This is a single arm phase 2 trial is to evaluate the efficacy of SRS plus adagrasib for the treatment of brain metastases for patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC). A total of 30 patients will be enrolled on this study.

开始日期2024-05-01

申办/合作机构

Hoosier Cancer Research Network

[+2]

NCT05853575 / Recruiting临床2期

A Randomized Study of Two Dosing Regimens of Adagrasib in Patients With Previously Treated Non-Small Cell Lung Cancer With KRAS G12C Mutation

This study will evaluate the efficacy of two dosing regimens of adagrasib (600 mg BID versus 400 mg BID) in patients with NSCLC with KRAS G12C mutation.

开始日期2024-02-01

申办/合作机构

Mirati Therapeutics, Inc.

100 项与阿达格拉西相关的临床结果

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100 项与阿达格拉西相关的转化医学

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100 项与阿达格拉西相关的专利（医药）

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128

项与阿达格拉西相关的文献（医药）

2024-04-01·Acta pharmacologica Sinica

From bench to bedside: current development and emerging trend of KRAS-targeted therapy

Review

作者: Liu, Qiu-Pei ; Chen, Yi ; Ding, Jian ; Xie, Hua

Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers with mutations predominantly occurring in codon 12. These mutations disrupt the normal function of KRAS by interfering with GTP hydrolysis and nucleotide exchange activity, making it prone to the GTP-bound active state, thus leading to sustained activation of downstream pathways. Despite decades of research, there has been no progress in the KRAS drug discovery until the groundbreaking discovery of covalently targeting the KRAS^G12C mutation in 2013, which led to revolutionary changes in KRAS-targeted therapy. So far, two small molecule inhibitors sotorasib and adagrasib targeting KRAS^G12C have received accelerated approval for the treatment of non-small cell lung cancer (NSCLC) harboring KRAS^G12C mutations. In recent years, rapid progress has been achieved in the KRAS-targeted therapy field, especially the exploration of KRAS^G12C covalent inhibitors in other KRAS^G12C-positive malignancies, novel KRAS inhibitors beyond KRAS^G12C mutation or pan-KRAS inhibitors, and approaches to indirectly targeting KRAS. In this review, we provide a comprehensive overview of the molecular and mutational characteristics of KRAS and summarize the development and current status of covalent inhibitors targeting the KRAS^G12C mutation. We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS activation-associated proteins Src homology-2 domain-containing phosphatase 2 (SHP2) and son of sevenless homolog 1 (SOS1), and shed light on current challenges and opportunities for drug discovery in this field.

2024-03-01·Bioorganic chemistry

Multiple medicinal chemistry strategies of targeting KRAS: State-of-the art and future directions

Review

作者: Wang, Jinxin ; Shang, Yanguo ; Hao, Qingjing ; Shen, Tao ; Fu, Shengnan ; Ying, Hanjie

KRAS is the most frequently mutated oncogene and drives the development and progression of malignancies, most notably non-small cell lung cancer (NSCLS), pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). However, KRAS proteins have maintained the reputation of being "undruggable" due to the lack of suitable deep pockets on its surface. One major milestone for KRAS inhibition was the discovery of the covalent inhibitors bond to the allosteric switch-II pocket of the KRAS^G12C protein. To date, the FDA has approved two KRAS^G12C inhibitors, sotorasib and adagrasib, for the treatment of patients with KRAS^G12C-driven cancers. Researchers have paid close attention to the development of inhibitors for other KRAS mutations and upstream regulatory factors. The KRAS targeted drug discovery has entered a state of rapid development. This article has aimed to present the current state of the art of drug development in the KRAS field. We systematically summarize recent advances in the discovery and optimization processes of direct KRAS inhibitors (including KRAS^G12C, KRAS^G12D, KRAS^G12A and KRAS^G12R inhibitors), indirect KRAS inhibitors (SOS1 and SHP2 inhibitors), pan-KRAS inhibitors, as well as proteolysis-targetingchimeras degrades and molecular chaperone modulators from the perspective of medicinal chemistry. We also discuss the current challenges and opportunities of KRAS inhibition and hope to shed light on future KRAS drug discovery.

