Background

Investigational agent pelcitoclax is a dual BCL-2/BCL-xL inhibitor that enhances antitumor effects of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib in preclinical models. In pts with TKI-naïve EGFR-mutant NSCLC, pelcitoclax plus osimertinib was well tolerated and showed preliminary efficacy (Zhang L et al. J Clin Oncol 2022 ). Here, we provide updated safety and efficacy results of this combination therapy.

Methods

The recommended phase 2 dose of pelcitoclax was established at 160 mg weekly plus osimertinib 80 mg daily. After completion of dose escalation and 2 dose expansions, pts were divided into 3 cohorts by treatment line: Cohorts 1 and 2 (EC-1 and EC-2) included pts with disease resistant to first- and third-generation EGFR-TKIs, respectively; Cohort 3 (EC-3) included pts whose disease was previously untreated with EGFR-TKIs.

Results

As of February 16, 2023, 64 pts (median age, 56 years; 54% female) were treated with pelcitoclax plus osimertinib. Among them, 8 were in EC-1, 29 in EC-2, and 27 in EC-3. Among 26 efficacy-evaluable pts in EC-3, 20 partial responses (PRs [76.9%]) were observed. For pts with TP53 and EGFR-positive mutations in EC-3, 13/16 (81.3%) PRs were observed, and the median progression-free survival (range) was 16.39 (8.11-NR) months. Preliminary biomarker data from pts in EC-2 suggested that high BCL-xL expression was associated with antitumor efficacy. A total of 64 (100%) pts in all cohorts experienced treatment-related adverse events (TRAEs), which were grade ≥ 3 in 12 (18.8%). Common TRAEs included increased aspartate aminotransferase (70.4%) and alanine aminotransferase (59.3%), reduced platelet counts (33.3%), increased serum amylase (25.9%), and increased blood creatinine (22.2%).

Conclusions

Based on these findings, pelcitoclax plus osimertinib is of potential clinical interest to improve outcomes of pts with TP53- and EGFR-mutant NSCLC. Further studies are needed to elucidate the role of pelcitoclax when combined with osimertinib in treating this pt population. Internal study: APG1252NC101; CT.gov: NCT04001777.

Clinical trial identification

NCT04001777.

Editorial acknowledgement

Editorial support was provided by Ashutosh K. Pathak, MD, PhD, MBA, FRCP (Edin.), Stephen W. Gutkin, Ndiya Ogba, PhD, and Paul O. Fletcher, PhD, with funding from Ascentage Pharma Group Corp Ltd (Hong Kong).

Legal entity responsible for the study

Ascentage Pharma.

Funding

Ascentage Pharma Group Corp Ltd (Hong Kong).

Disclosure

L. Men: Financial Interests, Institutional, Full or part-time Employment: Ascentage Pharma; Financial Interests, Institutional, Stocks/Shares: Ascentage Pharma. E. Liang: Financial Interests, Institutional, Full or part-time Employment: Ascentage Pharma; Financial Interests, Institutional, Stocks/Shares: Ascentage Pharma. D. Yang: Financial Interests, Institutional, Leadership Role: Ascentage Pharma; Financial Interests, Institutional, Full or part-time Employment: Ascentage Pharma; Financial Interests, Institutional, Stocks or ownership: Ascentage Pharma. L. Zhang: Financial Interests, Institutional, Research Grant, research grant & Trial Chair: AZ; Financial Interests, Institutional, Research Grant: BMS, Roche; Financial Interests, Institutional, Trial Chair: QiLu Pharm, Henrui Pharm, Novartis, Hansoh Pharma, China Shiyao Pharma, Kelun Pharm. Y. Zhai: Financial Interests, Institutional, Leadership Role: Ascentage Pharma; Financial Interests, Institutional, Stocks or ownership: Ascentage Pharma; Financial Interests, Institutional, Full or part-time Employment: Ascentage Pharma. All other authors have declared no conflicts of interest.

Background

ABBV-637 is an antibody-drug conjugate consisting of an epidermal growth factor receptor (EGFR)–targeting antibody and BCL-X_Linhibitor. Preclinical data demonstrate potent antitumor activity of ABBV-637 plus OSI in mutant EGFR NSCLC through reactivation of the apoptotic pathway.

Methods

This phase 1 dose escalation and expansion study (NCT04721015) explored the safety and preliminary efficacy of ABBV-637 as second- (2L) and third-line (3L) combination therapy with OSI. Enrolled adults had relapsed/refractory (RR) NSCLC with EGFR mutation, ECOG 0–1, and prior response and subsequent disease progression on OSI. Enrolled patients being treated at 2L and 3L had no inclusion/exclusion criteria for specific targetable mutations. ABBV-637 (12 or 20 mg/kg) was dosed IV Q4W; OSI (80 mg) was given daily in 28-day cycles. Endpoints included the rates of treatment-emergent adverse events (TEAEs), objective response (ORR), disease control (DCR), and best overall response. Disease- and drug-related biomarkers were evaluated.

Results

Forty-two patients were treated; median age was 65 (range: 44–79), and 64% had ≥2 prior lines of therapy. Median duration of ABBV-637 treatment was 113 days (range: 28–288). Most common TEAEs were increases in aspartate (38%) and alanine aminotransferase (33%), nausea (33%), and fatigue (21%). The ORR was 14% in 3L cohorts and 10% in 2L (Table). DCR was 73% and 65% in 3L and 2L, respectively. In 2L, confirmed responders did not have targetable bypass alterations. Table: 1318MO

Conclusions

ABBV-637 plus OSI showed clinical activity and a manageable safety profile in patients with RR NSCLC. Biomarker data suggest that response to ABBV-637 plus OSI may be enriched by excluding patients with targetable bypass mechanisms; ongoing research is needed to confirm association of mutation and patient selection.

Clinical trial identification

NCT04721015.

Editorial acknowledgement

AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Medical writing support was provided by Vasileios Stamou, PhD, of Fishawack Facilitate Ltd, part of Fishawack Health, funded by AbbVie.

Legal entity responsible for the study

AbbVie Inc.

Funding

AbbVie.

