PO.CTP01.03 · 进行中的临床试验

RASolve 301：一项在既往接受过治疗的RAS突变型NSCLC患者中比较daraxonrasib（RMC-6236）与多西他赛的3期研究

RASolve 301: A Phase 3 study of daraxonrasib (RMC-6236) vs. docetaxel in patients with previously treated RAS-mutant NSCLC

编号 CT215 展板 10 时间 4/21 09:00–12:00 区域 Section 51 主讲 Ferdinandos Skoulidis, MD;PhD

分会场 Phase II and Phase III Clinical Trials in Progress

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作者与单位 Authors & Affiliations

Ferdinandos Skoulidis¹, Kathryn C. Arbour², Sanjay Popat³, Colin R. Lindsay⁴, Hidehito Hironouchi⁵, Gérard Zalcman⁶, Alessandra Curioni-Fontecedro⁷, Jarushka Naidoo⁸, Adrianus J. de Langen⁹, Lin Tao¹⁰, Erica Su¹⁰, Minoti Hiremath¹⁰, Achim Rittmeyer¹¹, Melissa Johnson¹²

¹The University of Texas MD Anderson Cancer Center, Houston, TX,²Memorial Sloan Kettering Cancer Center, New York, NY,³Royal Marsden Hospital-Sutton, Sutton, United Kingdom,⁴The Christie Hospital, Manchester, United Kingdom,⁵National Cancer Center Hospital, Tokyo, Japan,⁶Hôpital Bichat - Claude Bernard, Paris, France,⁷HFR Fribourg, Kantonsspital Fribourg, Villars-sur Glâne, Switzerland,⁸Beaumont Hospital, Dublin, Ireland,⁹Antoni van Leeuwenhoek, Amsterdam, Netherlands,¹⁰Revolution Medicines Inc, Redwood City, CA,¹¹LKI Lungenfachklink Immenhausen, Immenhausen, Germany,¹²SCRI Oncology Partners, Nashville, TN

摘要 Abstract

中文摘要

背景：既往接受过治疗的非小细胞肺癌（NSCLC）患者代表着重大的未满足医疗需求。在患者接受铂类化疗和/或免疫检查点抑制剂后，多西他赛单药治疗通常是主要的治疗手段，多项研究报告的客观缓解率（ORR）为9.2%-14.7%，中位无进展生存期（mPFS）为3.0-4.5个月，中位总生存期（mOS）为9.1-11.8个月。RAS突变发生于约30%的NSCLC病例，其中非G12C变异占60%。这些变异大多为G12X突变（如G12D、G12V等），目前尚无获批的靶向治疗。在一项正在进行的1期单药试验（NCT05379985）中，120-220 mg每日一次的daraxonrasib（RMC-6236，一种口服、RAS(ON)多选择性、针对GTP结合型突变和野生型RAS的三复合物抑制剂）在NSCLC患者中显示出可控的安全性和初步疗效。截至2024年9月30日的数据截止时（N=73），≥2例患者报告的≥3级治疗相关不良事件（TRAE）包括皮疹（n=5，7%）、呕吐（n=2，3%）和贫血（n=2，3%），无4级或5级TRAE。在40例既往接受过一线或二线治疗（包括免疫治疗和铂类化疗）的RAS G12X突变型NSCLC患者中，120-220 mg的daraxonrasib带来38%的确认ORR，中位缓解持续时间（DOR）为15.1个月（95% CI：11.1，无法估计[NE]），mPFS为9.8个月（95% CI：6，12.3），mOS为17.7个月（95% CI：13.7，NE）。这些初步数据为daraxonrasib在既往接受过治疗的局部晚期或转移性RAS突变型NSCLC患者中的持续开发提供了充分依据。方法：RASolve 301是一项全球性、多中心、开放标签、随机3期研究（NCT06881784），旨在评估daraxonrasib与多西他赛在既往接受过治疗的局部晚期或转移性RAS突变型NSCLC患者中的疗效和安全性。患者按1:1随机分配接受多西他赛或daraxonrasib。主要入选标准：病理确诊的NSCLC，年龄≥18岁，ECOG体能状态为0或1，既往接受过抗PD(L)-1药物和铂类化疗，以及基于当地检测确认的RAS突变。符合条件的RAS突变定义为KRAS/NRAS/HRAS在密码子12、13或61（G12、G13或Q61）处的非同义突变。主要排除标准包括未经治疗的中枢神经系统转移、既往接受过RAS靶向治疗，或存在有获批靶向治疗的可靶向驱动突变。双主要终点为RAS G12X突变（不含G12C，即G12X-C）患者的PFS和OS。主要次要终点包括所有RAS突变患者的PFS和OS，以及根据RECIST v1.1评估的ORR。该研究将在全球招募约420例患者，包括来自美国（含波多黎各）站点的患者。

