LBPO.ET04 · 实验与分子治疗 · Late-Breaking

Impact of first-line (1L) amivantamab-lazertinib vs osimertinib on second-line (2L) progression-free survival (PFS)

编号 LB474 展板 21 时间 4/22 09:00–12:00 区域 Section 53 主讲 Mary Angelozzi

分会场 Late-Breaking Research: Experimental and Molecular Therapeutics 4

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作者与单位

David R. Spigel¹, Danny Nguyen², Hidetoshi Hayashi³, Byoung Chul Cho⁴, Sanjay Popat⁵, James Chih-Hsin Yang⁶, Scott Owen⁷, Antonio Passaro⁸, Clarissa Baldotto⁹, Julian Kam¹⁰, Seema Sethi¹¹, Sujay Shah¹¹, Jiarui Zhang¹¹, Joshua C. Curtin¹¹, Nicolas Girard¹², William N. William Jr¹³

¹Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN,²City of Hope Comprehensive Cancer Center, Duarte, CA,³Department of Medical Oncology, Kindai University Faculty of Medicine, Sakai, Osaka, Japan,⁴Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of,⁵Royal Marsden Hospital NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom,⁶National Taiwan University Cancer Center, National Taiwan University Hospital, Taipei, Taiwan,⁷McGill University Health Centre, Montréal, QC, Canada,⁸Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan, Italy,⁹Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil,¹⁰Johnson & Johnson, Raritan, NJ,¹¹Johnson & Johnson, Spring House, PA,¹²Institut du Thorax Curie-Montsouris, Paris, France; Paris-Saclay University, UVSQ-Versailles, France,¹³Oncoclínicas, São Paulo, Brazil

摘要 Abstract

Background: In MARIPOSA, 1L amivantamab plus lazertinib (ami-laz) showed a statistically significant and clinically meaningful OS benefit vs osimertinib (osi; HR, 0.75; P =0.005). Ami-laz significantly reduced acquired MET amp ( P =0.002) and EGFR resistance mutations ( P =0.01) vs osi, with no significant increase in other resistance pathways (e.g., RTK signaling, cell cycle), suggesting ami-laz changes the biology of disease. PFS after first subsequent therapy, often used to assess 2L outcomes, may be biased due to significantly longer 1L PFS seen for ami-laz vs osi (HR, 0.70; P <0.001) in MARIPOSA. Here, we evaluated 2L PFS in participants (pts) in MARIPOSA, measured from time of first subsequent therapy initiation. Methods: To evaluate the effects of starting with ami-laz vs osi on long-term outcomes, we assessed 2L PFS, defined as time from initiation of first subsequent therapy to second objective progressive disease (PD) by investigator, or death. Analyses are post-hoc/exploratory with nominal P values. Acquired resistance was assessed from paired baseline and end of treatment (EOT) plasma samples as previously characterized (Besse ESMO 2024). ctDNA was assessed by NGS. Known resistance mechanisms included EGFR/MET -dependent (e.g., C797S, MET amp) and/or EGFR/MET -independent resistance (e.g., PIK3CA , RAS/RAF , cell cycle, TP53/Rb1 LOF); absence of these alterations constituted ‘unknown' resistance. Results: As of the 4 Dec 2024 final analysis data cutoff, median follow-up for pts who received a subsequent therapy (post-ami-laz, 154; post-osi, 209) was 37.9 mo, which was consistent with the randomized population. Demographics and baseline disease characteristics at the start of 1L tx were balanced. In both arms, the majority of pts started a subsequent regimen that most commonly included platinum chemotherapy and/or an EGFR-targeting agent. In total, EOT acquired resistance data were available for 226 pts. Among all pts who started a first subsequent therapy after 1L ami-laz vs osi, median 2L PFS was 8.4 vs 5.3 mo (HR, 0.72; 95% CI, 0.54-0.95; P =0.02). Harboring unknown resistance was associated with longer PFS, regardless of arm. Median 2L PFS was 4.6 months for pts with known resistance vs 7.4 months for pts with unknown resistance (HR, 0.63; 95% CI, 0.45-0.90; P =0.01), illustrating that outcomes remain worse for pts with common, tractable acquired resistance mutations (e.g., C797S, MET amp) compared to those harboring unknown resistance mutations. Conclusion: Starting with 1L ami-laz provides long-term durable survival, as demonstrated by improved 1L and 2L PFS vs osi. Development of known resistance at end of 1L tx results in poor prognosis, while unknown resistance mechanisms may not. Ami-laz is the only combination regimen that reduces the most common resistance mechanisms (e.g., EGFR/MET ). Changing the biology of disease may be an important factor for long-term survival.