Disclosure

J.K. Rotow: Financial Interests, Personal and Institutional, Advisory Board: AbbVie, AstraZeneca, BioAtla, Loxo, Lilly; Financial Interests, Personal and Institutional, Principal Investigator: AbbVie, AstraZeneca, BioAtla, Loxo, Lilly; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: G1 Therapeutics, Genentech, Guardant, Janssen, Sanofi, Summit, Takeda, Gritstone Oncology; Financial Interests, Institutional, Principal Investigator: Bicycle Therapeutics, Daiichi Sankyo, Blueprint, Enliven, EpimAb, ORIC, Redcloud. S.N. Waqar: Financial Interests, Institutional, Research Funding: SWOG-Clinical Trials Partnership; Financial Interests, Personal, Other, Honorarium: Hoosier Cancer Research Network; Financial Interests, Personal, Advisory Board: AstraZeneca ; Financial Interests, Institutional, Principal Investigator: AbbVie, Ariad Pharmaceuticals, Genentech, Immunomedics, Millennium Pharmaceuticals, Roche, Astellas Pharma, Daiichi Sankyo, Cullinan Pearl, Verastem Oncology, GSK/GSK, Janssen, Elevation Oncology, Genentech, Loxo Oncology, Takeda. K.P. Papadopoulos: Financial Interests, Personal, Advisory Board: Turning Point Therapeutics, Bicycle, Basilia; Financial Interests, Institutional, Full or part-time Employment: START; Financial Interests, Personal, Ownership Interest: START; Financial Interests, Institutional, Local PI, For conduct of clinical trial: 3D Medicines, AbbVie, ADC Therapeutics, Amgen, Anheart Therapeutics, Bayer, Daiichi Sankyo, EMD Serono, F-Star, Incyte, Jounce Therapeutics, Lilly, Linnaeus Therapeutics, Merck, Mersana, Mirati Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revolution Medicines, Syros Pharmaceuticals, Tempest Therapeutics, Treadwell Therapeutics. J. Hung: Financial Interests, Personal, Other, Speaker Honoraria: AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Eli Lilly and Company, Novartis, Ono Pharma, Chugai, Merck, Janssen Pharma, Takeda. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: Next Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med. H. Gan: Financial Interests, Personal, Advisory Board: Merck Serono, Telix Pharma, Curis. T. Yoshida: Financial Interests, Personal, Advisory Board: Pfizer, MSD, Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Pfizer, Takeda, Lilly, Ono Pharmaceutical, Novartis, Daiichi Sankyo, MSD, BMS; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis, Amgen, Daiichi Sankyo, BMS, MSD, Ono Pharmaceutical, BluePrint, Chugai Pharmaceutical, AbbVie. C.S. Kuo: Financial Interests, Personal, Other, Speaker Honoraria: AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Eli Lilly, Novartis, Ono Pharma, Chugai, Merck, Janssen Pharma, Takeda, Guardant Health; Financial Interests, Personal, Other, Consulting: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Chugai, Takeda, Novartis, Guardant Health. 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, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. 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. G. Morrison-Thiele: Financial Interests, Personal and Institutional, Full or part-time Employment: AbbVie; Financial Interests, Personal and Institutional, Stocks/Shares: AbbVie. R. Robinson: Financial Interests, Personal and Institutional, Full or part-time Employment: AbbVie; Financial Interests, Personal and Institutional, Stocks/Shares: AbbVie. N. Rudraganguly: Financial Interests, Personal and Institutional, Full or part-time Employment: AbbVie, AbbVie. R. Saab: Financial Interests, Personal and Institutional, Full or part-time Employment: AbbVie; Financial Interests, Personal and Institutional, Stocks/Shares: AbbVie. 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, Founder: Daan Biotherapeutics. All other authors have declared no conflicts of interest.

Background

BAY 2927088, an oral, reversible, potent tyrosine kinase inhibitor, has anti-tumour activity against EGFR and HER2 mutations, including ex20ins, in preclinical models. Here we report preliminary safety and efficacy of BAY 2927088 in pts with EGFR- or HER2-mutant NSCLC.

Methods

This is an ongoing, open-label, multicentre, first-in-human, phase I trial. Eligible pts must have advanced NSCLC with an EGFR and/or HER2 mutation and disease progression after ≥1 systemic treatment. BAY 2927088 is orally administered daily in 21-day cycles and follows a Bayesian adaptive dose-selection model. Backfill is concurrent and includes escalation doses found to be safe and potentially efficacious. The primary objectives of the study are safety, tolerability, pharmacokinetics and maximum tolerated dose. Secondary objectives include the overall response rate (ORR) and the recommended phase II dose. Data cut-off was 18 August 2023.

Results

A total of 76 pts from the dose-escalation/backfill phases were evaluable for safety. 59% were female, median age 60 (range 35-81) years, and 72% never smokers. 97% of pts had received ≥1 systemic anti-cancer treatment. EGFR and HER2 ex20ins mutations were present in 18% and 26% of pts, respectively. Five dose-limiting toxicities were reported in 5 pts. Overall, 87%/25% of pts had drug-related any-grade/grade 3-4 treatment-emergent adverse events (TEAEs). No pts had drug-related TEAEs leading to treatment discontinuation. The most common drug-related TEAEs were diarrhoea (75%, mainly grade 1-2), paronychia (25%) and dry skin (22%). The ORR was 26% overall (18/69, including 4 unconfirmed partial responses [uPR]). Of note, the ORR was 60%, including 1 complete response, 8 PR and 3 uPR, in 20 evaluable pts with HER2 ex20ins mutant disease.

Conclusions

In an early phase I analysis of pts with EGFR- or HER2-mutant NSCLC, BAY 2927088 demonstrated a manageable safety profile up to 60 mg daily. In pts with HER2 ex20ins mutant disease, BAY 2927088 showed encouraging preliminary anti-tumour activity. These results warrant further investigation of BAY 2927088 in pts with NSCLC.

Clinical trial identification

NCT05099172.

Editorial acknowledgement

Medical writing and editorial assistance were provided by Complete HealthVizion.

Legal entity responsible for the study

Bayer AG.

Funding

Bayer AG.