2024-02-01·Pharmacological research

Outcomes following KRASG12C inhibitor treatment in patients with KRASG12C-mutated solid tumors: A systematic review and meta-analysis

Review

作者: Gao, Yi-Bo ; He, Jie ; Zhou, Xiao-Xiang ; Chen, Qi-An ; Cao, Zheng ; Lin, Wei-Hao ; Feng, Xiao-Li

OBJECTIVE:

To assess the efficacy and safety of FDA-approved KRAS^G12C inhibitors in patients with KRAS^G12C-mutated solid tumors.

METHODS:

We searched PubMed, EMBASE, Cochrane Library, and major international conferences for clinical trials published in English up to March 6, 2023. Clinical trials investigating sotorasib or adagrasib and reporting the clinical outcomes of the objective response rate (ORR), disease control rate (DCR), or incidence rate of grade ≥ 3 adverse events (AEs) were eligible. The primary endpoint was the ORR. Secondary endpoints included the DCR, incidence rate of grade ≥ 3 AEs, and odds ratio (OR) of the ORR between patients with or without co-mutation. The Random-effects model was applied for the outcomes of interest.

RESULTS:

18 studies with 1224 patients were included in this meta-analysis. The pooled ORR, DCR, and incidence rate of grade ≥ 3 AEs were 31 % (95 % CI, 25-37 %), 86 % (95 % CI, 82-89 %), and 29 % (95 % CI, 23-36 %), respectively. KRAS^G12C-mutated NSCLC patients with a co-mutation of KEAP1 exhibited a worse ORR than those with wild-type KEAP1 (OR: 0.35, 95 % CI: 0.16-0.77).

CONCLUSIONS:

This study provided a comprehensive understanding of the efficacy and safety of KRAS^G12C inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRAS^G12C inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRAS^G12C inhibitor treatment.

576

项与阿达格拉西相关的新闻（医药）

2024-06-30

·循因缉药

祛魅的肿瘤NGS：谁让“内卷”变成了“内耗”

