LBA55 - Mechanisms of acquired resistance to first-line amivantamab plus lazertinib versus osimertinib in patients with EGFR-mutant advanced non-small cell lung cancer: An early analysis from the phase III MARIPOSA study

Background

In the phase 3 MARIPOSA study (NCT04487080), first-line amivantamab plus lazertinib (ami+laz) significantly improved progression-free survival vs osimertinib (osi) in patients (pts) with EGFR-mutant advanced non-small cell lung cancer (NSCLC; hazard ratio, 0.70; P<0.001). C797S and MET amplification (METamp) are the most common resistance mechanisms to osi, which amivantamab targets. Here, we report acquired resistance mechanisms for pts with disease progression on first-line ami+laz vs osi.

Methods

A total of 858 pts with treatment naïve, EGFR-mutant (Ex19del/L858R) locally advanced/metastatic NSCLC were evenly randomized to receive ami+laz or osi. Paired blood samples were collected at baseline and end of treatment (EOT; defined as at disease progression/treatment discontinuation or within 90 days of discontinuation) for analysis of detectable circulating tumor DNA (ctDNA) by next-generation sequencing (Guardant 360 CDx). All P-values are nominal.

Results

Among pts who discontinued treatment, 113/215 (53%) for ami+laz and 140/252 (56%) for osi had matched baseline and EOT ctDNA data. Significantly fewer pts receiving ami+laz vs osi had acquired METamp (4.4% vs 13.6%; P=0.017) or other EGFR (C797S, L718X, G724X) resistance mutations (0.9% vs 7.9%; P=0.014). The incidence of acquired TP53 resistance mutations was numerically lower for ami+laz vs osi (9.7% vs 12.9%). Paired TP53/RB1 loss of function (LOF) resistance mutations, which are associated with small cell transformation, were also numerically lower for ami+laz vs osi (0.9% vs 2.9%). No significant differences were observed among other resistance pathways for ami+laz and osi. Full resistance profiles will be shared at the meeting.

Conclusions

Ami+laz had significantly lower rates of EGFR and MET resistance alterations with trends for lower rates of TP53 resistance mutations and RB1 loss compared with osi. These initial findings suggest that first-line ami+laz is changing the biology of acquired resistance and demonstrate clear proof of mechanism with potent inhibition of resistance via the EGFR and MET pathways.

Clinical trial identification

NCT04487080.

Editorial acknowledgement

Medical writing assistance was provided by Claire E. Brady, PharmD, of Lumanity Communications Inc and funded by Janssen Global Services LLC.

Legal entity responsible for the study

Janssen Pharmaceuticals.

Funding

Janssen Global Services LLC.