Disclosure

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. G. Daniele: Financial Interests, Institutional, Research Grant, Grants or contracts: Gilead; Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Gilead, GSK. T.A. Leal: Financial Interests, Personal, Other, All support for the present publication (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): Bayer; Financial Interests, Institutional, Research Grant, Grants or contracts: Advaxis, Pfizer; Financial Interests, Personal, Other, Consulting fees: Jazz Pharmaceuticals, AstraZeneca, EMD Serono, Merck, Boehringer Ingelheim, Blueprint, Bayer, Genentech, Lilly, Janssen, Mirati, Takeda, Daiichi Sankyo, Eisai, Novocure, Amgen, Roche, Regeneron; Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Targeted Oncology, Opinions in Lung Cancer, SITC, OncLive, Aptitude Health, Cardinal Health, Ideo, Grace, Vindico, Peerview, Medscape, Curio, Larvol, ASTRO, I3 Health, UpToDate, Bioascend; Financial Interests, Personal, Advisory Board, Participation on a Data Safety Monitoring Board or Advisory Board: NCI CCR PD-L1 Committee, DSMB; Financial Interests, Personal, Leadership Role, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: GASCO Board Member. 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 Diagnostics 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., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K., 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., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, 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.; Non-Financial Interests, Member: American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. Y. Shinno: Financial Interests, Institutional, Research Funding: Ono Pharmaceutical, Janssen Pharmaceutical, Japan Clinical Research Operations, Taiho Pharmaceutical, Bayer; Financial Interests, Personal, Other, Honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Ono Pharmaceutical, Eli Lilly Japan. K. Nishino: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., NSD, Amgen, Janssen Pharmaceutical K.K., Novartis Pharmaceuticals, Eli Lilly Japan, Takeda Pharmaceutical Co.,Ltd., Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Nippon Kayaku; Financial Interests, Institutional, Other, Research grant: Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD, AbbVie, Daiichi Sankyo Company, Limited, Amgen, Sanofi K.K., Janssen Pharmaceutical K.K., Novartis Pharmaceuticals, Pfizer, Eli Lilly, Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Chugai Pharmaceutical, Merus, AstraZeneca; Financial Interests, Institutional, Other, Research grant: Eisai Co., Ltd.; Financial Interests, Personal, Invited Speaker, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker, Advisory Board: Merck Biopharma Co., Ltd., AstraZeneca. T. Sakamoto: Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Merck KGaA, Kyowa Kirin Co., Ltd., Novartis Pharma K.K., AstraZeneca K.K., Janssen Pharmaceutical K.K., MSD K.K., Illumina K.K., Takeda Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd., Pfizer Japan Inc., Hisamitsu Pharmaceutical Co., Inc., Ono Pharmaceutical Co., Ltd.. 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, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. J.C. Ruffinelli: Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pierre-Fabre, Amgen, Bristol Myers Squibb; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Ipsen, Merck Sharp and Dohme, Merck, Advanced Accelerator Applications. N. Gallot: Financial Interests, Personal, Full or part-time Employment, I am employed by ClinBAY Ltd, a Contract Research Organization undertaking contracted statistical analyses for the study presented in the publication funded by Bayer: ClinBAY Ltd; Financial Interests, Personal, Full or part-time Employment, I am employed by ClinBAY Ltd, a Contract Research Organization undertaking contracted statistical analyses of other oncology studies funded by Bayer: ClinBAY Ltd; Financial Interests, Personal, Stocks/Shares, I hold stocks from the commercial entity: Sanofi. Z. Wang: Financial Interests, Personal, Full or part-time Employment: Bayer; Financial Interests, Personal, Stocks/Shares: Bayer. C. Chen: Financial Interests, Personal, Full or part-time Employment: Bayer. B. Brennan: Financial Interests, Personal, Full or part-time Employment: Bayer HealthCare Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Bayer HealthCare Pharmaceuticals, Inc., Roche. S. Pu: Financial Interests, Personal, Full or part-time Employment: Bayer HealthCare Pharmaceuticals, Inc.. M. Kornacker: Financial Interests, Personal, Stocks/Shares: Bayer AG; Financial Interests, Personal, Full or part-time Employment: Bayer AG. P. Grassi: Financial Interests, Personal, Full or part-time Employment: Bayer S.p.A.. 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, Coordinating PI: Eli Lilly, EMD Serono, Regeneron, Janssen; Financial Interests, Institutional, Research Grant: Arrivent; Financial Interests, Institutional, Funding: Teligene. 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, Steering Committee Member: Novartis. B. Goh: Financial Interests, Institutional, Other, Contract with my institution for clinical trial costs: Bayer AG; Non-Financial Interests, Personal, Non remunerated activity, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Drug Advisory Committee, Ministry of Health, Singapore. All other authors have declared no conflicts of interest.

Background

For patients (pts) with EGFR-mutated NSCLC after failure of EGFR TKI and platinum-based chemotherapy (PBC), available therapies provide limited benefit. CNS metastases occur in the majority of these pts and portend a poor prognosis. HER3-DXd (patritumab deruxtecan) is an antibody-drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. In the phase 2 HERTHENA-Lung01 trial (NCT04619004), HER3-DXd showed promising efficacy and a manageable safety profile in pts with advanced EGFR-mutated NSCLC following an EGFR TKI and PBC. Pts with stable brain metastases (treated or untreated) were included. We report an exploratory analysis of intracranial efficacy.

Methods

In pts (N=225) treated with HER3-DXd 5.6 mg/kg IV Q3W, intracranial responses were assessed by blinded independent central review of cranial CT/MRI (CNS BICR; per CNS RECIST) at baseline, every 6 wk to wk 24, every 12 wk thereafter.

Results

95 pts had brain metastases at baseline; 23 had measurable target lesions and 72 only had nontarget lesions. Pts had a median of 3 (range, 1-11) prior systemic therapies in the advanced setting. As of 21 Nov 2022, median study duration was 13.1 (range, 9.0-20.5) mo, median treatment duration was 4.2 (range, 0.7-14.7) mo. CNS BICR confirmed objective response rate (cORR) was 20% (Table; in pts with no prior radiotherapy to the brain, cORR was 37%). Median duration of response was 8.5 mo. 60% of pts had a CNS best objective response of SD and 14% had PD. In pts with target lesions, 15/23 had a reduction in the sum of diameters (cORR, 22%).

Conclusions

HER3-DXd demonstrated efficacy in EGFR-mutated NSCLC CNS metastases, with durable responses. These data add to the growing body of evidence that systemic treatment is feasible in pts with brain metastases and support further investigation of HER3-DXd in this context. Table: 1319MO

Clinical trial identification

NCT04619004.

Editorial acknowledgement

Medical editorial assistance was provided by Amos Race, PhD, CMPP (Articulate Science, LLC), and funded by Daiichi Sankyo, Inc. Editorial support was provided in accordance with Good Publication Practice guidelines.

Legal entity responsible for the study

Daiichi Sankyo.

Funding

Daiichi Sankyo.

