CTCAE item library) were reported descriptively as baseline-adjusted worst score. PROs were also analyzed for East Asia vs. non-East Asia subgroups.

Results

In ITT-pembro (selpercatinib n=129 and control n=83), selpercatinib delayed TTCD of pulmonary symptoms (hazard ratio [HR]=0.34, 95% CI: 0.20-0.55) and physical function (HR=0.54, 95% CI: 0.39-0.75). Patients in the selpercatinib arm reported worse PRO-CTCAE scores of dry mouth, diarrhea, and arm/leg swelling, whereas those in the control arm reported worse scores of nausea, fatigue, and decreased appetite. Results were consistent in the ITT population. PROs were similar between East Asia and non-East Asia subgroups.

Conclusions

PRO data were consistent with the favorable efficacy of selpercatinib compared with platinum-based chemotherapy +/- pembro. Selpercatinib significantly delayed TTCD of pulmonary symptoms and physical function and was well-tolerated in these patient populations.

Clinical trial identification

NCT04194944.

Editorial acknowledgement

Keerthana Muthiah, Eli Lilly and Company.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

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., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Novartis Pharma K.K., 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., Medpace Japan K.K., Haihe Biopharma Co., Ltd.; 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., Merck Biopharma Co., Ltd., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical&Biological Laboratoires 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., Craif Inc., Life Technologies Japan Ltd., NEC Corporation., Novartis Pharma K.K., 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. S. Novello: Financial Interests, Personal, Invited Speaker: AZ, MSD, Eli Lilly, Novartis, BeiGene, Amgen; Financial Interests, Personal, Advisory Board: BI, BMS, Pfizer, Takeda, Roche, Sanofi, Amgen; Financial Interests, Institutional, Coordinating PI, IIT: MSD, BI; Non-Financial Interests, Personal, Leadership Role, president of this european advocacy: WALCE. P. Garrido Lopez: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BMS, GSK, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Sanofi, 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, Steering Committee Member, CACZ885V2201C_CANOPY-N trial: Novartis; Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen; Financial Interests, Institutional, Local PI: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma; Financial Interests, Personal, Steering Committee Member, IO102-012/KN-764 trial: IO Biotech; Financial Interests, Personal, Steering Committee Member, JNJ-61186372 (JNJ-372) Clinical Development Program: Janssen; Non-Financial Interests, Personal, Leadership Role, Council member as Women for Oncology Committee ChairFellowship 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; 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. J.A. Alatorre Alexander: Financial Interests, Personal, Funding, Payments Done to Health Pharma Professional Reseach: Eli Lilly and Company; Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting fees: BMS; Financial Interests, Personal, Other, Support for attending meetings and/or travel: MSD, AstraZeneca, Roche; Financial Interests, Personal, Advisory Board: BMS, MSD, AstraZeneca, TAKEDA, Roche, Amgen, Janssen, ASO PHARMA. N. Reinmuth: Financial Interests, Personal, Invited Speaker, including Ad-Boards: AstraZeneca; Financial Interests, Personal, Invited Speaker: Amgen, Lilly, Pfizer, Takeda, Merck, Hoffmann-La Roche, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, including Advisory Boards: Bristol Myers Squibb, Boehringer Ingelheim, MSD; Financial Interests, Institutional, Invited Speaker: Sanofi. A. Gilligan: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. N. Payakachat: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. C. Zhou: Financial Interests, Personal, Invited Speaker, Honoraria: Eli Lily, 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. All other authors have declared no conflicts of interest.

Background

Once targeted therapies and platinum-based chemotherapy (PBC) become ineffective in patients (pts) with advanced/metastatic (a/m) NSCLC with AGAs, few treatments with limited benefit are available. Dato-DXd is an antibody-drug conjugate composed of a TROP2 directed monoclonal antibody covalently linked to a highly potent cytotoxic payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. We report primary results from the global, open-label, phase 2 TROPION-Lung05 trial (NCT04484142) evaluating Dato-DXd in pts with a/m NSCLC with AGAs progressing on or after ≥1 AGA-specific therapy and PBC.

Methods

Dato-DXd 6 mg/kg was given every 21 days to pts with a/m NSCLC, ECOG status 0 or 1, and ≥1 documented AGA in EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET. The primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR) and disease control rate (DCR) by BICR, and safety.

Results

A total of 137 pts received ≥1 dose and had a median age of 61.0 y; 71.5% had ≥3 prior lines of therapy for a/m NSCLC; 56.9% had EGFR mutations. As of 14 Dec 2022, 85.4% discontinued therapy, 63.5% had disease progression, and 49.6% died. Median pt duration on study was 15.2 months (mo); cORR was 35.8%, DCR, 78.8%, and median DOR, 7.0 mo; similar response was seen in pts with EGFR mutations (Table). The most common grade ≥3 TEAEs were stomatitis (9.5%), anemia (5.8%), and increased amylase (5.8%). Table: 518MO

Primary results (N=137)

Conclusions

Dato-DXd showed encouraging antitumor activity, with a clinically meaningful and durable response, in heavily pretreated pts with NSCLC with AGAs. The safety profile was manageable and consistent with prior safety observed with Dato-DXd. These data support inclusion of pts with AGAs in the TROPION-Lung01 study (NCT04656652).