利益披露 Disclosure

D. R. Spigel, Genentech/Roche (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), Takeda (Inst), Evelo Therapeutics (Inst), Bayer (Inst Other, Consulting or Advisory Role. EMD Serono (Inst), Molecular Templates (Inst), Amgen (Inst), Curio Science (Inst), Intellisphere (Inst), Ipsen (Inst), Jazz Pharmaceuticals (Inst), Mirati Therapeutics (Inst) Other, Consulting or Advisory Role. Puma Biotechnology (Inst), Sanofi/Aventis (Inst), Exelixis (Inst), Novocure (Inst), Regeneron (Inst), Lilly (Inst), Janssen (Inst), Evidera (Inst) Other, Consulting or Advisory Role. Genentech/Roche (Inst), Novartis (Inst), Celgene (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), AstraZeneca (Inst), University of Texas Southwestern Medical Center—Simmons Cancer Center (Inst) ). Merck (Inst), G1 Therapeutics (Inst), Neon Therapeutics (Inst), Takeda (Inst), Nektar (Inst), Celldex (Inst), Clovis Oncology (Inst), Daiichi Sankyo (Inst), EMD Serono (Inst), Astellas Pharma (Inst) ). GRAIL (Inst), Transgene (Inst), Aeglea Biotherapeutics (Inst), Ipsen (Inst), BIND Therapeutics (Inst), Eisai (Inst), ImClone Systems (Inst), Immunogen (Inst), Janssen Oncology (Inst) ). MedImmune (Inst), Molecular Partners (Inst), Agios (Inst), GlaxoSmithKline (Inst), Tesaro (Inst), Cyteir (Inst), Apollomics (Inst), Novocure (Inst), Elevation Oncology (Inst) ). Calithera Biosciences (Inst), Arcus Biosciences (Inst), Arrys Therapeutics (Inst), Bayer (Inst), BeiGene (Inst), BioNTech (Inst), Blueprint Medicines (Inst), Boehringer Ingelheim (Inst) ). Denovo Biopharma (Inst), Hutchison MediPharma (Inst), Incyte (Inst), Kronos Bio (Inst), Loxo Oncology (Inst), Macrogenics (Inst), Molecular Templates (Inst), Oncologie (Inst), Pfizer (Inst) ). PTC Therapeutics (Inst), PureTech (Inst), Razor Genomics (Inst), Repare Therapeutics (Inst), Rgenix (Inst), Tizona Therapeutics Inc (Inst), Verastem (Inst) ). AstraZeneca, Genentech, Novartis Other, Travel, Accommodations, Expenses. ASCO Other, leadership. D. Nguyen, Janssen Oncology, Taiho Pharmaceutical, and Black Diamond Therapueitcs Other, received payment or honoraria. Taiho Oncology and Johnson & Johnson/Janssen Other, travel, accommodations, expenses. Takeda, Novartis, Seagen, and Pfizer Other, other relationships. Takeda, Novartis, and Johnson & Johnson/Janssen Other, uncompensated relationships. Janssen Oncology and Black Diamond Therapeutics Other, consulting or advisory role. H. Hayashi, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, and Johnson & Johnson Other, consulting or advisory role. Sysmex Patent, Other, holds patents, royalties, or other intellectual property. Johnson & Johnson, Ono Pharmaceutical, Bristol Myers Squibb Japan, Eli Lilly, Boehringer Ingelheim, AstraZeneca Japan, Chugai Pharma, Pfizer, Merck Sharp & Dohme, Novartis, Merck, BioPharma, Amgen, A Other, received honoraria. IQVIA Services Japan K.K., Eisai Co. Ltd., Syneos Health Clinical K.K., EP-CRSU Co. Ltd., EPS Corporation, Shionogi & Co. Ltd., Nippon Kayaku Co. Ltd., Otsuka Pharmaceutical Co. Ltd. ). Takeda Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., MSD K.K., Sanofi K.K., Amgen Inc., Chugai Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd. ). Bristol-Myers