真的是“低价产品”来背这口锅吗？ ——前言 “太卷了，快活不下去了” 最近和行业里很多朋友交流，类似的表述一直被大家挂在嘴边。卷，看上去是一个公认的事实。但对于造成这个局面的原因，大家的理解则不尽相同。有精准吐槽是“xx友商不讲武德的低价策略” 也有灵魂质疑“这技术实际没解决任何问题啊” ...... 如是总总，不一一列举。那么，究竟是谁把肿瘤NGS推进当下这个火坑的？如昨天所说，知道问题虽然大概率没有能立马改变局面的“速”解，但至少可以避免我们去选择错误的解法。借着这个话题，我抛砖，期待引玉。 1. 祛魅的技术 2. 内卷or内耗 3. 选择的权力 PS：本文引用资料均来自公开渠道，个人观点仅供参考，欢迎留言区探讨。 01 “祛魅期” 技术的演进有很多经典的模型，比如Gartner Hype Cycle（技术成熟度曲线）：萌芽期、膨胀期、谷底期、复苏期、成熟期但这些模型往往时间跨度太长，作为个人的我们很难完整的感受。肿瘤NGS行业大部分伙伴的入行时间应该和我类似（2016年前后），事实上我们感受到的是这么三个阶段：狂热期、退烧期、祛魅期当前毫无疑问是“祛魅期”。虽然祛魅期是问题最多的时候，但并不天然和行业乱战挂钩。 02 “内卷 or 内耗” 任何行业都终将进入祛魅期。差别只在于进入的姿势：一种是内卷，一种是内耗。我们以“巧克力饼干”做一个通俗的举例： “内卷”是市场上同时出现了奥利奥和趣多多，二者你来我往打的不亦乐乎，但用户是最终吃的都是巧克力饼干。 “内耗”是市场上同时出现了奥利奥和奥利给，二者同样大战三百回合，但有部分用户最终吃了屎。这个举例很荒缪对不对？因为正常人肯定能分辨出来，并不会选择吃奥利给。大多数消费品行业都是如此，奥利给即使做成了巧克力味让第一波人上了当，也会快速的被市场出清，比如耳熟能详的保时泰。这里有一个前提：产品的好坏是能被轻易区分的。而一旦无法区分，行业就会进入内耗。 03 “反面教材” 而肿瘤NGS恰好就是这样一个典型的“反面教材” ——它的产品好坏是很难区分的。是的，虽然大家想尽了各种办法去证明自身的质量，但很可惜，它是几乎“无法感知”的。为此做出过诸多努力的朋友们可能不服气，但很抱歉，但事实就大概如下面这张图。我举个例子大家就能明白。最近几天新药圈的一个大新闻是BMS的KRAZATI被FDA批准，成为第一个用于CRC患者的KRAS G12C靶向药。在所有的CRC患者中，携带KRAS G12C的比例大约是4%左右，而根据药物获批的KRYSTAL-1临床实验，KRAZATI的ORR（客观应答率，可以简单理解为用了药能看到效果）为34%，相比于目前的标准治疗（化疗±VEGF/VEGFR抑制剂）提升了至少5倍。我们假设有两个NGS产品：产品A：检测KRAS G12C的敏感性是100% 产品B：检测KRAS G12C的敏感性是50% 从数值上看，质量天差地别，对吧？如果在平行宇宙α用产品A检测100个CRC患者，而在平行宇宙β改用产品B的话，会发生什么？平行宇宙α：检测到4个携带KRAS G12C的患者，最终在大约1～2个患者身上看到了KRAZATI的疗效。平行宇宙β：检测到2个携带KRAS G12C的患者，最终在大约0～1个患者身上看到了KRAZATI的疗效。