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OrigAMI-2：一项在左侧RAS/BRAF野生型转移性结直肠癌中比较amivantamab与cetuximab（两者均联合FOLFOX或FOLFIRI）作为一线治疗的随机3期研究

OrigAMI-2: A randomized, phase 3 study of amivantamab vs cetuximab, both in combination with FOLFOX or FOLFIRI, as first-line treatment in left-sided RAS / BRAF wild-type metastatic colorectal cancer

编号 CT217 展板 12 时间 4/21 09:00–12:00 区域 Section 51 主讲 Bing Xia
分会场 Phase II and Phase III Clinical Trials in Progress
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作者与单位 Authors & Affiliations

Dirk Arnold1, Andres Cervantes2, Michel Ducreux3, Sae-won Han4, Heinz-Josef Lenz5, Kei Muro6, Kanwal Raghav7, Lin Shen8, Jaw Yuan Wang9, Pei Jye Voon10, Hung-Chuh Hsu11, Bing Xia12, Ryota Iwasawa13, Shamita Carrigan13, Brooke Diorio14, Patricia Lorenzini14, Sandip Acharya15, Seema Sethi13, Mahadi Baig14, Filippo Pietrantonio16

1Asklepios Tumorzentrum Hamburg, AK Altona, Hamburg, Germany,2INCLIVA University of Valencia, Valencia, Spain,3Université Paris-Saclay, Department of Medical Oncology, Gustave Roussy, Inserm Unité Dynamique des Cellules Tumorales, Villejuif, France,4Seoul National University Hospital, Seoul, Korea, Republic of,5USC Norris Comprehensive Cancer Center, Los Angeles, CA,6Aichi Cancer Center Hospital, Nagoya, Japan,7MD Anderson Cancer Center, Houston, TX,8Beijing Cancer Hospital, Beijing, China,9Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan,10Department of Radiotherapy and Oncology, Sarawak General Hospital, Kuching, Sarawak, Malaysia,11College of Medicine, Chang Gung University, Taoyuan, and Division of Hematology-Oncology Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan,12Johnson & Johnson, San Diego, CA,13Johnson & Johnson, Spring House, PA,14Johnson & Johnson, Raritan, NJ,15Johnson & Johnson, Hyderabad, India,16Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