Disclosure

M.L. Johnson: Financial Interests, Institutional, Advisory Role: Genentech/Roche, AstraZeneca, Calithera Biosciences, Merck, Sanofi, Mirati Therapeutics, Ribon Therapeutics, AbbVie, GSK, Gritstone Bio, Janssen Oncology, Lilly, Amgen, Daiichi Sankyo, Eisai, Axelia Oncology, Black Diamond Therapeutics, CytomX Therapeutics, EcoR1 Capital, Editas Medicine, Genmab, Ideaya Biosciences, ITeos Therapeutics, Oncorus, Regeneron, Turning Point Therapeutics, Astellas Pharma, Checkpoint Therapeutics, Genocea Biosciences, Molecular Axiom, Novartis, Revolution Medicines, Takeda, VBL Therapeutics; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AbbVie, AstraZeneca, Genentech, Incyte, Merck, Pfizer, Sanofi; Financial Interests, Institutional, Research Funding: EMD Serono, Kadmon, Janssen, Mirati Therapeutics, Genmab, Pfizer, AstraZeneca, Stem CentRx, Novartis, Array BioPharma, Regeneron, Merck, Hengrui Pharmaceutical, Lycera, BeiGene, Tarveda Therapeutics, Loxo, AbbVie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, Sanofi, CytomX Therapeutics, Dynavax Technologies, Corvus Pharmaceuticals, Incyte, Genocea Biosciences, Gritstone Bio, Amgen, Genentech/Roche, Adaptimmune, Syndax, Neovia Oncology, Acerta Pharma, Takeda, Shattuck Labs, GSK, Apexigen, Atreca, OncoMed, Lilly, Immunocore, University of Michigan, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, BerGenBio, Calithera Biosciences, Tmunity Therapeutics, Inc., Seven and Eight Biopharmaceuticals, Rubius Therapeutics, Curis, Silicon Therapeutics, Dracen, PMV Pharma, Artios, BioAtla, Elicio Therapeutics, Erasca, Inc, Harpoon, Helsinn Healthcare, Hutchison MediPharma, Ideaya Biosciences, IGM Biosciences, Memorial Sloan-Kettering Cancer Center, NeoImmuneTech, Numab, RasCal, Relay Therapeutics, Revolution Medicines, Tempest Therapeutics, Tizona Therapeutics, Inc., Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics. P.A. Jänne: Financial Interests, Personal, Advisory Role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai Pharma, Roche/Genentech, Loxo, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Group, Sanofi, Biocartis, Daiichi Sankyo, Silicon Therapeutics, Nuvalent, Inc., Eisai, Bayer, Syndax, AbbVie, Allorion Therapeutics, Accutar Biotech, Transcenta, Monte Rosa Therapeutics, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality Therapeutics; Financial Interests, Personal, Licencing Fees or royalty for IP, I am a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp. I receive post-marketing royalties from this invention: Patent; Financial Interests, Personal, Stocks or ownership: Gatekeeper Pharmaceuticals, Loxo; Financial Interests, Personal, Research Funding: AstraZeneca, Astellas Pharma, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Puma Biotechnology, Takeda, Revolution Medicines. 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 Fisher; 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: Preferred Network. 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, 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, 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, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President: ASEICA( Spanish Association of Cancer Research ); Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Genzyme Corporation, Chugai Pharmaceutical, Eisai, Inivata, Ipsen, Turning Point Therapeutics. 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, Invited Speaker, IIT: MSD, BI; Non-Financial Interests, Leadership Role, president of this european advocacy: WALCE. H. Hayashi: Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Janssen; Financial Interests, Personal, Licensing Fees or royalty for IP: Sysmex; Financial Interests, Personal, Financially compensated role, 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, Research Funding: Ono Pharmaceutical, Boehringer Ingelheim, AstraZeneca; Financial Interests, Institutional, Research Funding: AbbVie, AC Medical, Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Lilly Japan, EPS Associates Co., Ltd., GSK, Japan Clinical Research Operations, Kyowa Kirin, Merck Serono, Novartis, Otsuka, Parexel, Pfizer, PPD-SNBL, Quintiles Inc., Taiho Pharmaceutical, Takeda, Yakult Honsha, Chugai Pharma, Sysmex. D. Kim: Financial Interests, Personal, Invited Speaker: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Taiwan Lung Cancer Society, 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: Hanmi, Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer Ingelheim, Daiichi Sankyo, 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, Advisory Role: Amgen, BMS / Ono Pharmaceuticals, Daiichi Sankyo, Janssen, GSK, Pfizer, AstraZeneca, SK Biopharm, Takeda, Yuhan; Non-Financial Interests, Member of Board of Directors: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Asian Thoracic Oncology Research Group; Other, Travel support for advisory board meeting attendance: Amgen, Daiichi Sankyo; Other, Clinical trial research funding to my institution: Asian Thoracic Oncology Research Group. 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. S.C. Kao: Financial Interests, Institutional, Invited Speaker: AstraZeneca, BMS, MSD, Roche, BeiGene; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Boehringer, MSD, Novartis, Roche, Takeda, Amgen, BeiGene. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, GSK, Janssen, Merck Sharp & Dohme, Pfizer, Sanofi, Takeda, Merck Serono, Peptomyc, F. Hoffmann-La Roche, Novartis, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, PeerVoice, Pfizer, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono, Sanofi, Takeda, Touch Oncology; Financial Interests, Institutional, Other, Grant for oncology innovation: Merck Healthcare KGAa; Financial Interests, Institutional, Other, Fundación Merck Salud; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen Cilag International NV, GSK Research & Development Limited, AbbVie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO; Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform). J.C. Yang: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, Lilly, MSD Oncology, Merck Serono, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda, Amgen, Incyte; Financial Interests, Institutional, Advisory Role: Merck Serono, Janssen, GSK, Amgen, Takeda, Daiichi Sankyo, AstraZeneca, Novartis, MSD Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer; Financial Interests, Personal, Financially compensated role, Honoraria: Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Lilly, Pfizer. 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, Sanofi, Roche; Financial Interests, Personal, Other, Member of DMSB: Daiichi Sankyo. Q. Dong: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks or ownership: Daiichi Sankyo. A. Sporchia: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks or ownership: Daiichi Sankyo. D.W. Sternberg: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks or ownership: Daiichi Sankyo. H.A. Yu: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Lilly; Financial Interests, Personal, Other: Astellas Pharma; Financial Interests, Institutional, Research Funding: AstraZeneca, Astellas Pharma, Lilly, Novartis, Pfizer, Daiichi Sankyo, Cullinan Oncology, Janssen Oncology, Erasca, Inc; Financial Interests, Personal, Research Funding: Blueprint Medicines.

Background

∼20% of pts with HER2m NSCLC have BM at metastatic diagnosis. T-DXd is the first HER2-directed therapy for pts with pretreated, advanced HER2m NSCLC. We report post hoc pooled analyses of T-DXd efficacy/safety in this population with vs without baseline (BL) BMs from DESTINY-Lung01 (DL-01) and DESTINY-Lung02 (DL-02).