最近在了解感染检测赛道的时候，最大的learning是：医生在乎的是最后的治疗效果，而不是检测结果本身。代入这句话去看上面的结果：一位医生能有多大概率、在多大程度上感受到这两者的真实差距？所以我从不认为“低价低质的产品”应该为行业的内耗去背锅，这只是部分玩家在当前局面下选择了一个“自身最优解”。这是“果”，不是“因”，道德有瑕疵，但并不犯罪。当产品的好坏不能被轻易感知的，行业就一定会进入“纯价格竞争”的内耗吗？倒也未必，因为市场里不只有“消费者”。 04 “瘸腿的证” 技术的“短板”是无国界的。中国肿瘤NGS遇到的“个体感知上无法区分质量”在鹰酱和霓虹酱那也会遇到。那为什么他们没进入内耗？因为区分质量的方法除了“感知”还有“认证”。还是上面平行宇宙α和β的例子，中国每年新发的结直肠癌患者是大约55万例，假如是这个检测基数呢？真实的差距不再仅仅是“产品数值差异”，而是清晰的“获益感知差异”。基于这种大基数下的“感知差异”，一定有一个东西能够清晰的给产品A和产品B进行区分。我们管这个叫：“拿证”。有了证，即使是技术已经进入了祛魅期，依然可以通过在应用端严格的准入和使用限制来避免奥利给带来的内耗。比如霓虹国，可以清晰的看到在拿证体系下是如何去梳理市场竞争的。 “都是托您的福” “不，是雅您的思” 等等，国内不是也有证吗？基因江湖的九哥整理了目前所有拿证的肿瘤NGS试剂盒，从2018年开始一共有19个：但，很可惜，这些都是“瘸腿”的证。何为瘸腿？仔细看看这19张证，如果严格按照获批的预期用途，有哪一张是兑现了NGS技术优势并真正满足临床实际需求的呢？瘸腿的证，当做某些商业模式的“敲门砖”自然够用，但期待它能“拨乱反正”未免有点强人所难了。有时大家会聊到“拿证无用论”，大抵也是因为如此。 05 “何以解忧” 理论上，我是说理论上，肿瘤NGS走出“内耗”的解法并不难。当“拿证”的产品能够真实满足临床需要时，一切的规则都可以围绕着这些注册证被建立起来 ——奥利给会被市场淘汰，奥利奥和趣多多则会在成本、服务上“内卷”。内卷并不会弄死行业，内耗才会。但不是所有的问题，都能“速”解。中国医疗器械注册体系的正式建立是2000年，当年的1月4日公布了《医疗器械监督管理条例》，满打满算不过24年。而就算以1976年《医疗器械修正案》的通过为节点，美国的这套体系也已经有48年，多了一倍的实践时间。时间上的差距，勤奋、好学能够弥补一部分，但有一些依然只能靠时间。除了时间呢？还得有先行者。海王说“早一步是先驱，早两步可能成了先烈”，但精准踩点这种事情往往只是神话故事。昨天预告发出后也有朋友跟我聊到“为了早知道一点撞的头破血流，意义是什么呢”。因为“成为先驱”往往是建立在“甘当先烈”的基础上。我经常不赞同“拿证无用论”，倒不是真的觉得现在多拿一两张证能解决行业的问题。但如果大家都因为“内耗”的现状而放弃了拿证的努力，放弃了和监管部门在沟通、推动中共同成长，这行业才真的没希望了。最终解就在那，总得有人去西天取经。万幸的是，目前依然有不少“不合群”的逆行者。从内心里，我希望他们都能成为先驱。 “人生如逆旅，我亦是行人” （蹭胖哥流量，随缘关注）别忘了点赞、在看、分享一键三连哦这篇文章三易其稿从将近过万字改到两千多字我自己还是挺开心的少说点废话，对大家都是好事情点关注、不迷路，加星标、快一步啊朋友们

