Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC.

IF 4.4 3区 医学 Q2 ONCOLOGY Targeted Oncology Pub Date : 2024-05-01 Epub Date: 2024-05-13 DOI:10.1007/s11523-024-01055-y
Danielle Brazel, Misako Nagasaka
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Abstract

Kristen Rat Sarcoma viral oncogene (KRAS) mutations are one of the most common oncogenic drivers found in 12-14% of non-small cell lung cancer (NSCLC) and 4% of colorectal cancer tumors. Although previously difficult to target, sotorasib and adagrasib are now approved for previously treated NSCLC patients with KRAS G12C mutations. In preclinical studies, divarasib was 5 to 20 times as potent and up to 50 times as selective as sotorasib and adagrasib. While sotorasib met its primary endpoint in the phase III second line study against docetaxel, the progression-free survival (PFS) benefit was small and no overall survival (OS) benefit was observed. Adagrasib has demonstrated clinical benefit in the phase I/II KRYSTAL-1 study setting, however, 44.8% of patients reported grade 3 or higher toxicities. Divarasib has been studied in a phase I dose expansion cohort with promising efficacy [objective response (ORR) 53.4% and PFS 13.1 months]. Although most patients reported toxicities, the majority were low-grade and manageable with supportive care. Here we discuss these results in the context of the evolving KRAS G12C landscape.

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用于 NSCLC 的 KRAS G12C 抑制剂不断演变的格局中的 Divarasib。
克里斯汀鼠肉瘤病毒癌基因(KRAS)突变是最常见的致癌驱动因素之一,在12%-14%的非小细胞肺癌(NSCLC)和4%的结直肠癌肿瘤中均有发现。索拉西布(sotorasib)和阿达拉西布(adagrasib)虽然以前很难成为靶向药物,但现在已被批准用于先前接受过治疗的 KRAS G12C 突变的 NSCLC 患者。在临床前研究中,divarasib 的药效是 sotorasib 和 adagrasib 的 5 到 20 倍,选择性高达 50 倍。虽然在与多西他赛相比的 III 期二线研究中,sotorasib 达到了主要终点,但无进展生存期(PFS)的获益很小,也没有观察到总生存期(OS)的获益。Adagrasib 在 I/II 期 KRYSTAL-1 研究中显示出临床获益,但 44.8% 的患者出现了 3 级或更高的毒性反应。Divarasib已在I期剂量扩增队列中进行了研究,疗效喜人[客观反应(ORR)53.4%,PFS 13.1个月]。虽然大多数患者都报告了毒性反应,但大多数都是低度毒性反应,并且可以通过支持性治疗加以控制。在此,我们将结合不断发展的 KRAS G12C 情况讨论这些结果。
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来源期刊
Targeted Oncology
Targeted Oncology 医学-肿瘤学
CiteScore
8.40
自引率
3.70%
发文量
64
审稿时长
>12 weeks
期刊介绍: Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes: Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches. Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways. Current Opinion articles that place interesting areas in perspective. Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations. Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement. Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.
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