Methods

Pts with and without BMs were evaluated from the DL-01 (data cutoff [DCO], Dec 3, 2021) HER2m cohort (6.4 mg/kg; 35 and 56 pts) and the DL-02 (DCO, Dec 23, 2022) cohorts treated with T-DXd 5.4 mg/kg (32 and 70 pts) or 6.4 mg/kg (19 and 31 pts); 6.4 mg/kg arms were pooled. Pts with stable BL BMs (asymptomatic; not requiring treatment) were eligible. Tumor assessments were performed every 6 weeks (MRI/CT). Systemic objective response rates (ORRs), duration of response (DoR), sites of progression, and treatment-emergent adverse events (TEAEs) were determined in pts with and without BL BMs. Intracranial (IC)-ORR, IC-DCR, and IC-DoR were analyzed in pts with measurable and nonmeasurable BL BMs.

Results

31% and 38% of pts given T-DXd 5.4 mg/kg and 6.4 mg/kg, respectively, had detectable BL BMs, among whom 46.9% and 55.6% had untreated BMs. Systemic ORRs were similar (Table). IC-ORRs were 25.0% (5.4 mg/kg) and 18.5% (6.4 mg/kg) with complete IC responses in 4 and 1 pts. In pts with BL BMs, IC progression occurred in 13/32 and 20/54 pts on T-DXd 5.4 mg/kg and 6.4 mg/kg, respectively; in pts without BL BMs, 1/70 and 8/87 had IC progression. Generally similar safety outcomes were seen in pts with vs without BMs, with a trend of higher rates of grade ≥3 TEAEs in pts with BMs (64.5% vs 47.1% [5.4 mg/kg]; 75.9% vs 63.2% [6.4 mg/kg]).

Conclusions

T-DXd showed IC activity in pts with metastatic HER2m NSCLC, some with complete IC responses. The presence of BL BMs did not impact systemic response among pts treated with T-DXd. Table: 1321MO

Efficacy summary

Clinical trial identification

NCT03505710; NCT04644237.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Eileen McIver, PhD and Cindy M. Rigby, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc., and AstraZeneca.

Funding

Daiichi Sankyo, Inc., and AstraZeneca.

Disclosure

B.T. Li: Financial Interests, Institutional, Funding, Clinical trial funding: Daiichi Sankyo, Amgen, Bolt Biotherapeutics, Genentech, Hengrui, Eli Lilly; Financial Interests, Institutional, Funding, Clinical trial funding, uncompensated advisory: AstraZeneca; Financial Interests, Personal, Invited Speaker, Academic Travel Support: Amgen. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Novartis, GSK, Novartis, Janssen, AbbVie, Roche, Pfizer, Daiichi Sankyo, Inc., MSD, Gilead Sciences, Inc., Seagen, Pierre Fabre. K. Goto: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co., Ltd, AstraZeneca K.K.; Financial Interests, Institutional, Research Grant: Daiichi Sankyo Co., Ltd; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca K.K. E.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Boehringer Ingelheim, Roche, Eli Lilly, Takeda, Sanofi, Janssen, BMS; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Institutional, Other, DSMB member: DSI; Financial Interests, Institutional, Local PI: Pfizer, AZ, Genmab, DSI, Sanofi. J. De Langen: Financial Interests, Institutional, Advisory Role, Consultancy: AstraZeneca, MSD, Roche, Boehringer Ingelheim, Pfizer, Eli Lilly, Blueprint Medicines; Financial Interests, Institutional, Advisory Role, Consulting Fees: BMS; Financial Interests, Institutional, Research Funding: AstraZeneca, BMS, Merck Serono, MSD, Roche, Merus. 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 Fisher; 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: Preferred Network; Financial Interests, Institutional, Coordinating PI: Guardant Health; Non-Financial Interests, Member of Board of Directors: Cancer Net Japan, JAMT. K. Ninomiya: Financial Interests, Personal, Speaker’s Bureau: Kyowa Kirin, AstraZeneca, Lilly Japan, MSD KK, Chugai Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Bristol Myers Squibb, Janssen Pharmaceutical, Nippon Boehringer Ingelheim, Electa. T. Kubo: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical, BMS, Taiho Pharmaceutical, Kyowa Hakko Kirin, AstraZeneca, Ono Pharmaceutical, Nippon Kayaku, Chugai, MSD, Eli Lilly, Pfizer, Novartis, Boehringer Ingelheim, Towa Pharmaceutical. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, Eisai, 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: Amgen, AstraZeneca, AbbVie, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GSK, Janssen, Merck Serono, Novartis, Peptomyc, Pfizer, Sanofi, Takeda; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, MedScape, Merck Sereno, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology; Financial Interests, Personal, Other, Independent member: Grifols; Non-Financial Interests, Personal, Other, Member of the Nominating Commitee and Compliance Committee: ESMO; Non-Financial Interests, Personal, Other, Member of Scientific Committee: ETOP; Non-Financial Interests, Personal, Leadership Role, President of the Spanish Society For Medical Oncology: SEOM. H. Hayashi: Financial Interests, Personal, Invited Speaker: Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd; Financial Interests, Personal, Advisory Board: AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd; Financial Interests, Personal, Advisory Board, Manuscript fee: Guardant Health ; Financial Interests, Personal, Funding: AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co. Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Bristol Myers Squibb Co. Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Merck Serono Co. Ltd., Merck Biopharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., SymBio Pharmaceuticals Ltd., AbbVie Inc., inVentiv Health Japan, ICON Japan K.K., Gritstone Oncology Inc., Parexel International Corp., Kissei Pharmaceutical Co. Ltd., EPS Corp., Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc./IQVIA Services Japan K.K., EP-CRSU Co. Ltd., Linical Co. Ltd., Eisai Co. Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co. Ltd., Bayer Yakuhin Ltd., EPS International Co. Ltd., Otsuka Pharmaceutical Co. Ltd.; Financial Interests, Personal, Full or part-time Employment: Nippon Boehringer Ingelheim Co. Ltd.. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bayer Yakuhin, Ltd., Incyte biosciences Japan, Merck Biopharma Co., Ltd., Janssen Pharmaceutical K.K., Bristol Myers Squibb Company, Medical Mobile Communications Co., Ltd, Novartis Pharma K.K., Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K.; Financial Interests, Personal, Writing Engagement: Yodosha Co., Ltd.; Financial Interests, Institutional, Research Grant: Amgen Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co.,Ltd., EP-CRSU Co., Ltd., EPS Corporation., Eisai Co., Ltd., GSK K.K., MSD K.K., IQVIA Services Japan K.K., Janssen Pharmaceutical K.K., Kobayashi Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Nippon Kayaku Co.,Ltd., Sanofi K.K., PRA Healthsciences, SRL Medisearch Inc., Syneos Health Clinical K.K., Taiho Pharmaceutical Co.,Ltd., Takeda Pharmaceutical Co.,Ltd., CMIC Co., Ltd., Pfizer R&D Japan G.K., Labcorp Development Japan K.K., Pfizer Japan Inc., Shionogi & Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Ascent Development Services, Eisai Inc., Bayer Yakuhin, Ltd. M. Nagasaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis, EMD Serona, Pfizer, Eli Lilly, Genentech; Financial Interests, Personal, Other, Consultant for tumor board: Caris Life Sciences; Financial Interests, Personal, Speaker’s Bureau: Takeda, Janssen, Mirati, Blueprint Medicine; Non-Financial Interests, Personal, Other, Travel Support: AnHeart Therapeutics. K.M.C. Pereira: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. A. Taguchi: Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo Co., Ltd. A. Ali: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. M. Karnoub: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. R. Yonemochi: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P.A. Jänne: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, SFJ Pharmaceuticals, Voronoi, Biocartis, Novartis, Sanofi, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Monte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality; Financial Interests, Personal, Funding: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Funding: Daiichi Sankyo, Takeda Oncology; Financial Interests, Personal, Advisory Board: Mirati Therapeutics; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals; Financial Interests, Institutional, Funding: Puma; Financial Interests, Personal, Invited Speaker: Revolution Medicines; Financial Interests, Personal, Royalties: LabCorp. All other authors have declared no conflicts of interest.