2024-06-29

·生物探索

Cancer Cell｜任胜祥/周彩存/李飞/张喆/蒋涛合作提供KRAS G12D突变靶向治疗新策略

引言 KRAS G12D是实体瘤中最常见KRAS突变亚型，在胰腺癌（PDAC）和结直肠癌（CRC）中排第1，在肺腺癌（LUAD）中排第2【1】。与KRAS G12C癌蛋白不同，KRAS G12D缺乏靠近switch-Ⅱ结合口袋的活性残基，使得开发共价抑制剂极具挑战性【1-3】。目前，一些研究团队基于不同策略研发了数个KRAS G12D抑制剂。例如，非共价抑制剂MRTX1133可结合switch-Ⅱ口袋，抑制KRAS G12D核苷酸交换及下游效应分子结合，从而发挥抗肿瘤效果【4,5】。其他抑制剂，如RMC-9805【6】、TH-Z835【7】及BI-2852【8】等也处于研究当中。然而，这些药物仍处于临床前/初步临床研究阶段，临床上KRAS G12D仍缺乏有效靶向策略。此外，KRAS抑制剂面临的另一重大挑战为不可避免的耐受【9-12】。临床上，KRAS G12C抑制剂单药治疗客观有效率（ORR）为7.1%-53.4%，中位无进展生存期（PFS）为4.0-13.1个月【13-20】，亟需联合治疗以增强疗效、增加获益人群。对此，Yaeger【17】和Hallin【4】等分别发现KRAS G12C和KRAS G12D抑制剂联合西妥昔单抗可增强疗效。这些研究充分说明寻找KRAS G12D抑制剂协同增敏靶标的重要性。 2024年6月27日，同济大学附属上海市肺科医院任胜祥、周彩存教授团队与复旦大学基础医学院李飞团队及恒瑞公司药物研发团队合作在Cancer Cell上发表题为Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer的文章，提供了首个临床有效KRAS G12D特异性抑制剂——HRS-4642，及其与蛋白酶体抑制剂联合的治疗新策略。在这项研究中，作者团队研发了一款高亲和力、选择性、长时效、非共价的KRAS G12D抑制剂，HRS-4642。体外，研究团队首先通过SPR实验确认HRS-4642特异性结合KRAS G12D，其亲和力为KRAS G12C的21倍，野生型KRAS蛋白的17倍。随后通过结合抑制实验，发现HRS-4642抑制KRAS G12D与SOS1或RAF1结合，发挥双重阻滞作用，进而抑制下游MEK-ERK信号通路。在16个人源细胞系中，HRS-4642特异性抑制KRAS G12D突变细胞系增殖（IC50值为0.55-66.58 nM之间），而对其他KRAS突变亚型或野生型细胞系作用极弱（IC50值为248.50到大于10,000 nM）。体内，通过构建AsPC-1、GP2d异种移植瘤模型及肺腺癌PDX模型，确认HRS-4642显著抑制KRAS G12D肿瘤生长，且具有较好的药代动力学（PK）、药效学（PD）特征，倾向于瘤内蓄积。在其I期临床研究（NCT05533463）中，HRS-4642也展示出临床活性。2名接受过多线标准抗肿瘤治疗的晚期非小细胞肺癌（NSCLC）患者，分别接受200mg和300mg HRS-4642（每周一次）治疗后，靶病灶分别缩小53%和31%，达部分缓解（PR）标准。这使得HRS-4642成为第一个被报道临床有效的KRAS G12D特异性抑制剂。研究团队进一步通过体外全基因组CRISPR筛选，绘制了HRS-4642的增敏/耐受图谱。对筛选数据进行富集分析，确定蛋白酶体或可为HRS-4642增敏靶标。对TCGA数据进行分析也发现，蛋白酶体signature低表达与泛癌、肺腺癌及胰腺癌长生存相关。团队进而通过体内外联合给药实验，明确了HRS-4642联合蛋白酶体抑制剂卡非佐米在体外协同杀伤KRAS G12D突变细胞系，体内联合抑制KRAS G12D肿瘤生长。并通过RNA-seq、DIA蛋白质谱等手段，发现HRS-4642与卡非佐米联合治疗主要通过下调Notch4信号通路及上调IFNα信号通路发挥协同抗肿瘤作用。除了提供HRS-4642靶向及其联合蛋白酶体抑制剂治疗新策略，研究团队通过流式细胞术、免疫组化等还发现，HRS-4642单药或联合卡非佐米可显著促进KRAS G12D肿瘤中CD3+、CD4+、CD8+ T细胞的浸润及激活，促进肿瘤免疫微环境（TIME）“炎化”，为KRAS G12D肿瘤靶免联合提供了理论基础。模式图（Credit: Cancer Cell）参考文献 Zeissig, M.N., Ashwood, L.M., Kondrashova, O., and Sutherland, K.D. (2023). Next batter up! Targeting cancers with KRAS-G12D mutations. Trends Cancer 9, 955–967. Fell, J.B., Fischer, J.P., Baer, B.R., Blake, J.F., Bouhana, K., Briere, D.M., Brown, K.D., Burgess, L.E., Burns, A.C., Burkard, M.R., et al. (2020). Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer. J. Med. Chem. 63, 6679–6693. Lanman, B.A., Allen, J.R., Allen, J.G., Amegadzie, A.K., Ashton, K.S., Booker, S.K., Chen, J.J., Chen, N., Frohn, M.J., Goodman, G., et al. (2020). Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors. J. Med. Chem. 63, 52–65. Hallin, J., Bowcut, V., Calinisan, A., Briere, D.M., Hargis, L., Engstrom, L.D., Laguer, J., Medwid, J., Vanderpool, D., Lifset, E., et al. (2022). Anti-tumor efficacy of a potent and selective non-covalent KRASG12D in- hibitor. Nat. Med. 28, 2171–2182. Wang, X., Allen, S., Blake, J.F., Bowcut, V., Briere, D.M., Calinisan, A., Dahlke, J.R., Fell, J.B., Fischer, J.P., Gunn, R.J., et al. (2022). Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J. Med. Chem. 65, 3123–3133. Jiang, L., Menard, M., Weller, C., Wang, Z., Burnett, L., Aronchik, I., Steele, S., Flagella, M., Zhao, R., Evans, J.W.W., et al. (2023). Abstract 526: RMC- 9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers. Cancer Res. 83, 526. Mao, Z., Xiao, H., Shen, P., Yang, Y., Xue, J., Yang, Y., Shang, Y., Zhang, L., Li, X., Zhang, Y., et al. (2022). KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge. Cell Discov. 