摘要 Abstract

中文摘要
背景：约50%被诊断为转移性结直肠癌（mCRC）的患者为KRAS、NRAS和BRAF野生型（RAS/BRAF WT）。左侧RAS/BRAF WT mCRC的标准初始治疗为双药化疗（FOLFOX或FOLFIRI）联合抗EGFR治疗。然而，耐药几乎不可避免。MET改变是已知的EGFR抑制耐药机制，MET扩增发生于5%-23%的EGFR耐药mCRC。Amivantamab是一种具有免疫细胞导向活性的EGFR-MET双特异性抗体，已获FDA批准用于EGFR突变晚期非小细胞肺癌的4项适应症。在1b/2期OrigAMI-1研究（NCT05379595）中，amivantamab联合FOLFOX或FOLFIRI在RAS/BRAF WT mCRC参与者中显示出快速且持久的抗肿瘤活性，无论肿瘤原发部位如何（Pietrantonio ESMO 2024）。这项3期随机研究的目的是评估amivantamab与cetuximab（两者均联合FOLFOX或FOLFIRI）作为左侧RAS/BRAF WT不可切除或转移性CRC参与者一线治疗的疗效。 方法：多中心、全球性OrigAMI-2研究（NCT06662786）计划在21个国家的216个站点开展。符合条件的参与者将经当地检测确认为KRAS、NRAS和BRAF野生型，患有左侧不可切除或转移性结直肠癌，且针对晚期疾病未经治疗。左侧疾病定义为原发肿瘤起源于脾曲、降结肠、乙状结肠、直肠乙状结肠或直肠。主要排除标准包括已知dMMR/MSI-H状态、HER2阳性或扩增肿瘤，以及既往接受过EGFR或MET靶向药物。约1000名参与者将按1:1随机分配接受皮下注射amivantamab（与重组人透明质酸酶[rHuPH20]共同配制）或静脉注射cetuximab，两者均联合FOLFOX或FOLFIRI（由研究者选择）。随机化将按化疗选择（FOLFOX或FOLFIRI）、局限性疾病（是或否）以及既往辅助治疗（是或否）进行分层。主要终点为盲态独立中心审查评估的无进展生存期。次要终点包括总生存期、客观缓解率、缓解持续时间和患者报告结局。安全性评估将包括监测不良事件和实验室异常。
查看英文原文 English abstract
Background: Approximately 50% of patients diagnosed with metastatic colorectal cancer (mCRC) are wild-type for KRAS , NRAS , and BRAF ( RAS/BRAF WT). Standard initial therapy for left-sided RAS/BRAF WT mCRC is doublet chemotherapy (FOLFOX or FOLFIRI) combined with anti-EGFR therapy. However, resistance is nearly inevitable. MET alterations are known resistance mechanisms to EGFR inhibition, with MET amplification occurring in 5%-23% of EGFR-resistant mCRC. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that is approved by the FDA for 4 indications in EGFR -mutated advanced non-small cell lung cancer. In the phase 1b/2 OrigAMI-1 study (NCT05379595), the combination of amivantamab plus FOLFOX or FOLFIRI demonstrated rapid and durable antitumor activity, regardless of tumor sidedness, in participants with RAS / BRAF WT mCRC (Pietrantonio ESMO 2024). The objective of this phase 3 randomized study is to assess the efficacy of amivantamab, as compared with cetuximab, both in combination with FOLFOX or FOLFIRI, as first-line therapy for participants with left-sided RAS / BRAF WT unresectable or metastatic CRC. Methods: The multicenter, global OrigAMI-2 study (NCT06662786) is planned to open in 216 sites in 21 countries. Eligible participants will be WT for KRAS , NRAS , and BRAF by local testing, have left-sided unresectable or metastatic colorectal cancer, and be treatment-naïve for advanced disease. Left-sided disease will be defined as a primary tumor arising from the splenic flexure, descending colon, sigmoid colon, rectosigmoid, or rectum. Key exclusion criteria include known dMMR/MSI-H status, HER2-positive or amplified tumor, and prior exposure to EGFR or MET targeting agents. Approximately 1000 participants will be randomly assigned 1:1 to receive subcutaneous amivantamab (co-formulated with recombinant human hyaluronidase [rHuPH20]) or intravenous cetuximab, both combined with FOLFOX or FOLFIRI (investigator's choice). Randomization will be stratified by chemotherapy choice (FOLFOX or FOLFIRI), limited disease (yes or no), and prior adjuvant therapy (yes or no). The primary endpoint will be progression-free survival by blinded independent central review. Secondary endpoints include overall survival, objective response rate, duration of response, and patient-reported outcomes. Safety assessments will include monitoring adverse events and laboratory abnormalities.
利益披露 Disclosure
D. Arnold, Amgen, Aptitude Health, Art Tempi Media, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Clinical Care Options, Eisai, Research to Practice, GSK, Imedex, iOMEDICO (Germany), Ipsen, MCI Other, invited speaker. Merck Serono, PeerMD (China), PRMA Consulting, Sanofi (Genzyme), Servier, Sirtex, Streamitup Germany, Tactics MD LLC, Viatris, and WebMD Health Corp Other, invited speaker. Amgen, AstraZeneca, Boston Scientific, Bristol Myers Squibb, CRA International, Gilead, Janssen-Cilag, Merck Sharp & Dohme, Onkowissen, Pierre Fabre Other, advisory board. Seagen, Takeda, and Terumo Other, advisory board. AbbVie (institution) ). OncoLytics, Phanes Therapeutics, AIO (German Cancer Society), ASCO, DGHO, EORTC, and ESO Other, other non-financial interests. Elsevier and Sanofi (Genzyme) Other, other