Daraxonrasib

随着中国药企不断加入，KRAS靶点竞赛更具观赏性。撰文丨黄仲平技术产业的发展一浪接着一浪，自创新药产业在中国落地生根以来，经历了振奋人心的潮起时刻，也经历了很长一段时间的潮落。但这是产业发展的必然规律，技术演进并非线性发展，而是充满曲折。KRAS在被发现后40年时间里曾被视为“不可成药”的药物靶点，但随着近年来对相关机制的研究深入，针对KRAS突变的药物治疗领域取得了突破性进展，特别是多款靶向KRAS的药物的获批，使这一“不可成药”靶点逐渐变得火热。在刚刚落幕的美国癌症研究协会(AACR)年会上，KRAS抑制剂火热程度直逼去年下半年开始大热的双抗，众多大型MNC都在紧盯着这个领域，下一个产业热点呼之欲出。KRAS究竟有何魅力？一片大蓝海市场1982年，Robert A. Weinberg等人在人类膀胱癌细胞T24/EJ中发现了HRAS，使得RAS成为第一个被发现的人类肿瘤基因。RAS家族目前已知有KRAS、NRAS和HRAS三个亚型。KRAS突变以单碱基错义突变为主，绝大多数发生在密码子G12、G13或Q61上。KRAS G12突变包括G12A、G12C、G12D、G12V等亚型，以G12C、G12D和G12V突变为主。大多数情况下，KRAS都处于失活态，KRAS突变导致和GTP结合的KRAS蛋白占比提升，使得KRAS无需上游RTK的信号即可处于激活状态，进而持续地激活下游细胞生长通路，导致肿瘤发生。简单来说，KRAS就像一个开关，突变后这个开关就处于常开的状态，一直刺激细胞生长。KRAS相关通路，来源：参考资料1在全球和中国KRAS突变阳性癌症中，发病人数排名前三的癌种为结直肠癌、非小细胞肺癌、胰腺癌。约有40%-50%的结直肠癌患者，30%的非小细胞肺癌患者及80%-90%的胰腺癌患者存在KRAS突变阳性。这其中，G12C是KRAS最常见的突变之一，KRAS G12C突变发生在约14%的非小细胞肺癌、约4%的结直肠癌以及约3%的胰腺癌患者中；在中国人群中，KRAS G12C突变发生在约4.3%的肺癌、约2.5%的结直肠癌患者以及约2.3%的胆管癌患者中。全球主要KRAS突变阳性癌症的发病人数均呈上升趋势。2016年至2024年，发病人数从180万人增长至200.9万人，并预计于2030年增长至256万人；同期，中国主要KRAS突变癌种的发病人数从42.1万人增长达到47.7万人，并预计于2030年达到64.1万人。尽管存在巨大未被满足的市场需求，但针对KRAS靶点的开发之路遍布荆棘，充满坎坷。成功的先行者转机出现在2013年，Kevan Shokat团队使用一种基于二硫键片段的化学文库方法筛选出了与KRAS G12C突变蛋白选择性共价结合的“化合物12”，使针对KRAS突变的靶向治疗成为可能。2016年，Matthew P. Patricelli等人在“化合物12”的基础上进一步优化出首个在体外模型中表现出药物候选效力的KRAS G12C抑制剂。2018年，Wellspring Biosciences在Cell上发表了KRAS G12C抑制剂ARS-1620的临床前数据，引发了第一波大范围的KRAS研发热潮。国内外药企迅速跟进，2018至2020年国内关于KRAS的专利申请有一两百篇，上百个公司关注和扎堆布局KRAS，火热程度堪比PD-1/L1。截至目前，全球范围内已有4款KRAS抑制剂获批。最早摘取胜利果实的是安进的Sotorasib（AMG510），于2021年获美国FDA加速批准，适应证为用于治疗既往接受过至少一种全身治疗的KRAS G12C突变的局部晚期或转移性非小细胞肺癌成人患者。但FDA并没有完全批准Sotorasib，并要求安进在2028年2月前开展并完成额外的验证性研究。2021至2024年，Sotorasib销售额分别为0.9亿美元、2.85亿美元、2.80亿美元和3.5亿美元。目前，Sotorasib在国内由百济神州负责开发和商业化工作。2025年1月，FDA批准了Sotorasib联合帕尼单抗（Panitumumab）用于治疗经治的KRAS G12C突变的转移性结直肠癌（mCRC）患者。第二款获批的KRAS抑制剂来自Mirati开发的Adagrasib，同样也是靶向KRAS G12C，于2022年12月获FDA加速批准，用于至少接受过一次系统治疗的KRAS G12C突变局部晚期或转移性NSCLC患者。但加速批准也意味着Adagrasib还需经历“转正”考验。在商业化方面，Adagrasib在2023年前三季度仅仅拿下0.36亿美元的销售额。2023年10月，BMS收购了Mirati。在BMS强大的销售网络下，2024年全年，Adagrasib销售额为1.18亿美元。目前，Adagrasib在国内的独家权利由再鼎医药拥有。已获批KRAS G12C抑制剂情况，来源：药创新整理令人欣喜的是，获批的另外两款KRAS G12C抑制剂均来自中国，分别是信达生物/劲方生物的氟泽雷塞和正大天晴/益方生物的格索雷塞。氟泽雷塞于2024年8月获国家药监局批准上市，用于单药治疗至少接受过一种系统性治疗的KRAS G12C突变型晚期非小细胞肺癌（NSCLC）成人患者。根据获批的临床数据显示，独立影像学评审委员会（IRRC）评估的确认客观缓解率（cORR）达49.1%，疾病控制率（DCR）达90.5%，中位无进展生存期（PFS）9.7个月，显示出优秀的临床疗效。格索雷塞也不遑多让，一项关键性II期研究数据显示，受试者的ORR达到52.0%，DCR为88.6%，PFS为9.1个月，中位总生存期（OS）为14.1个月。优异的数据使得格索雷塞于2024年11月获得国家药监局批准，适用于治疗至少接受过一种系统性治疗的KRAS G12C突变型的晚期非小细胞肺癌（NSCLC）成人患者。由于对KRAS G12C抑制剂的研究较早，MNC跟进的项目也基本以KRAS G12C靶点为主，因此追赶者甚众。KRAS G12C抑制剂部分研发管线，来源：太平洋证券在国内，谈到KRAS靶点，就绕不开加科思，这家有着强烈创新情怀的Biotech，是国内为数不多专注于开发KRAS抑制剂的药企之一。戈来雷塞（JAB-21822）是加科思自主研发的KRAS G12C小分子抑制剂，在非小细胞肺癌（NSCLC）、结直肠和胰腺导管腺癌均有研究，其中KRAS G12C突变二线非小细胞肺癌的NDA已于2024年5月获得优先审评。根据发布在《自然-医学》的注册性IIB期研究结果显示，戈来雷塞后线治疗117例KRAS G12C突变的NSCLC的ORR为47.9%，DCR为86.3%，中位PFS为8.2个月，中位OS为13.6个月。罗氏开发的KRAS G12C小分子抑制剂Divarasib也十分凶猛。在I期研究中，Divarasib单药治疗经治的KRAS G12C突变NSCLC的ORR为53.4%，中位PFS为13.1个月。治疗经治的KRAS G12C突变结直肠癌的ORR为29.1%，中位PFS为5.6个月。治疗其他KRAS G12C实体瘤的ORR为36%。目前开展的KRASCENDO-1 III期试验，则敢于直接头对头对照Sotorasib或Adagrasib二线治疗KRAS G12C突变NSCLC的疗效。默沙东开展的III期研究评估MK-1084联合K药治疗PD-L1≥50%的KRAS G12C突变NSCLC则直奔一线方案，实力不容小觑。