8, 5. Kessler, D., Gmachl, M., Mantoulidis, A., Martin, L.J., Zoephel, A., Mayer, M., Gollner, A., Covini, D., Fischer, S., Gerstberger, T., et al. (2019). Drugging an undruggable pocket on KRAS. Proc. Natl. Acad. Sci. USA 116, 15823–15829. Awad,M.M.,Liu,S.,Rybkin,I.I.,Arbour,K.C.,Dilly,J.,Zhu,V.W.,Johnson, M.L., Heist, R.S., Patil, T., Riely, G.J., et al. (2021). Acquired Resistance to KRASG12C Inhibition in Cancer. N. Engl. J. Med. 384, 2382–2393. Sattler, M., Mohanty, A., Kulkarni, P., and Salgia, R. (2023). Precision oncology provides opportunities for targeting KRAS-inhibitor resistance. Trends Cancer 9, 42–54. Akhave, N.S., Biter, A.B., and Hong, D.S. (2021). Mechanisms of Resistance to KRASG12C-Targeted Therapy. Cancer Discov. 11, 1345–1352. Zhu, C., Guan, X., Zhang, X., Luan, X., Song, Z., Cheng, X., Zhang, W., and Qin, J.-J. (2022). Targeting KRAS mutant cancers: from druggable therapy to drug resistance. Mol. Cancer 21, 159. Skoulidis, F., Li, B.T., Dy, G.K., Price, T.J., Falchook, G.S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., et al. (2021). Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N. Engl. J. Med. 384, 2371–2381. Hong, D.S., Fakih, M.G., Strickler, J.H., Desai, J., Durm, G.A., Shapiro, G.I., Falchook, G.S., Price, T.J., Sacher, A., Denlinger, C.S., et al. (2020). KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N. Engl. J. Med. 383, 1207–1217. de Langen, A.J., Johnson, M.L., Mazieres, J., Dingemans, A.-M.C., Mountzios, G., Pless, M., Wolf, J., Schuler, M., Lena, H., Skoulidis, F., et al. (2023). Sotorasib versus docetaxel for previously treated non- small-cell lung cancer with KRASG12C mutation: a randomised, open-la- bel, phase 3 trial. Lancet 401, 733–746. Strickler, J.H., Satake, H., George, T.J., Yaeger, R., Hollebecque, A., Garrido-Laguna, I., Schuler, M., Burns, T.F., Coveler, A.L., Falchook, G.S., et al. (2023). Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer. N. Engl. J. Med. 388, 33–43. Yaeger, R., Weiss, J., Pelster, M.S., Spira, A.I., Barve, M., Ou, S.-H.I., Leal, T.A., Bekaii-Saab, T.S., Paweletz, C.P., Heavey, G.A., et al. (2023). Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N. Engl. J. Med. 388, 44–54. Janne, P.A., Riely, G.J., Gadgeel, S.M., Heist, R.S., Ou, S.-H.I., Pacheco, J.M., Johnson, M.L., Sabari, J.K., Leventakos, K., Yau, E., et al. (2022). Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N. Engl. J. Med. 387, 120–131. Bekaii-Saab, T.S., Yaeger, R., Spira, A.I., Pelster, M.S., Sabari, J.K., Hafez, N., Barve, M., Velastegui, K., Yan, X., Shetty, A., et al. (2023). Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation. J. Clin. Oncol. 41, 4097–4106. Sacher, A., LoRusso, P., Patel, M.R., Miller, W.H., Garralda, E., Forster, M.D., Santoro, A., Falcon, A., Kim, T.W., Paz-Ares, L., et al. (2023). Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. N. Engl. J. Med. 389, 710–721. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.ccell.2024.06.001 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床1期