Squibb Company, SRL Medisearch Inc., Johnson & Johnson Pharmaceutical K.K., PRA Health Sciences Inc., CMIC Co. Ltd., Astellas Pharma Inc., Pfizer R&D Japan G.K. ). Ascent Development Services, Labcorp Development Japan K.K., Eisai Inc., Kobayashi Pharmaceutical Co. Ltd., Bayer Yakuhin Ltd., Pfizer Japan Inc., AstraZeneca K.K., AbbVie Inc. ). Daiichi Sankyo Co. Ltd., A2 Healthcare Corp., Novartis Pharma K.K., Eli Lilly Japan K.K., Merck Biopharma Co. Ltd., Medpace Japan K.K., Kyowa Kirin Co. Ltd., Japanese Gastric Cancer Association ). Thoracic Oncology Research Group, Clinical Research Support Center Kyushu, West Japan Oncology Group, Japan Clinical Cancer Research Organization ). Comprehensive Support Project for Oncological Research of Breast Cancer, EPS International Co. Ltd., Mebix Inc., Ono Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd., Covance Japan Inc. ). Japan Clinical Research Operations Medical Research Support ). AbbVie, Kyowa Kirin, Daiichi Sankyo/UCB Japan, Guardant Health, Novocure, Takeda, Hisamitsu, NihonKayaku, and Nippon Kayaku Other, received honoraria. B. Cho, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Pfizer, Yuhan Corporation, Johnson & Johnson, Takeda, Merck Sharp & Dohme, Ono Pharmaceutical, Eli Lilly, Medpacto, Blueprint Medicines Other, consulting or advisory role. Cyrus Therapeutics, Guardant Health, Novartis, CJ, Abion, BeiGene, CureLogen, Onegene Biotechnology, GI-Cell, HK Inno-N, Imnewrun Biosciences Inc, Hanmi, Kanaph Therapeutics, BridgeBio, and Oscotec Other, consulting or advisory role. Interpark Bio and J Ints Bio Other, leadership role. DAAN Biotherapeutics Other, other relationships. Theravance, Gencurix, BridgeBio, Kanaph Therapeutics, Cyrus Therapeutics, Interpark Bio, and J Ints Bio Stock, Other Business Ownership. Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Johnson & Johnson, Yuhan Corporation, Ono Pharmaceutical, Dizal Pharma, Merck Sharp & Dohme ). AbbVie, GI Innovation, Eli Lilly, Blueprint Medicines, Interpark Bio, LG Chem, Oscotec, GI-Cell, Abion, Boehringer Ingelheim, CJ Bioscience, CJ Blossom Park, Cyrus, Genexine, Nuvalent Inc ). Oncternal Therapeutics, Regeneron, BridgeBio, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J Ints Bio, Hanmi, and CHA Bundang Medical Center ). Champions Oncology, Crown Bioscience, and Imagen Patent, Other, holds patents, royalties, or other intellectual property. S. Popat, Boehringer Ingelheim, Novartis, Amgen, Johnson & Johnson, Daiichi Sankyo, AstraZeneca, Bayer, Bristol Myers Squibb, Blueprint Medicines, Merck Serono, Guardant Health, BeiGene, Takeda, Eli Lilly Other, served on advisory boards. Eli Lilly, Roche, Turning Point Therapeutics, GSK, Merck Sharp & Dohme, Pfizer, Sanofi, and EQRx Other, served on advisory boards. Medscape and VJOncology Other, invited speaker. Elsevier, Amgen, Merck Sharpe & Dohme, and Blueprint Medicines Other, other relationships. ARIAD Pharmaceuticals, Boehringer Ingelheim, Celgene, Takeda, Turning Point Therapeutics, Roche, Johnson & Johnson, Bristol Myers Squibb, and Eli Lilly Other, served as a coordinating PI. AstraZeneca, Roche, GSK, and Trizell Other, served as a local PI. Guardant Health ). British Thoracic Oncology Group and European