Ramucirumab plus erlotinib versus placebo plus erlotinib in previously untreated EGFR-mutated metastatic non-small-cell lung cancer (RELAY): exploratory analysis of next-generation sequencing results.

Background: Ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) over placebo + ERL (PBO + ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes.
Patients and Methods: Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and postdiscontinuation follow-up. EGFR and co-occurring/treatment-emergent (TE) genomic alterations in ctDNA were analyzed using Guardant360 NGS platform.
Results: In those with valid baseline samples, detectable activating EGFR alterations in ctDNA (aEGFR+) were associated with shorter PFS [aEGFR+: 12.7 months (n = 255) versus aEGFR-: 22.0 months (n = 131); hazard ratio (HR) = 1.87, 95% confidence interval (CI) 1.42-2.51]. Irrespective of detectable/undetectable baseline aEGFR, RAM + ERL was associated with longer PFS versus PBO + ERL [aEGFR+: median PFS (mPFS) = 15.2 versus 11.1 months, HR = 0.63, 95% CI 0.46-0.85; aEGFR-: mPFS = 22.1 versus 19.2 months, HR = 0.80, 95% CI 0.49-1.30]. Baseline alterations co-occurring with aEGFR were identified in 69 genes, most commonly TP53 (43%), EGFR (other than aEGFR; 25%), and PIK3CA (10%). PFS was longer in RAM + ERL, irrespective of baseline co-occurring alterations. Clearance of baseline aEGFR by C4 was associated with longer PFS (mPFS = 14.1 versus 7.0 months, HR = 0.481, 95% CI 0.33-0.71). RAM + ERL improved PFS outcomes, irrespective of aEGFR mutation clearance. TE gene alterations were most commonly in EGFR [T790M (29%), other (19%)] and TP53 (16%).
Conclusions: Baseline aEGFR alterations in ctDNA were associated with shorter mPFS. RAM + ERL was associated with improved PFS outcomes, irrespective of detectable/undetectable aEGFR, co-occurring baseline alterations, or aEGFR+ clearance by C4. aEGFR+ clearance by C4 was associated with improved PFS outcomes. Monitoring co-occurring alterations and aEGFR+ clearance may provide insights into mechanisms of EGFR tyrosine kinase inhibitor resistance and the patients who may benefit from intensified treatment schedules.
Competing Interests: Disclosure EBG declares grants from ABL-Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Dynavax Technologies, EMD Serono, Eli Lilly and Company, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis; consulting fees from AbbVie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly and Company, Gilead, GlaxoSmithKline, Ipsen, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio; payment for expert testimony from UCLA relating to motif neoepitopes for cancer immunotherapy; leadership/fiduciary role with LUNGevity and Jonsson Comprehensive Cancer Center at UCLA. JVH declares advisory board/committee membership with Genentech, Mirati Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, DAVA Oncology, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Immunocore, and Novartis; research support from AstraZeneca, Boehringer-Ingelheim, Spectrum, and Takeda; royalties and licensing fees from Spectrum. MR declares consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; support for meetings/travel from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; board participation for Daiichi and Sanofi. KN declares grants from Nippon Boehringer-Ingelheim, West Japan Oncology Group, Thoracic Oncology Research Group, North East Japan Study Group, Clinical Research Support Center Kyushu, Nichirei Biosciences Inc., Eli Lilly and Company, Hitachi, Sysmex, and Otsuka Pharmaceutical; consulting fees from SymBio Pharmaceuticals, Solasia Pharma, Eli Lilly and Company, and Otsuka Pharmaceutical; honoraria from Chugai, Pfizer, Eli Lilly and Company, MSD, Novartis Pharma, AstraZeneca, Amgen, Merck Biopharma, Roche Diagnostics, Yakult Honsha, Guardant Health, Takeda Pharmaceuticals, Boehringer-Ingelheim Japan, FUJIREBIO, Bristol-Myers Squibb, Merck Biopharma, Janssen Pharmaceutical Daiichi-Sankyo, and Ono Pharmaceutical. MN declares honoraria from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly and Company, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer-Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. SN declares grants from Eli Lilly and Company; consulting fees from BMS, Eli Lilly and Company, Takeda, Roche, Pfizer, AstraZeneca, BI, MSD, AbbVie, PharmaMar, and BeiGene; support for meetings and/or travel from Eli Lilly and Company, Thermo Fisher, and Takeda; participation on advisory boards for Guardant Health, GSK, Novocure, Amgen, AstraZeneca, Janssen, and Eli Lilly and Company; and declares leadership/fiduciary roles as President of WALCE (Women against Lung Cancer in Europe) Onlus. LPA declares grants from MSD, AstraZeneca, Pfizer, and BMS; consulting fees from Eli Lilly and Company, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, and Daiichi-Sankyo; honoraria from AstraZeneca, Janssen, Merck, and Mirati; member of the board of directors of Altum Sequencing and Genomica; principal investigator for studies sponsored by Alkermes, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, IO Biotech, Janssen-Cilag, Eli Lilly and Company, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda, and Tesaro. SP declares consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly and Company, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, Takeda, and Pfizer; payment for expert testimony from Roche and Merck Serono; support for attending meetings and/or travel from Janssen and Roche; unpaid leadership/fiduciary roles in British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board. SPA declares no conflicts of interest. HG was an employee and stockholder of Eli Lilly and Company during the time of study analysis and manuscript preparation; contributions to the manuscript were made as part of the roles at Eli Lilly and Company. BDB and CVG are full-time employees and minor shareholders of Eli Lilly and Company. KN declares grants to institution from AstraZeneca, MSD, Ono Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis, Pfizer Japan Inc., Bristol-Myers Squibb, Eli Lilly and Company, Chugai Pharmaceutical, Daiichi-Sankyo, Merck, Paraxel International Corp., PRA Health Sciences, EPS Corporation, Kissei Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., PPD-SNBL K.K., SymBio Pharmaceuticals Limited, IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co. Ltd., EP-CRSU Co. Ltd., Mebix, Janssen Pharmaceutical K.K., AbbVie Inc., Bayer Yakuhin Ltd., Eisai, Mochida Pharmaceutical Co. Ltd. Covance Japan Inc., Japan Clinical Research Operations, Takeda Pharmaceutical Co. Ltd., GlaxoSmithKline, Sanofi, Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical Co. Ltd., SRL Inc., Pfizer R&D Japan G.K., and Amgen Inc.; consulting fees from Eli Lilly and Company, KYORIN Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., and Pfizer Japan Inc.; honoraria from Ono Pharmaceutical Co. Ltd., Amgen Inc. Nippon Kayaku Co. Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly and Company, MSD, Pfizer Japan Inc., Nippon Boehringer-Ingelheim Co. Ltd., Taiho Pharmaceutical Co. Ltd., Bayer Yakuhin, CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Roche Diagnostics K.K., AbbVie Inc, Merck Biopharma Co. Ltd., Kyowa Kirin Co. Ltd., Takeda Pharmaceutical Co. Ltd., 3H Clinical Trial Inc., Care Net Inc., Medical Review Co. Ltd., Medical Mobile Communications Co. Ltd., Yodosha Co. Ltd., Nikkei Business Publications Inc., Japan Clinical Research Operations, CMIC Co. Ltd., Novartis, TAIYO Pharma Co. Ltd., KYORIN Pharmaceutical Co. Ltd., and Bristol-Myers Squibb K.K.; patents planned, issued, or pending with Daiichi-Sankyo. 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