国内布局KRAS G12C抑制剂研发的药企包括璎黎药业、泽璟制药、翰森制药等等，均处于早期阶段。但是，技术的进展实在太快，这边临床试验才刚启动，那边新的疗法又在不断涌现，针对KRAS靶点的研究呈现一派喷涌的局面。后来者众KRAS G12C抑制剂仅适用于G12C突变患者，对于其他突变或者野生型的患者并不适用，覆盖人群有限，使得批准上市的适应证范围较窄。同时部分患者在用药一段时间后会出现KRAS G12D、G12V等新的突变，或通过上游RTK信号激活绕过KRAS G12C抑制，导致产生耐药性。要想在KRAS突变上取得重大突破，其他位点的药物研发尤为重要。目前，其他点位和其他药物类型的临床研究层出不穷，泛KRAS抑制剂、分子胶、PROTAC等形式的靶点研究已相继成型。KRAS G12DMRTX1133原是Mirati研发的一款选择性非共价KRAS G12D抑制剂，研发进度较为靠前。自BMS收购Mirati后，于2025年3月宣布放弃该项目，十分可惜。据BMS发言人透露，一个重要原因是MRTX1133药代动力学数据“高度可变且不理想”。虽然MRTX1133折戟，但全球范围内仍有数十款靶向KRAS G12D的新药已经进入临床研究阶段，其中部分管线已经进入II期。进度较快的管线包括劲方医药的GFH375（II期）、恒瑞医药的HRS-4642（I期）、阿斯利康的AZD0022（I期）、海博为药业的HBW-012336（I期）、艾力斯的AST2169（I期）、安斯泰来的ASP3082（I期）等等。KRAS G12D抑制剂部分管线，来源：药创新整理泛KRAS抑制剂为克服KRAS G12C抑制剂的耐药性，泛KRAS抑制剂以共价或非共价结合方式广泛抑制包括G12C、G12D、G13D在内的多种突变形式，有望突破当前KRAS靶向药的覆盖度和耐药性方面的局限，被视为当前攻克KRAS驱动型癌症的关键方向。目前泛KRAS抑制剂的研发目前均处于早期阶段，进入临床的管线包括加科思的JAB-23E73（I期）、Revolution的RMC-6236（I期）、璎黎药业的TEB-17231（I期）、百济神州的BGB-53038（I期）、辉瑞的PF-07934040（I期）、勃林格殷格翰的BI1701963（I期）等等。泛KRAS抑制剂部分研发管线，来源：药创新整理此外，以mRNA疫苗、PROTAC、TCR-T细胞疗法等形式开发的针对KRAS靶点的药物也在不断涌现。如Moderna研发的mRNA-5671是一种可针对KRAS G12C、G12D、G12V和G13D等多种突变体的癌症疫苗，已进入临床I期。Astellas研发的PROTAC药物ASP3082通过将E3泛素连接酶连接到KRAS G12D突变蛋白促进其降解，已进入临床I期。Affini-T Therapeutics研发的AFNT-212是新型TCR-T细胞疗法，通过表达针对KRAS G12D突变蛋白高亲和力的TCR，实现对肿瘤细胞更强的杀伤能力，已进入临床I期。结语从G12C到G12D，从特异靶向到广谱抑制再到多形式药物研发，针对KRAS靶点的突破日新月异，“不可成药”已经彻底成为历史。在接下来的几年中，我们将会看到一些令人振奋的成果出现，当然，也会看到一些项目遗憾退场，这正是科研攻关的魅力所在。特别是在中国药企接连不断加入下，技术叠加产业的双重谐振，使得这场KRAS靶点竞赛更具观赏性。后续发展如何，“药创新”还将持续关注。参考文献：1、《3种癌症都有的靶点，如何打破“不可成药”魔咒？》，与癌共舞，2025-3-22版权声明：本文内容及图片，如有侵权请联系删除。免责声明：本文内容仅作信息交流学习，并不反映任何意见及观点。往期推荐乐威医药荣获2024年度EcoVadis承诺奖牌乐威医药再获三项国家专利知识产权乐威医药公益3.12植树行动

REDWOOD CITY, Calif., May 14, 2025 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a late-stage clinical oncology company developing targeted therapies for patients with RAS-addicted cancers, today announced the first patient has been dosed in RASolve 301, a global, randomized, open-label Phase 3 clinical trial. RASolve 301 will evaluate the safety and efficacy of daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, in patients with previously treated, locally advanced or metastatic RAS mutant non-small cell lung cancer (NSCLC) compared to docetaxel chemotherapy. RASolve 301 is anticipated to enroll approximately 420 patients with NSCLC worldwide who have received one to two prior lines of therapy for the treatment of advanced disease including an anti-PD-1/anti-PD(L)-1 agent and platinum-based chemotherapy. The pivotal clinical trial is designed to include a core population of patients with NSCLC carrying RAS mutations at position G12 (G12X), and an expanded population that also includes patients with tumors carrying other specific RAS mutations. The dual primary endpoints are progression-free survival (PFS) and overall survival (OS) in the core patient population. Key secondary endpoints include PFS, OS and objective response rate (ORR) in the expanded population. “We are pleased that dosing is underway in the RASolve 301 Phase 3 clinical trial, an important step in developing daraxonrasib, a highly innovative compound