Disclosure

B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BeiGene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi Aventis, Springer Healthcare Ltd, 4D Pharma, AbbVie, Da Voltera, Eli Lilly, Ellipse Pharma Ltd, F-Star, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Socar Research, Taiho Oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD; Financial Interests, Institutional, Local PI: AbbVie, Amgen, Blueprint Medicines, Daiichi Sankyo, Pfizer, Roche-Genentech, Turning Point Therapeutics, Nuvalent, Enliven, Prelude Therapeutics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Ose Immunotherapeutics, Sanofi, Taiho; Financial Interests, Institutional, Steering Committee Member: BeiGene, GSK, Janssen, Takeda, Genmab; Financial Interests, Institutional, Funding: Cristal Therapeutics. S. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca/MedImmune, Roche, Merck Sharp & Dohme, Pfizer, Eli Lilly, BMS/Ono, Takeda, Janssen, IMBdx, Merck (German), Novartis, Abion, Abion, BeiGene, ImmuneOncia, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca/MedImmune, Roche, Merck Sharp & Dohme, Eli Lilly, Amgen, Yuhan; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme, AstraZeneca, Lunit. S. Lu: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Zai Lab, GenomiCare, Yuhan, Roche, Menarini, InventisBio Co. Ltd; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, Hansoh Pharma, Hengrui Therapeutics; Financial Interests, Institutional, Research Funding: AstraZeneca, ison MediPharma, Bristol Myers Squibb, Hengrui Therapeutics, BeiGene, Roche, Hansoh, Lilly Suzhou Pharmaceutical Co. J.R. Rodriguez Cid: Financial Interests, Personal, Other, All Support: Janssen; Financial Interests, Personal, Other, Consulting Fees: Novartis, Roche, AstraZeneca, Merck Sharp & Dohme, Bristol Myers, Teva.; Financial Interests, Personal, Speaker’s Bureau: Amgen, Roche, Merck Sharp&Dohme, Bristol Myers, AstraZeneca, Janssen, Teva, Takeda, Novartis, Pfizer; Financial Interests, Personal, Other: Amgen, Roche, Merck Sharp & Dohme, Bristol Myers, AstraZeneca, Janssen, Teva, Takeda, Novartis, Pfizer. H. Hayashi: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb Co. Ltd, AstraZeneca K.K, Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo K.K, Eli Lilly Japan K.K, Merck Biopharma Co. Ltd, MSD K.K., Novartis Pharmaceuticals K.K, Pfizer, Takeda Pharmaceutical Co. Ltd; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb Co. Ltd, Eli Lilly Japan K.K, Pfizer, AstraZeneca K.K, Daiichi Sankyo Co. Ltd; Financial Interests, Personal, Royalties, Currently no provided: Sysmex; Financial Interests, Personal, Steering Committee Member: Janssen Pharmaceutical K.K., GSK plc., Daiichi Sankyo, Inc.; Financial Interests, Institutional, Local PI: IQVIA Services Japan K.K, Syneos Health Clinical K.K., EPS Corporation., Nippon Kayaku Co.,Ltd., Takeda Pharmaceutical Co.,Ltd., MSD K.K., Amgen Inc., Taiho Pharmaceutical Co.,Ltd., Bristol Myers Squibb Company, Janssen Pharmaceutical K.K., CMIC Co., Ltd., Pfizer R&D Japan G.K., Labcorp Development Japan K.K., Kobayashi Pharmaceutical Co., Ltd., Pfizer Japan Inc., AbbVie Inc., A2 Healthcare Corp., Eli Lilly Japan K.K., Medpace Japan KK, EPS International Co.,Ltd,., Covance Japan Inc., EP-CRSU Co., Ltd., GSK K.K., Sanofi K.K., Chugai Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co., Ltd., PRA Health Sciences Inc., Astellas Pharma Inc., Ascent Development Services, AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., Merck Biopharma Co., Ltd, Mochida Pharmaceutical Co., Ltd., Japan Clinical Research Operations; Financial Interests, Institutional, Research Grant: Japanese Gastric Cancer Association, Clinical Research Support Center Kyushu, Japan Clinical Caner Research Organization, Ono Pharmaceutical Co.,Ltd., Medical Research Support, Eisai Co., Ltd, Shionogi & Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Bayer Yakuhin, Ltd, Kyowa Kirin Co.,Ltd.; Financial Interests, Institutional, Funding: SRL Medisearch Inc., Eisai Inc., Thoracic Oncology Research Group(TORG), West Japan Oncology Group (WJOG), Comprehensive Support Project for Oncological Research of Breast Cancer (CSPOR-BC), Mebix, Inc.; Non-Financial Interests, Member: West Japan Oncology Group, Japanese Society of Medical Oncology. D. Nguyen: Financial Interests, Personal, Advisory Board, 5/6/23, Advisory Panel on mEGFR lung cancer in AAPI population: Janssen; Non-Financial Interests, Other, Panel discussion, non-compensated, regarding Equity, etc: Takeda; Other, Safety Review Committee, non-compensated, clinical trial: Seagen; Other, Funding for publication fees: Novartis, Pfizer. J.C. Yang: Financial Interests, Institutional, Advisory Board: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Amgen, Novartis, Bayer, GSK, Takeda Oncology, Puma Pharmaceuticals, Yuhan Pharmaceuticals, Ono Pharmaceuticals, Merck Serono, MSD, Pfizer, Eli Lilly, Roche/Genentech, Janssen, Gilead, Blueprint Medicine, Eisai, Sanofi, Taiho, BMS, Omega Therapeutics, InHeart Therapeutics, Regeneron; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Novartis; Financial Interests, Institutional, Coordinating PI: AstraZeneca, MSD; Financial Interests, Coordinating PI: Dizal Pharmaceutical; Financial Interests, Steering Committee Member: Numab, Merck, Daiichi Sankyo, Eli Lilly, Janssen, Arrivant, Cullinan; Financial Interests, Institutional, Steering Committee Member: Ipsen, Takeda Oncology; Non-Financial Interests, Member: IASLC, ASCO. A.C. Gelatti: Financial Interests, Personal, Speaker’s Bureau: Roch, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Daiichi Sankyo, Inc., Janssen, Pfizer, Lilly, Novartis, Takeda; Financial Interests, Personal, Other, Support: Daiichi Sankyo, Inc., Amgen, Janssen; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Beingene, Pfizer, Amgen. S. Owen: Financial Interests, Personal, Advisory Board: Janssen, Bristol Myers Squibb, Novocure, Roche. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology, AnHeart Therapeutics, BMS, Daiichi Sankyo; Financial Interests, Personal, Ownership Interest: MBrace Therapeutics, BlossomHill Therapeutics; Financial Interests, Personal, Stocks/Shares: Nuvalent; Financial Interests, Institutional, Local PI: Pfizer, Mirati, JNJ/jassen, Merus, Revolution Medicine. M. Ennis, S. Sethi, J.M. Bauml, J. Zhang, J.C. Curtin: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks or ownership: Johnson & Johnson Innovative Medicine. B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Medpacto, Blueprint medicines, RandBio, Hanmi, GC Cell, Gilead, Ridgeline Discovery GmbH; Financial Interests, Personal, Advisory Board: Kanaph Therapeutic Inc, Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, Amgen, AstraZeneca, Regeneron, Seagen, Samsung Bioepis; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, Kanaph Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: CHA Bundang Medical Center, Mogam Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, Gradiant Bioconvergence, Therapex, GI Innovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio Therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, JINTSbio, Hanmi, Daewoong Pharmaceutical Co., Ltd., Vertical Bio AG, Korea Institute of Oriental Medicine, National Research Foundation of Korea, KHIDI; Other, Founder: Daan Biotherapeutics; Other, Invited speaker: ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer, Liangyihui Network Technology Co., Ltd.. All other authors have declared no conflicts of interest.