查看英文原文 English abstract

Background: Previously treated non-small cell lung cancer (NSCLC) patients represent a significant unmet medical need. After patients have received platinum-based chemotherapy and/or immune checkpoint inhibitors, docetaxel monotherapy is often the mainstay of treatment, with reported objective response rates (ORRs) of 9.2%-14.7%, median progression-free survival (mPFS) of 3.0-4.5 months, and median overall survival (mOS) of 9.1-11.8 months across multiple studies. RAS mutations occur in ~30% of NSCLC cases, with non-G12C variants making up 60%. The majority of these are G12X mutations (e.g., G12D, G12V, etc.), for which no approved targeted therapies are available. In an ongoing Phase 1 monotherapy trial (NCT05379985), 120-220 mg daily daraxonrasib (RMC-6236), an oral, RAS(ON) multi-selective, tri-complex inhibitor of GTP-bound mutant and wild-type RAS, showed manageable safety and preliminary efficacy in patients with NSCLC. As of a September 30, 2024 data cutoff (N=73), Grade ≥3 treatment-related adverse events (TRAEs) reported in ≥2 patients included rash (n=5, 7%), vomiting (n=2, 3%), and anemia (n=2, 3%), with no Grade 4 or Grade 5 TRAEs. In 40 patients with RAS G12X-mutant NSCLC previously treated with one or two lines of therapy (including immunotherapy and platinum-based chemotherapy), daraxonrasib at 120-220 mg resulted in a confirmed ORR of 38%, median duration of response (DOR) of 15.1 months (95% CI: 11.1, Not Estimable [NE]), mPFS of 9.8 months (95% CI: 6, 12.3), and a mOS of 17.7 months (95% CI: 13.7, NE). These preliminary data provide strong rationale for the continued development of daraxonrasib in patients with previously treated, locally advanced or metastatic, RAS-mutant NSCLC. Methods: RASolve 301 is a global, multicenter, open-label, randomized Phase 3 study (NCT06881784) designed to evaluate efficacy and safety of daraxonrasib vs. docetaxel in patients with previously treated, locally advanced or metastatic, RAS-mutant NSCLC. Patients are randomized 1:1 to receive either docetaxel or daraxonrasib. Key eligibility criteria: pathologically confirmed NSCLC, age ≥18 years, ECOG performance status of 0 or 1, prior treatment with an anti-PD(L)-1 agent and platinum-based chemotherapy, and a documented RAS mutation based on local testing. Eligible RAS mutations are defined as nonsynonymous mutations in KRAS/NRAS/HRAS at codons 12, 13, or 61 (G12, G13, or Q61). Key exclusion criteria include untreated central nervous system metastases, prior RAS-directed therapy, or presence of an actionable driver mutation for which there is an approved targeted therapy. Dual primary endpoints are PFS and OS in patients with RAS G12X mutations excluding G12C (G12X-C). Key secondary endpoints include PFS and OS in patients with all RAS mutations, and ORR per RECIST v1.1. The study will enroll ~420 patients globally, including from sites in the USA (including Puerto Rico).