Background

Up to 50% of patients (pts) with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases (mets), which are a major source of mortality in NSCLC. Lazertinib (laz), a CNS-active 3^rd-generation (gen) tyrosine kinase inhibitor (TKI) targeting mutant epidermal growth factor receptor (EGFR), improved progression-free survival (PFS) vs the 1^st-gen TKI gefitinib (gef) in the LASER301 study. Here, we compared laz vs gef among LASER301 pts with CNS mets.

Methods

In the phase 3 LASER301 study (NCT04248829), treatment (tx)-naïve pts with EGFR-mutated advanced or metastatic NSCLC were randomized 1:1 to laz (240 mg/day) or gef (250 mg/day). Pts with symptomatic/unstable CNS mets were excluded. If tx was required for pts with asymptomatic/stable CNS mets, radiation and/or surgery, and steroids were completed >2 weeks before randomization. Magnetic resonance imaging was performed at screening, every 6 weeks for 18 months (mo), then every 12 weeks relative to randomization, using the same modality at each follow-up. Endpoints assessed by blinded independent central review and RECIST v1.1 included intracranial PFS (iPFS), intracranial objective response rate (iORR), intracranial duration of response (iDoR), and depth of intracranial response.

Results

Of 393 pts in LASER301, 45 (23%) receiving laz and 41 (21%) receiving gef had measurable and/or non-measurable baseline (BL) CNS mets. BL characteristics were balanced between groups, with most pts having 1–3 CNS lesions (laz: 91%, gef: 83%). Median BL target lesion size was 20.0 mm (laz) and 16.0 mm (gef). Median iPFS in the laz group was 28.2 mo (95% confidence interval [CI]: 14.8, 28.2) vs 8.4 mo (6.7, not reached [NR]) in the gef group (hazard ratio: 0.42; 95% CI: 0.20, 0.89; P=0.02). iORR was higher for the laz (n=17, 94%) vs gef (n=11, 73%) group. At data cutoff, median iDoR in the laz group was NR (8.3, NR) vs 6.3 mo (2.8, NR) in the gef group. The median best change from BL in CNS target lesion size was -57% and -47% for laz (n=17) and gef (n=14), respectively. No new safety signals were identified from LASER301.

Conclusions

In pts with BL CNS mets, laz significantly improved iPFS vs gef with more durable responses. Laz has the potential to improve CNS outcomes in NSCLC.

Clinical trial identification

NCT04248829.

Editorial acknowledgement

Dylan Mori of Lumanity Communications Inc.

Legal entity responsible for the study

Yuhan Corporation.

Funding

Yuhan Corporation.

Disclosure

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. 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, Founder: Daan Biotherapeutics. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daiichi Sankyo, Merck, Boronoi. K.H. Lee: Financial Interests, Personal, Other, Consultant: BMS, Eli Lilly, Pfizer, AstraZeneca, MSD, Yuhan; Financial Interests, Personal, Research Funding: MSD. A. Zimina: Non-Financial Interests, Principal Investigator, Participation as PI in Yuhan LASER-301 trial: Yuhan. Y. Lee: Financial Interests, Personal, Speaker’s Bureau: Pfizer, Boryung, Eli Lilly, Takeda; Financial Interests, Personal, Other, Consultant: Ono, Takeda, Yuhan, Guardant Health. L. Yueh Ni: Financial Interests, Personal, Other, Panel of Discussion for Hepatocellular Carcinoma: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory Board Meeting for early breast cancer management in our current practice.: Roche; Financial Interests, Personal and Institutional, Local PI, Research Title: A multicentre, open-label, single-arm, molecular profiling study of patient with EGFR mutation-positive locally advanced or metastatic NSCLC treated with Osimertinib: AstraZeneca; Financial Interests, Personal and Institutional, Local PI, Research Title: A Phase 3 Double-blinded, Two-arm Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) versus Placebo as Adjuvant Therapy in Participants with Hepatocellular Carcinoma and Complete Radiological Response after Surgical Resection or Local Ablation (KEYNOTE-937): MSD; Financial Interests, Personal and Institutional, Local PI, Research Title: A Phase III, Randomized, Double-blind Study to Assess the Efficacy and Safety of Lazertinib versus Gefitinib as the First-line Treatment in Patients with Epidermal Growth Factor Receptor Sensitizing Mutation Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer: Yuhan; Financial Interests, Personal and Institutional, Local PI, Research Title: A phase II randomized study of the combination of Ribociclib plus goserelin acetate with Hormonal Therapy versus physician choice chemotherapy in premenopausal or perimenopausal patients with hormone receptor-positive/HER2-negative inoperable locally advanced or metastatic breast cancer - RIGHT Choice Study: Novartis; Financial Interests, Personal and Institutional, Local PI, Research Title: A Global, Randomized, Phase 3, Open-Label Study of REGN2810 (Anti-PD-1 Antibody) versus Platinum-Based Chemotherapy in First-Line Treatment of Patients with Advanced or Metastatic PD-L1+ Non-Small Cell Lung Cancer: Regeneron; Financial Interests, Personal and Institutional, Local PI, Research Title: A Phase 3 study to Evaluate Zimberelimab (AB122) Monotherapy Compared to Standard Chemotherapy or Zimberelimab Combined with AB 154 in Front-Line, PD-L1 Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer: Arcus; Financial Interests, Personal and Institutional, Local PI, Research Title: A Prospective, Multicenter, Non-Interventional Genomic Profiling Study in Subjects with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) using Foundation Medicine: Roche; Financial Interests, Personal and Institutional, Local PI, Research Title: A Phase 3, randomize, double-blind trial of pembrolizumab (MK-3475) with or without lenvatinib (E7080/MK-7902) in participants with treatment naive, metastatic non-small cell lung cancer (NSCLC) whose tumors have a tumor proportion score (TPS) greater than or equal to 1% (LEAP-007): MSD. Y.K. Pang: Financial Interests, Personal, Research Funding: MSD, AstraZeneca, Sanofi.; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Specialised Therapeutics, MSD, Boehringer Ingelheim, Sanofi-Aventis, Orient Europharma, Eurodrug Laboratories.. C.H. Fong: Financial Interests, Personal, Local PI, Investigator fees: Yuhan Corporation, Janssen Research & Development, LLC, Arcus Biosciences, Inc., Novartis Pharmaceuticals, Hoffmann-La Roche. J.H. Kang: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Merck, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Boeringer Ingelheim, Roche, MSD, Ono, Yuhan, Takeda; Financial Interests, Personal, Research Grant: ONO, Daiichi Sankyo, Boeringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Yuhan. P. Danchaivijitr: Financial Interests, Personal, Speaker’s Bureau: MSD, Roche, AstraZeneca, BMS; Financial Interests, Personal, Advisory Board: MSD, Roche, AstraZeneca, BMS. H. Lee: Financial Interests, Personal, Full or part-time Employment: Yuhan. S. Park: Financial Interests, Personal, Full or part-time Employment: Yuhan Co. I. Cicin: Other, Principal investigator: Jounce Therapeutic. All other authors have declared no conflicts of interest.