Thoracic Oncology Platform Other, leadership role. ALK Positive UK, International Association for the Study of Lung Cancer, Lung Cancer Europe, and the Ruth Strauss Foundation Other, advisory role. the European Society of Medical Oncology Other, officer. Mesothelioma Applied Research Foundation Other, member of the board of directors. J. Yang, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda Other, honoraria. AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, GSK, Hansoh Pharma, Incyte Other, consulting or advisory role. Johnson & Johnson, Eli Lilly, Merck Serono, Merck Sharp & Dohme Oncology, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Yuhan Corporation Other, consulting or advisory role. Pfizer Travel. S. Owen, Johnson & Johnson, Bristol Myers Squibb, Novocure, and Roche Other, consulting or advisory role. A. Passaro, Roche/Genentech, Bristol Myers Squibb, AstraZeneca, MSD Oncology, Pfizer, Boehringer Ingelheim, Janssen, Novartis, Daiichi Sankyo Europe GmbH, Bayer Other, consulting or advisory role. AstraZeneca, Janssen, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, MSD Oncology Other, speakers’ bureau. C. Baldotto, Oncologia D'Or Employment, Other, leadserhsip, honoraria. Roche, Amgen, AstraZeneca, MSD, Takeda, Pfizer, Johnson & Johnson, BMS, Daiichi, Servier Other, consulting, advisory role. Roche, Amgen, AstraZeneca, MSD, Takeda, Pfizer, Johnson & Johnson, BMS, Daiichi, Servier Other, speaker's bureau. Roche, AstraZeneca, Johnson & Johnson, BMS, Amgen ). AstraZeneca Other, expert testimony. Daiichi, Amgen, AstraZeneca, MSD, Pfizer, Johnson & Johnson Travel. J. Kam, Johnson & Johnson Employment, Stock. S. Sethi, Johnson & Johnson Employment, Stock. S. Shah, Johnson & Johnson Employment, Stock. J. Zhang, Johnson & Johnson Employment, Stock. J. C. Curtin, Johnson & Jophnson Employment, Stock. N. Girard, AbbVie, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Roche, Janssen, LEOPharma, Eli Lilly, Merck Sharp & Dohme, Novartis, Sivan, Mirati Therapeutic Other, received consulting fees. Mirati, Pfizer, Sanofi, and Takeda Other, received consulting fees. AbbVie, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Roche, Janssen, LEO Pharma, Eli Lilly, Merck Sharp & Dohme, Novartis, Sivan Other, received payment or honoraria. Pfizer, Sanofi, and Takeda Other, received payment or honoraria. Janssen, Amgen, and Bristol Myers Squibb Travel. Roche Other, participated on a data safety monitoring board or advisory board. W. N. William Jr, AstraZeneca, Janssen, Merck, BMS, Sanofi, MSD ), to insitution. Roche/Genentech, AstraZeneca, Janssen, Merck, BMS, Sanofi, MSD, Pfizer, Takeda, Novartis, Boehringer Ingelheim, Eli Lilly, Bayer Other, consulting fees. Roche /Genentech, AstraZeneca, Janssen, Merck, BMS, Sanofi, MSD, Pfizer, Takeda, Novartis, Boehringer Ingelheim, Eli Lilly, Baye Other, Payment or honoraria for lectures, presentations, speakers bureaus. AstraZeneca, Merck, BMS, Daiichi Sankyo, Sanofi, Janssen Travel. Io9 Stock, Other, Participation on a Data Safety Monitoring Board or Advisory Board. Sociedade Brasileira de Oncologia Clínica, Latin American Cooperative Oncology Group Other, unpaid.

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