that targets a diverse array of RAS mutations that drive tumor growth in 30% of NSCLC cases,” said Mark A. Goldsmith M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. “For the vast majority of these RAS cancer drivers, there are currently no approved targeted drugs that can be used in place of chemotherapy. In this trial we are collaborating with physicians globally to evaluate the potential of daraxonrasib as a new therapy for people living with RAS mutant lung cancer.” The company’s decision to evaluate daraxonrasib as a monotherapy in this NSCLC setting was informed by early evidence from a single-arm trial showing the compound had an acceptable safety profile and encouraging antitumor activity. Daraxonrasib is also being evaluated in the RASolute 302 clinical trial, which is a global, randomized Phase 3 trial evaluating daraxonrasib versus standard of care chemotherapy in second-line patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC). About Non-Small Cell Lung Cancer and RAS MutationsMore than 197,000 people are diagnosed with non-small cell lung cancer (NSCLC) in the U.S. each year.1 Despite treatment advancements, NSCLC remains a leading cause of cancer-related mortality worldwide, primarily due to its late-stage diagnosis and limited response to conventional therapies. RAS mutations are among the most common oncogenic drivers in NSCLC, occurring in approximately 30% of cases.2 A significant challenge in treating NSCLC is its genetic diversity, with different mutations including RAS G12X, G13X and Q61X each playing a crucial role in the development and progression of NSCLC in this patient population. About Daraxonrasib Daraxonrasib (RMC-6236) is an oral, direct RAS(ON) multi-selective inhibitor with the potential to help address a wide range of cancers driven by oncogenic RAS mutations. Daraxonrasib suppresses RAS signaling by blocking the interaction of RAS(ON) with its downstream effectors. It does so by targeting oncogenic RAS mutations G12X, G13X and Q61X that are common drivers of major cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). About Revolution Medicines, Inc. Revolution Medicines is a late-stage clinical oncology company developing novel targeted therapies for patients with RAS-addicted cancers. The company’s R&D pipeline comprises RAS(ON) inhibitors designed to suppress diverse oncogenic variants of RAS proteins. The company’s RAS(ON) inhibitors daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor; elironrasib (RMC-6291), a RAS(ON) G12C-selective inhibitor; and zoldonrasib (RMC-9805), a RAS(ON) G12D-selective inhibitor, are currently in clinical development. The company anticipates that RMC-5127, a RAS(ON) G12V-selective inhibitor, will be its next RAS(ON) inhibitor to enter clinical development. Additional development opportunities in the company’s pipeline focus on RAS(ON) mutant-selective inhibitors, including RMC-0708 (Q61H) and RMC-8839 (G13C). For more information, please visit www.revmed.com and follow us on LinkedIn. Forward Looking Statements This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. Any