利益披露 Disclosure

F. Skoulidis, AstraZeneca; Amgen; Revolution Medicines; Novartis; BridgeBio; Beigene; BergenBio; Guardant Health; Calithera Biosciences; Tango Therapeutics; Hookipa Pharma; Novocure; MSD; Roche Other, Consulting. Amgen; Mirati Therapeutics; Revolution Medicines; Pfizer; Novartis; MSD Other, Researcher/Grant/Contract. BioNTech; Moderna Stock. ESMO; Japanese Lung Cancer Society; Medscape; Intellisphere; VSPO McGill Universite de Montreal; RV Mais Promocao Eventos; MJH Life Sciences; IDEOlogy Health; MI&T; PER; CURIO; DAVA Oncology Other, Honoraria. American Association for Cancer Research; International Association for the Study of Lung Cancer Other, Honoraria. K. C. Arbour, Revolution Medicines, Inc; Bristol Meyer Squibb; Lilly; Genentech; Verastem Other, Researcher/Grant/Contract (PAID TO INSTITUTE). Revolution Medicines, Inc Travel. Amgen; Novartis; Revolution Medicines; Lilly; Regeneron; AstraZeneca; G1 Therapeutics; Merck; Bristol Meyer Squibb Other, Advisory board participation. S. Popat, Anheart Therapeutics; Amgen; Arcus Biosciences; AstraZeneca; Bayer; BMS; Boehringer Ingelheim; Daiichi Sankyo; Ellipses; Erasca; Gilead; GSK; Guardant Health; IO Biotech; Janssen; Lilly; Merck KGaA; Other, Consulting fees. Mirati; MSD; Novocure; Novartis; Pfizer; Pharmamar; Pierre Fabre; Regeneron; Roche; Sanofi; Takeda; Turning Point Therapeutics Other, Consulting fees. Anheart Therapeutics; Amgen; Arcus Biosciences; AstraZeneca; Bayer; BMS; Boehringer Ingelheim; Daiichi Sankyo; Ellipses; Erasca; Gilead; GSK; Guardant Health; IO Biotech; Janssen; Lilly; Merck KGaA; Other, Advisory boards. Mirati; MSD; Novocure; Novartis; Pfizer; Pharmamar; Pierre Fabre; Regeneron; Roche; Sanofi; Takeda; Turning Point Therapeutics Other, Advisory boards. Amgen; AstraZeneca; Bayer; Gilead; Guardant Health; Janssen; Merck KGaA; Novocure; Pharmamar; Pfizer; Roche; Takeda Honoraria. Gilead Travel. British Thoracic Oncology Group; ALK Positive UK; Lung Cancer Europe; Ruth Strauss Foundation; ETOP-IBCSG Partners Foundation Board Other, Fiduciary Officer. C. R. Lindsay, Amgen Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, Clinical Investigator for a phase III clinical trial Invited Speaker, Personal, Advisory role; Invited Speaker, Personal, Educational Presentation/Workshop. Qiagen Other, Advisory Board, Personal. Apollomics Other, Researcher/Grant/Contract: Local Principal Investigator, Institutional, No financial interest, Principal Investigator for a phase II clinical trial. Boehringer Ingelheim Travel, Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, Clinical Investigator for a phase I-II clinical trial. Mirati Therapeutics Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, Clinical Investigator for a phase III clinical trial. Revolution Medicines, Inc. Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, Clinical Investigator for a phase I-II clinical trial; Research Grant, Institutional, Financial interest, Research funding which includes use of their medical products. Roche Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, C Clinical Investigator for a phase II clinical trial. H. Hironouchi, AstraZeneca K.K. Other, Payment or honoraria, Researcher/Grant/Contract: Payment to institution. Chugai Pharmaceutical Co., Ltd. Other, Payment or honoraria, Researcher/Grant/Contract: Payment to institution. MSD K.K. Other, Payment or honoraria, Researcher/Grant/Contract: Payment to institution. Bristol Myers Squibb K.K. Other, Payment or honoraria, Researcher/Grant/Contract: Payment to institution. Daiichi Sankyo Other, Researcher/Grant/Contract: Payment to institution. AbbVie GK Other, Researcher/Grant/Contract: Payment to institution. Eli Lilly Japan K.K. Other, Payment or honoraria. ONO PHARMACEUTICAL CO., LTD. Other, Payment or honoraria. G. Zalcman, Roche; Lilly; Pfizer; Bristol Myers Squibb; AstraZeneca; Boehringer Ingelheim; MSD Oncology; Inventiva Pharma; Da Volterra Other, Honoraria. Roche; Boehringer Ingelheim; Pfizer; Bristol