Background

Longitudinal imaging and circulating tumour DNA (ctDNA) can map tumour growth and patterns of metastatic spread on a lesion-by-lesion level. In this study, we investigated the role of ctDNA as a biomarker in monitoring tumour growth in 102 metastatic lung cancer patients enrolled in the TRACERx study, tracking volumetric dynamics of 341 metastases.

Methods

Patients were categorised based on total volume growth rate: Slow >100mm3/day, Stable <100mm3/day and Rapid >600mm3/day. Individual metastases within patients were categorised into ‘High’ and ‘Low’ growth rate based on the median growth rate for all lesions across the cohort. In addition, RNAseq data from 122 regions belonging to 44 metastases mapped to imaging at autopsy were analysed in 13 patients enrolled in the PEACE study. For 28 patients, ctDNA was used to track 200 clonal or subclonal mutations in 214 plasma samples to assess total disease burden and metastatic subclones.

Results

Growth rate correlated with number of lesions at relapse and overall survival (OS). Median OS was 55.0, 25.4 and 8.5 months for Slow, Stable and Rapid classes respectively (p<0.001). Gene set enrichment analysis demonstrated enrichment in signalling pathways associated with cell proliferation when comparing the gene expression patterns between ‘high’ and ‘low’ growth rate lesions. Early postsurgical ctDNA detection was associated with higher ctDNA shedding at disease relapse. Total ctDNA tracked with tumour volume in the post-relapse setting, and patients with extrathoracic relapse showed higher ctDNA shedding. For eight patients in the PEACE cohort, we assessed the subclonal composition of ctDNA, tracking lesions with specific subclones detected at autopsy. These subclones were mapped to metastatic lesions measured on imaging. ctDNA subclonal fraction tracked with changes in tumour volume upon treatment response and subsequent progression. For all eight patients’ lesion-specific subclones could be detected from day 1 post-surgery prior to detection by radiological imaging.

Conclusions

Our results demonstrate that ctDNA can accurately reproduce observed patterns of metastatic growth on imaging, suggesting it can be used in the detection and monitoring of metastatic disease.

Clinical trial identification

The TRACERx study (NCT01888601) is a prospective observational cohort study and PEACE (NCT03004755) is a national research autopsy programme, both approved by independent research ethics committees (13/LO/1546 and 13/LO/0972/AM05, respectively).

Legal entity responsible for the study

Cancer Research UK.

Funding

Cancer Research UK.

Disclosure

A. Hackshaw: Financial Interests, Institutional, Advisory Role: Roche. C.Z. Abbosh: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Other, PCT/GB2017/053289: Patent Application; Financial Interests, Personal, Other, PCT/US2017/028013: Patent Application; Financial Interests, Personal, Other, PCT/EP2022/077987: Patent Application. A.M. Frankell: Financial Interests, Personal, Other, PCT/EP2022/077987: Patent application. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016.: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020 . Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA Advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded Rubicon grant - October 2018 - April 2021.: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies.: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee.: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Other, Board of Directors: AACR; Non-Financial Interests, Advisory Role, EACR Advisory Council member: EACR. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Non-Financial Interests, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. All other authors have declared no conflicts of interest.

Background

Patients with metastatic non‒small-cell lung cancer (NSCLC) can receive anti PD-L1/PD-1 immunotherapy as a standard of care. However, prediction of response is challenging with existing biomarkers. Retrospective analyses have identified the clonality of mutations and neoantigens as potential biomarkers. However, the impact of intratumour heterogeneity (ITH) on immunotherapy response in patients with metastatic NSCLC has not been prospectively explored. The DARWIN II trial is a phase II, multi-centre molecularly stratified trial for patients with NSCLC to study the effect of ITH on response to treatment. The study is unique as patients were recruited from the TRACERx Lung Cancer observational cohort study, following relapse with metastatic disease.

Methods

A total of 65 patients from the TRACERx study, with spatially separated multi-region sampling of resected early lung cancer, who relapsed with metastatic disease were enrolled between November 2016 and March 2023 and received immunotherapy. Patients were recruited with any PDL1 tumour proportion score. Patients received atezolizumab or atezolizumab with chemotherapy. Multi-omic analysis, including deep (∼500x) whole exome, RNA, RRBS, and TCR sequencing of multi-region primary tumour samples and relapse biopsies was performed on 355 samples. All samples were processed on a uniform bioinformatic analysis pipeline and results corrected for tumour purity variation.