statements in this press release that are not historical facts may be considered "forward-looking statements," including without limitation statements regarding progression of clinical studies and findings from these studies, including the safety, tolerability and antitumor activity of the company’s candidates being studied and the durability of these results; dosing and enrollment in the company’s clinical trials; and the potential of daraxonrasib as a therapeutic option for NSCLC or PDAC. Forward-looking statements are typically, but not always, identified by the use of words such as "may," "will," "would," "believe," "intend," "plan," "anticipate," "estimate," "expect," and other similar terminology indicating future results. Such forward-looking statements are subject to substantial risks and uncertainties that could cause the company’s development programs, future results, performance or achievements to differ materially from those anticipated in the forward-looking statements. Such risks and uncertainties include without limitation risks and uncertainties inherent in the drug development process, including the company’s programs’ current stage of development, the process of designing and conducting preclinical and clinical trials, risks that the results of prior clinical trials may not be predictive of future clinical trials, clinical efficacy, or other future results, the regulatory approval processes, the timing of regulatory filings, the challenges associated with manufacturing drug products, the company’s ability to successfully establish, protect and defend its intellectual property, other matters that could affect the sufficiency of the company’s capital resources to fund operations, reliance on third parties for manufacturing and development efforts, changes in the competitive landscape, and the effects on the company’s business of the global events, such as international conflicts or global pandemics. For a further description of the risks and uncertainties that could cause actual results to differ from those anticipated in these forward-looking statements, as well as risks relating to the business of Revolution Medicines in general, see Revolution Medicines’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the “SEC”) on May 7, 2025, and its future periodic reports to be filed with the SEC. Except as required by law, Revolution Medicines undertakes no obligation to update any forward-looking statements to reflect new information, events or circumstances, or to reflect the occurrence of unanticipated events. Revolution Medicines Media & Investor Contact:media@revmed.com investors@revmed.com 1 American Cancer Society. Key Statistics for Lung Cancer. Available at: https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html. Accessed May 2025.2 Reita D, Pabst L., Pencreach E, et al. Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance. Cancers (Basel). 2022; 14(15):1321. doi: 10.3390/cancers14051321. A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/2e5dbb1b-2634-4a05-8783-3174ae608dbb