2024-06-24

·FiercePharma

BMS, Mirati's Krazati cements lead over Amgen's Lumakras with FDA approval in colorectal cancer

Aside from moving into a second indication to Lumakras’ one, Krazati further cemented its lead in the KRAS race this past March when BMS unveiled positive confirmatory results from the late-stage KRYSTAL-12 study in lung cancer. Despite coming to market second, Bristol Myers Squibb’s Mirati Therapeutics-inherited cancer med Krazati has gained the lead on its Amgen rival Lumakras in a heated KRAS race. Late Friday, the U.S. FDA granted an accelerated approval for BMS’ KRAS inhibitor Krazati plus Eli Lilly’s Erbitux (cetuximab) to treat certain chemotherapy-experienced adults with KRAS-mutated locally advanced or metastatic colorectal cancer (CRC). Given that the approval is accelerated, BMS may have to further prove Krazati’s merit in CRC in a confirmatory trial to keep hold of the green light. The new nod comes after Krazati’s initial approval in previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC) in Dec. 2022. Krazati, also known as adagrasib, was the second KRAS-targeting drug to hit the U.S. market behind Lumakras, which snagged its initial approval in NSCLC in May 2021. BMS got its hands on Krazati when it agreed to buy out Mirati for around $4.8 billion last fall. Bristol closed the transaction in late January. CRC with a KRAS G12C mutation occurs in approximately 3% to 4% of colorectal cancer patients and has historically proven difficult to treat, according to Rona Yaeger, M.D., gastrointestinal oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center. The FDA based its approval on early results from Krazati’s 94-patient, phase 1/2 KRYSTAL-1 open-label study, in which the drug was administered in 600mg tablets twice a day along with Erbitux either weekly or biweekly, the FDA explained in a separate release. In the trial, the Krazati combo reached a confirmed objective response rate (ORR) of 34%--meeting its primary endpoint—and charted a median duration of response (DOR) of 5.8 months. Thirty-one percent of patients who responded to Krazati had a DOR of at least half-a-year, the FDA noted. Current late-line standard-of-care medicines in CRC yield limited objective response rates of around 1% to 6% after progression on chemotherapy, BMS pointed out. Aside from moving into a second indication to Lumakras’ one, Krazati further cemented its lead in the KRAS race this past March when BMS unveiled confirmatory results from the late-stage KRYSTAL-12 study that found the med significantly reduced the risk of tumor progression or death versus chemotherapy in certain NSCLC patients. Krazati’s confirmatory win marked another blow to Lumakras after Amgen recently applied for a full approval of its rival KRAS inhibitor leveraging progression-free survival data from the phase 3 CodeBreaK 200 trial. Problem was, the FDA figured the study’s results couldn’t be reliably interpreted, and a group of external advisers agreed. Despite this, the FDA has let Lumakras stay on the market while Amgen runs another confirmatory study. The California-based company expects that to be done no later than Feb. 2028. Meanwhile, Amgen is also gunning for a Lumakras approval in CRC. The company in October reported results from its phase 3 CodeBreaK 300 trial showing that 960mg Lumakras plus Vectibix extended patients' median progression-free survival to 5.6 months versus 2.2 months for standard treatments in chemo-refractory KRAS G12C colorectal cancer. Krazati, during its first earnings quarter under BMS’ wing, snared $21 million over the first three months of 2024.

临床结果上市批准临床3期并购

100 项与阿达格拉西相关的药物交易

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适应症	国家/地区	公司	日期
KRAS G12C突变结直肠癌	美国	Mirati Therapeutics, Inc.	2024-06-21
KRAS G12C突变非小细胞肺癌	美国	Mirati Therapeutics, Inc.	2022-12-12

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适应症	最高研发状态	国家/地区	公司	日期
晚期结直肠腺癌	临床3期	美国	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	阿根廷	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	澳大利亚	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	奥地利	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	比利时	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	巴西	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	加拿大	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	哥伦比亚	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	捷克	Mirati Therapeutics, Inc.	2021-03-15
晚期结直肠腺癌	临床3期	丹麦	Mirati Therapeutics, Inc.	2021-03-15