Results

The median PFS and OS were 4.5 and 10.0 months respectively. The proportion of patients with durable clinical benefit was 37.5 percent. A high clonal mutation burden was associated with a statistically significant improvement in response (OR = 5.7, 95% CI [1.1-45.0], p value = 0.04) whereas high total tumour mutation burden (>10 mut/Mb) was not. Additionally, we identified several associations between novel molecular features and immunotherapy response, including ITH of the transcriptome and DNA hyper-/hypo-methylation frequency.

Conclusions

This is the first trial to demonstrate prospectively that clonal mutations are associated with improved patient outcome and identify novel molecular features, related to ITH, as predictors of immunotherapy response in patients with NSCLC.

Clinical trial identification

NCT02314481.

Legal entity responsible for the study

University College London.

Funding

Roche.

Disclosure

C. Hiley: Financial Interests, Personal, Advisory Role: Genesiscare. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Advisory Board: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Carrick, Janssen, Pyramid Biosciences; Financial Interests, Institutional, Local PI: Blueprint, Astex, Bayer, BerGenBio, Immutep, Novartis, Nurix, Nuvalent, Roche, Seattle Genetics, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Travel expenses for congress: Immutep, Janssen; Other, Travel expenses: Roche. S. Quezada: Financial Interests, Personal, Advisory Board: Medicenna, DROIA oncology, Molecular Partners; Financial Interests, Personal, Full or part-time Employment: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares: Achilles Therapeutics; Financial Interests, Personal, Royalties: Dartmouth College, MSKCC, UCL. K.R. Litchfield: Financial Interests, Personal, Invited Speaker: Roche Tissue Diagnostics; Financial Interests, Personal, Other, Consulting work: Kynos Therapeutics, Monopteros Therapeutics, Tempus; Financial Interests, Personal, Invited Speaker, Invited speaker: Ellipses Pharma; Financial Interests, Institutional, Research Grant: Ono/LifeArc; Financial Interests, Institutional, Research Grant, Research funding: Genesis Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Collaboration on data analysis: Bms. A. Hackshaw: Financial Interests, Personal, Advisory Board, AH is an investigator for an academic study (SUMMIT) sponsored by UCL that is funded by GRAIL, Inc.; has received one honorarium for an advisory board meeting for GRAIL, Inc; received a consulting fee from Evidera Inc (for one GRAIL-initiated project): GRAIL Inc; Financial Interests, Personal, Other, For delivering general education/training in clinical trials: AbbVie, Boehringer Ingelheim, Clovis, Ipsen, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, MSD, UCB, Kyowa Kirin, Servier, Sobi, Pfizer, Roche; Financial Interests, Personal, Stocks/Shares, Shares were sold in 2020: Illumina, Thermo Fisher; Financial Interests, Institutional, Research Grant, Grant for a UCL-academic sponsored clinical trial: Roche, MSD, Autolus, AstraZeneca, Boehringer Ingelheim, GRAIL Inc, Takeda, Pfizer, Novartis, Bristol Myers Squibb, Janssen; Non-Financial Interests, Principal Investigator, Co-lead academic investigator for an observational study sponsored and conducted by Roche. Unpaid/no honoraria for this role.: Roche; Non-Financial Interests, Advisory Role, AH is on the scientific advisory board for Adela Bio and receives no payments/honoraria for this but has share options available: Adela Bio; Non-Financial Interests, Advisory Role, Unpaid member of advisory board: Navio. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Non-Financial Interests, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection.: Patent. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016.: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company.: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021.: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies.: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Trial Chair, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee.: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Other, Board of Directors: AACR; Non-Financial Interests, Advisory Role, EACR Advisory Council member: EACR. All other authors have declared no conflicts of interest.

Background

Checkpoint inhibitors (CPIs) improve survival of patients with metastatic non-small cell lung cancer (NSCLC). However, in many patients the duration of response is limited, and some patients derive no benefit at all. Among key determinants of CPI response are genomic alterations that impair the anti-tumour immune response. In primary NSCLC these alterations are common. However, due to challenges collecting metastasis samples, the prevalence and distribution of these alterations across metastases within patients, and how this impacts response to CPI is not known.

Methods

The PEACE autopsy study in tandem with the TRACERx study enables multi-region tumour sampling from diagnosis of NSCLC to death, allowing immune evasive capacity to be tracked across space and time. We performed exome sequencing on 84 primary tumour regions and 320 metastases from 21 patients recruited to these studies. Mutations and copy number alterations were called with our bioinformatic pipeline and used to infer tumour clones in each sample, their phylogenetic relationship and metastatic migration history. The neoantigen landscape and genomic alterations in genes involved in immune evasion (‘IE alterations’) were then characterised in each clone.

Results

We find IE alterations are frequent in metastases and emerge via distinct evolutionary paths. In a subset of patients, immune evasive primary tumour clones seed metastases, giving rise to metastases with poor T cell infiltrate that share IE alterations with the primary. In others, primary tumour seeding clones do not harbour IE alterations. Compared to patients with shared IE alterations, these patients’ metastases have higher T cell infiltrate and acquire more metastasis unique IE alterations after seeding. Measuring the radiological growth of individual metastases in 7 of these patients treated with CPIs in the DARWIN II trial, we observe homogenous progression of metastases in patients with shared IE alterations, while patients with metastasis unique IE alterations exhibit heterogeneous metastasis growth rates.

Conclusions

When IE alterations occur in relation to metastatic seeding dictates the distribution of immune evasive capacity across metastases, which impacts metastasis growth during CPI therapy.

Clinical trial identification

PEACE - NCT03004755, TRACERx - NCT01888601, DARWIN II - NCT02314481.

Legal entity responsible for the study

UCL Clinical Trials Centre.

Funding

The PEACE study and TRACERx study are funded by Cancer Research UK (grants C416/A21999 and C11496/A17786, respectively). The PEACE study is additionally supported by funding from the Rosetrees Trust (grant A2204). A subset of patients in this work were treated with immunotherapy on the DARWIN II study, which is an academic study sponsored by UCL funded by funded by Hoffman La Roche.

Disclosure

D. Moore: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Takeda; Financial Interests, Personal, Advisory Role: Thermo Fisher, Eli Lilly, Amgen, Janssen, MIM Software, Bristol Myers Squibb. N. McGranahan: Financial Interests, Institutional, Stocks/Shares: Achilles Therapeutics. C. Hiley: Financial Interests, Personal, Invited Speaker: AstraZeneca. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020 . Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company.: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies.: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Trial Chair, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee.: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Other, Board of Directors: AACR; Non-Financial Interests, Advisory Role, EACR Advisory Council member: EACR. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Non-Financial Interests, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. All other authors have declared no conflicts of interest.