relationships. A. Cervantes, Amgen, Foundation Medicine, Merck Serano, Roche, Transgene Other, advisory role. Actuate Therapeutics, Adaptimmune, Amcure, Amgen, Astellas Pharma, AstraZeneca Spain, Beyer, BeiGene, BMSi, FibroGen, Genentech, Lilly, MedImmune, Merck Serono, MSD, Natera, Novartis, SERVIER ). Sierra Oncology, Takeda ). M. Ducreux, Sandoz Employment. Bayer, Pierre Fabre, Roche/Genentech, TERUMO Other, honoraria. Abbvie, Abcely, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Daiichi Sankyo/AstraZeneca, GlaxoSmithKline, HalioDx, Ipsen, Lilly, Merck Serono, MSD, Novartis, Pierre Fabre, Rafael Pharma, Roche Other, Consulting or Advisory Role. Scandion Oncology, Servier, Sotio, Zymeworks Other, Consulting or Advisory Role. Amgen, AstraZeneca, Bayer, GalxoSmithKline, HalioDx, Lilly, Merck KGaA, MSD, Pierre Fabre, Roche, SERVIER Other, Speakers Bureau. Keocyt, Roche ). S. Han, AstraZeneca, Natera, and AbbVie Other, consulting or advisory role. Boryung, IMBdx, Hanmi, Loxo Oncology, Roche, Genentech, Mirati Therapeutics, Arcus Biosciences, Merck Sharp & Dohme, BeyondBio, Jeil Pharmaceutical, Janssen, Seagen, Lilly, MedImmune ), research funding (all to institution). Leap Therapeutics, Jiangsu Hengrui Pharmaceutical, GC Biopharma, AbbVie, Cell Biotech, Astellas, Merck, GSK, and AstraZeneca ), research funding (all to institution). H. Lenz, Bayer, Boehringer Ingelheim, Fulgent Genetics, G1 Therapeutics, Isofol Medical, Jazz Pharmaceuticals, Merck Serono, Oncocyte, Roche Other, Honoraria. 3T BioSciences, Bayer, BMS, Fulgent Genetics, GlaxoSmithKline, Merck Serono, Roche Other, Consulting or Advisory Role. K. Muro, Bayer, BMS, Chugai Pharma, Daiichi Sankyo/UCB Japan, Lilly, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Other, Honoraria. Amgen, AstraZeneca, Chugai Pharma, Ono Pharmaceutical, Soasia Pharma Other, Consulting to Advisory Role. Amgen, Astellas, Chugai Pharma, Daiichi Sankyo, Eisai, Merck KGaA, MSD, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, Taiho Pharmaceutical ). K. Raghav, AstraZeneca, Bayer, Eisai, Daiichi Sankyo, and Seagen Other, consulting or advisory role. Bayer Other, speakers bureau. Bayer (institution), Roche/Genentech (institution), Guardant Health (institution), Daiichi Sankyo/AstraZeneca (institution), HiberCell (institution), and Merck Serono (institution) ). L. Shen, AstraZeneca, Boehringer Ingelheim, MSD, SERVIER, Transcenta Holding Limited Other, Consulting or Advisory Role. BeiGene ). J. Wang, None. P. Voon, AstraZeneca, Novartis, Boehringer Ingelheim, Janssen-Cilag, Johnson & Johnson, Viracta Therapeutics, Inc., Roche, Merck KGaA, Merck Sharp & Dohme, BeiGene, Amgen, and Revolution Medicines Other, received grants or contracts. AstraZeneca, Novartis, Merck Sharp & Dohme, Pfizer, BeiGene, Amgen, Merck KGaA, Janssen-Cilag, and Johnson & Johnson Other, consulting fees. AstraZeneca, Novartis, Merck Sharp & Dohme, Pfizer, Amgen, Merck KGaA, Janssen-Cilag, and Johnson & Johnson Other, received payment or honoraria. H. Hsu, None. B. Xia, Johnson & Johnson Employment, Stock. R. Iwasawa, Johnson & Johnson Employment, Stock. S. Carrigan, Johnson & Johnson Employment, Stock. B. Diorio, Johnson & Johnson Employment, Stock. P. Lorenzini, Johnson & Johnson Employment, Stock. S. Acharya, Johnson & Johnson Employment, Stock. S. Sethi, Johnson & Johnson Employment, Stock. M. Baig, Johnson & Johnson Employment, Stock. F. Pietrantonio, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Incyte, Ipsen, Johnson & Johnson, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Seagen, Servier, and Takeda Other, honoraria as an invited speaker. Agenus, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Gilead, GSK, Incyte, Italfarmaco SpA, Jazz Pharmaceuticals, Johnson & Johnson, Merck Sharp & Dohme Other, consulting or advisory role. Merck Serono, Pfizer, Pierre Fabre, Revolution Medicines, Rottapharm Biotech, Servier, and Takeda Other, consulting or advisory role. Agenus, Amgen, AstraZeneca, Bristol Myers Squibb, GSK, Incyte, Johnson & Johnson, Lilly, and Rottapharm Biotech ), research funding (to Institution).

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