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03785249 (KRYSTAL-1, FDA_CDER) 人工标引	临床2期	KRAS G12C突变结直肠癌 KRAS G12C	94	Adagrasib + cetuximab	憲艱壓糧選衊淵觸顧築(鹹鹽鑰鹹遞獵範廠憲願) = 襯遞簾蓋選鏇積選觸範願餘鹽構製壓醖築顧廠 (顧夢範鬱鹹憲夢鬱簾醖, 25 ~ 45) 更多	积极	2024-06-21
NCT03785249 (KRYSTAL-1, FDA_CDER) 人工标引	临床2期	KRAS G12C突变非小细胞肺癌 KRAS G12C	112	Adagrasib	鬱繭廠膚構鏇鏇廠選窪(膚獵鏇選夢網窪窪醖鑰) = 鏇鏇範蓋範顧膚夢醖艱積憲選遞襯膚艱夢繭糧 (簾壓壓窪齋網網顧網壓, 34 ~ 53) 更多	积极	2024-06-21
NCT04685135 (KRYSTAL-12, ASCO2024) 人工标引	临床3期	KRAS G12C突变非小细胞肺癌 KRAS G12C	453	Adagrasib (ADA)	齋築獵鏇醖遞製艱選繭(夢憲蓋築鹹網選積製齋) = 繭糧鬱鬱廠鹽築鹽蓋憲蓋鏇艱鹽顧製壓糧淵遞 (蓋鹽壓選範築鏇築醖築 ) 更多	积极	2024-06-02
				Docetaxel (DOCE)	齋築獵鏇醖遞製艱選繭(夢憲蓋築鹹網選積製齋) = 繭膚膚積鹽構夢膚壓鑰蓋鏇艱鹽顧製壓糧淵遞 (蓋鹽壓選範築鏇築醖築 ) 更多
KRYSTAL-1 (Literature) 人工标引	临床1/2期	转移性结直肠癌 KRAS G12C	94	Adagrasib plus Cetuximab	襯壓窪淵網顧獵夢衊醖(糧構窪網構鏇遞鏇艱醖) = 鹽夢製遞範鹹簾鏇醖顧製鹽選廠齋夢蓋遞憲醖 (築獵選遞獵積夢窪鹽觸 ) 更多	积极	2024-04-08
NCT04685135 (KRYSTAL-12, Corporate Publications) 人工标引	临床3期	KRAS G12C突变非小细胞肺癌二线	43	KRAZATI	範鬱餘鏇積鏇鏇鬱遞積(襯鹽繭選鹹構淵範範壓) = met 鹹廠繭艱鹹夢夢蓋廠鹽 (糧餘製網餘憲鏇願憲鹽 ) 达到更多	积极	2024-03-28
				standard-of-care chemotherapy
KRYSTAL-1 study (NEWS) 人工标引	临床阶段不明	结直肠癌 KRAS	-	Adagrasib	製願範憲選構網鑰網築(顧範遞憲選獵製夢膚顧) = 齋淵範範壓顧繭鑰觸繭簾膚醖憲淵膚鑰夢蓋膚 (廠糧壓構積範觸壓襯襯 ) 更多	积极	2024-01-08
				Adagrasib + Cetuximab	製願範憲選構網鑰網築(顧範遞憲選獵製夢膚顧) = 鏇鏇廠餘夢積糧廠夢鹽簾膚醖憲淵膚鑰夢蓋膚 (廠糧壓構積範觸壓襯襯 ) 更多
ESMO2023	N/A	KRAS G12C突变的实体瘤	-	Combination of MRTX1257 and RT	構鬱夢鬱鑰網窪鑰範憲(鹹壓鹽醖窪艱構選淵繭) = 築夢簾構壓膚鑰窪糧願齋製淵醖築衊鑰鹹壓簾 (鑰淵憲壓齋壓顧膚願齋 )	-	2023-10-21
NCT04613596 (KRYSTAL-7, ESMO2023) 人工标引	临床2期	KRAS G12C突变非小细胞肺癌一线 KRAS G12C	148	Adagrasib 400 mg + Pembrolizumab 200 mg	製鏇鹽憲製憲壓鬱構淵(網願壓廠廠糧構糧艱鹹) = 遞簾餘積窪簾膚淵襯夢膚淵糧憲簾願衊遞遞積 (襯齋鹽顧衊願築鏇鏇鏇 ) 更多	积极	2023-10-20
				Adagrasib 400 mg + Pembrolizumab 200 mg (PD-L1 ≥50%)	製鏇鹽憲製憲壓鬱構淵(網願壓廠廠糧構糧艱鹹) = 淵糧鹹淵淵製鏇觸襯廠膚淵糧憲簾願衊遞遞積 (襯齋鹽顧衊願築鏇鏇鏇 ) 更多
NCT03785249 (KRYSTAL-1, WCLC2023) 人工标引	临床1/2期	KRAS G12C突变非小细胞肺癌 KRASG12C mutation	132	Adagrasib 600 mg BID	網鏇餘廠製範簾獵觸鹹(選願鬱鬱鑰餘顧觸獵齋) = 選憲遞鬱淵艱顧顧顧壓範壓範願鹽艱遞顧衊積 (壓願鏇觸齋糧艱觸襯積 ) 更多	积极	2023-09-10
				Adagrasib 600 mg BID (KEAP1 co-mutations)	艱醖衊鏇糧製襯齋鬱鹹(顧範淵窪鹽衊鑰糧鹽憲) = 鏇憲醖壓蓋範蓋構鏇築齋繭繭餘鑰齋鬱壓選膚 (構積壓鏇衊蓋夢憲獵願, 3.6 ~ 9.2)
NCT03785249 (KRYSTAL-1, Pubmed)	临床1/2期	脑转移瘤	-	Adagrasib 600 mg	製糧餘構願餘壓選窪糧(觸淵鏇範遞遞蓋淵蓋獵) = The most common CNS-specific TRAEs included dysgeusia (24%) and dizziness (20%) 範簾鹽鏇蓋鏇醖網淵遞 (觸齋襯遞獵鹹齋遞築顧 ) 更多	-	2023-06-16