Clinical trial identification

NCT04484142.

Editorial acknowledgement

Daiichi Sankyo.

Legal entity responsible for the study

Daiichi Sankyo.

Funding

Daiichi Sankyo.

Disclosure

S. Kitazono: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Ono Pharmaceutical Co, Chugai Pharmaceutical CO., LTD. L. Paz-Ares: Financial Interests, Personal, Other, Consulting role: Lilly, MSD, Roche, Pharmamar, Merck KGaA (Darmstadt, Germany), AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, Daichii Sankyo; Financial Interests, Personal, Other, Payment for honoraria for lectures, presentations, speakers bureaus, educational events: AstraZeneca, Janssen, Merck, Mirati; Financial Interests, Personal, Other, Member of the board of directors: Altum sequencing, Stab Therapeutics. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Yuhan, Amgen, ALPHA Pharmaceutical, BMS, Roche, Daiichi Sankyo, Merck, Pfizer. A.E. Lisberg: Financial Interests, Personal, Other, Consulting, Lectures or Advisory Role at Bayer, Daiichi Sankyo, Inc., AstraZeneca, Novocure, Eli Lilly, Oncocyte, Novartis, Regeneron, Janssen Oncology, MorphoSys, Sanofi group of companies, Molecular Axiom, Amgen, IQVIA, G1 Therapeutics, Bristol-Myers Squibb, Leica Biosystems, Jazz Pharmaceuticals, Pfizer, Platformq, HMP Global, MJH Associates, Med Learning, Clinical Care Options, Physicians Educational Resources, Curio Sciences, Vaniam Group, Medscape, Projects in Knowledge, Aptitude Health, MOASC, SITC; Grant/Research Support from Daiichi Sankyo, Inc., Calithera, AstraZeneca, Dracen, WindMIL, Duality Biologics, Effector Therapeutics, LUNGevity and NIH/NCI; Funding for the current study by Daiichi Sankyo Inc. and AstraZeneca. 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, Janssen, Medpacto, Blueprint medicines, RandBio, Hanmi; Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc, Bridgebio Therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; 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; Financial Interests, Institutional, Research Grant: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, 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, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center; Other, Personal, Other, Founder: DAAN Biotherapeutics; Employment: Yonsei University Health System; Invited speaker: ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Onoclogy, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer. E. Shum: Financial Interests, Personal, Advisory Board: AstraZeneca, Genentech, Boehringer-Ingleheim, Janssen, Regeneron; Financial Interests, Institutional, Funding: Delfi Diagnostics. E. Pons-Tostivint: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, BMS, Sanofi; No Financial Interests, Institutional, Local PI: AstraZeneca, BMS, Daiichi Sankyo, Sanofi, PDC line, Takeda, Amgen. 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, Local PI: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Preferred Network; Financial Interests, Personal and Institutional, Coordinating PI: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Financial Interests, Institutional, Coordinating PI: Guardant Health; Non-Financial Interests, Personal, Member of Board of Directors: Cancer Net Japan, JAMT. K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi sankyo, Lilly, Boehringer Ingelheim, Amgen, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Lilly, Daiichi sankyo, AbbVie, Taiho, MSD, Takeda, Amgen, Boehringer Ingelheim, Chugai; Financial Interests, Personal, Steering Committee Member: AstraZeneca. R. Heist: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Novartis, EMD Serono, Lilly, AstraZeneca, Regeneron, Sanofi; Financial Interests, Personal, Writing Engagement: Chugai Roche; Financial Interests, Personal, Other, review of cancer histories: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board, consulting honoraria: AbbVie; Financial Interests, Personal, Other, Consulting: Claim Therapeutics; Financial Interests, Institutional, Local PI: Daiichi Sankyo, Novartis, AbbVie, Roche, Incyte, Mirati, Agios, Corvus, Turning Point, Lilly, Exelixis; Financial Interests, Institutional, Local PI, clinical trial funding to institution, not to self: Erasca, Mythic; Non-Financial Interests, Personal, Member: IASLC, ASCO, AACR. P. Baas: Financial Interests, Institutional, Advisory Board: BMS, MSD; Financial interests, Institutional, advisory role: AmHeart, AstraZeneca, Takeda; Financial Interests, Institutional, Research Grant: MSD, BMS. 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. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, TAKEDA, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, Esai, Ipsen; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, BMS, Boehringer Ingelheim, Takeda, Illumina, Pfizer, Medscape; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Roche; Financial Interests, Personal, Other, DMSB: Roche. 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, Local PI, 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 Scientiffic Advisory Committee: CAC Hospital Universitari Parc Taulí. H. Zebger-Gong: Financial Interests, Institutional, Full or part-time Employment, full-time employee: Daiichi Sankyo; Financial Interests, Institutional, Stocks/Shares, stock options as an employee: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares, stocks during previous period as a former employee: Bayer. J. Sands: Financial Interests, Personal, Speaker, Consultant, Advisor: Arcus, AstraZeneca, Curadev; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Daiichi Sankyo, Pharma Mar, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Local PI: AstraZeneca; Financial Interests, Personal and Institutional, local PI: Daiichi Sankyo, PharmaMar, Amgen, Boehringer Ingelheim; Non-financial interests, institutional, local PI: Phanes, Legend, Genentech. All other authors have declared no conflicts of interest.