Myers Squibb; MSD Oncology; Inventiva Pharma; AstraZeneca; Da Volterra Other, Consulting/Advisory (payment to institution). Bristol Myers Squibb Other, Consulting/Advisory (personal). Roche; Pfizer; AstraZeneca; Bristol Myers Squibb; Takeda; Regeneron Other, Researcher/Grant/Contract (payment to institution). Roche; Lilly; Pfizer; Bristol Myers Squibb; Pfizer; AstraZeneca; AbbVie Travel. A. Curioni-Fontecedro, Amgen; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; Daichii Sankyo; Janssen; Medscape; Merck Sharp & Dohme; Roche/Genentech; Takeda Other, Consulting/Advisory. Amgen; AstraZeneca; Bristol Myers Squibb; Foundation Medicine; Medscape; Merck Sharp & Dohme; Roche/Genentech; Takeda Other, Speaker. Amgen; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; Merck Sharp & Dohme; Roche/Genentech Other, Researcher/Grant/Contract: Payment to institution. J. Naidoo, AstraZeneca; Bristol Myers Squibb; Roche/Genentech; Amgen; Arcus Biosciences; NGM Pharmaceuticals; Bayer; Regeneron; Takeda; Pfizer; Elevation Oncology; Abbvie; Kaleido Biosciences; Mirati; Other, Consulting. Daiichi Sankyo Other, Consulting. AstraZeneca; Bristol Myers Squibb; Roche/Genentech; Daiichi Sankyo Other, Honoraria. AstraZeneca; Bristol Myers Squibb; Roche/Genentech; Amgen; Arcus Biosciences; NGM Pharmaceuticals; Bayer; Regeneron; Takeda; Pfizer; Elevation Oncology; Abbvie; Kaleido Biosciences; Mirati; Other, Participation on a Data Safety Monitoring Board or Advisory Board. Daiichi Sankyo Other, Participation on a Data Safety Monitoring Board or Advisory Board. A. J. de Langen, AstraZeneca; BMS; Boehringer Ingelheim; Pfizer; Lilly; MSD Other, Advisor. AstraZeneca; BMS; Boehringer Ingelheim; MSD Other, Researcher/Grant/Contract. L. Tao, Revolution Medicines, Inc. Employment, Stock, Stock Option. E. Su, Revolution Medicines, Inc. Employment, Stock, Stock Option. M. Hiremath, Revolution Medicines, Inc. Employment, Stock, Stock Option. A. Rittmeyer, Abbvie; AstraZeneca; BMS; Boehringer Ingelheim; Daiichi Sankyo; Eli Lilly; Gilead; J&J; GSK; MSD; Novartis; Pfizer; Regeneron; Roche Other, Consultant. M. Johnson, Adaptimmune; Amgen; ArriVent BioPharma; AstraZeneca; Bayer; Black Diamond; BlossomHill Therapeutics; Boehringer Ingelheim; Boundless Bio; Bristol-Myers Squibb; Carisma Therapeutics Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . Conjupro Biotherapeutics; Corvus Pharmaceuticals; D3 Bio; Daiichi Sankyo; Lilly; Erasca; Exelixis; Genentech/Roche; Genmab; Genocea Biosciences; Harpoon; Helsinn Healthcare SA; IDEAYA Biosciences Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . IGM Biosciences; Immuneering Corporation; Immunitas Therapeutics; Immunocore; Incyte; Janssen; LockBody Therapeutics; Loxo Oncology; Merck; Merus; Mirati Therapeutics; Modex Therapeutics Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . NeoImmune Tech; Neovia Oncology; NextPoint Therapeutics; Novartis; Nuvalent; OncoC4; Palleon Pharmaceutical; Pfizer; Pierre Fabre; PMV Pharmaceuticals; Prelude Therapeutics; Puma Biotechnology Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . RasCal Therapeutics; Regeneron Pharmaceuticals; Revolution Medicines; Ribon Therapeutics; Shattuck Labs; Shanghai Junshi Biosciences; Silicon Therapeutics; Summit Therapeutics; Systimmune Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . Taiho Oncology; TCR2 Therapeutics; Tempest Therapeutics; TheRas; Tizona Therapeutics; Vividion; Zymeworks; Mythic Therapeutics Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . AbbVie; Amgen; AstraZeneca; BeOne Medicines; Biohaven Pharmaceuticals; BioNTech; Bristol-Myers Squibb; Daiichi Sankyo; Ellipses Pharma; Genentech / Roche; Gilead Sciences; GlaxoSmithKline; Janssen Other, Consulting paid to institution. Jazz Pharmaceuticals; Lilly; Merck; Nuvalent; Ottimo Pharma; Pfizer; Regeneron Pharmaceuticals; Revolution Medicines; Summit Therapeutics; Zai Laboratory Other, Consulting paid to institution.

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