达拉索拉西（RMC-6236）在既往接受过治疗的转移性RAS突变胰腺导管腺癌中的疗效与安全性：一项系统综述。
完整摘要 · 中文译文
引言：胰腺导管腺癌（PDAC）预后不良，超过90%的病例存在RAS基因突变。因此，直接抑制RAS是一种有前景但迄今难以实现的治疗策略。Daraxonrasib（RMC-6236）是一种首创的、口服的、非共价的、多选择性RAS活性形式抑制剂。它与亲环蛋白A形成细胞内三聚体复合物，阻断KRAS、NRAS和HRAS基因的突变型和野生型变体。本系统评价旨在评估daraxonrasib在既往接受过治疗的RAS突变PDAC患者中的疗效和安全性。方法：本评价按照PRISMA 2020指南进行。在PubMed、Web of Science和ClinicalTrials.gov中对2020年1月至2026年7月期间发表的研究进行了系统检索。两项研究符合纳入标准并进行分析：Phase 1-2 RMC-6236-001（n = 168）和Phase 3 RASolute 302试验（n = 500），共涉及668例患者。偏倚风险使用Cochrane RoB 2.0工具对随机试验进行评估，并使用非随机研究方法学指数（MINORS）工具进行评估。结果：在RASolute 302试验中，daraxonrasib在RAS G12突变患者群体中优于研究者选择的化疗方案，改善了中位总生存期（13.2个月对6.6个月；HR 0.40）、无进展生存期（7.3个月对3.5个月；HR 0.45）和客观缓解率（33.2%对11.8%；所有p < 0.001），并且还延迟了疼痛的发生。 以及生活质量下降。这些结果与此前的RMC-6236-001研究一致（在二线治疗中接受治疗的RAS G12突变患者中，客观缓解率（ORR）为35%，中位总生存期（OS）为13.1个月）。Daraxonrasib表现出可预测的毒性特征，主要包括1-2级皮肤和胃肠道症状，且与化疗相比，血液学毒性和治疗中断率较低。结论：在既往接受过治疗的转移性RAS G12突变胰腺导管腺癌（PDAC）患者中，Daraxonrasib显示出具有临床相关性和统计学显著性的疗效，且安全性可接受，该人群是目前可获得最强随机证据的人群。这些发现支持其作为该情况下一种有前景的新治疗选择的潜力。关于罕见RAS基因变异和RAS野生型疾病形式，仍需进一步研究。
完整摘要 · 英文原文
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis, and RAS gene mutations are present in more than 90% of cases. For this reason, direct RAS inhibition is a promising, but thus far difficult to achieve, therapeutic strategy. Daraxonrasib (RMC-6236) is a first-in-class, oral, non-covalent, multiselective inhibitor of the active form of RAS. It forms an intracellular trimeric complex with cyclophilin A, blocking both mutant and wild-type variants of the KRAS, NRAS, and HRAS genes. The aim of this systematic review was to evaluate the efficacy and safety of daraxonrasib in previously treated patients with RAS-mutated PDAC. Methods: This review was conducted in accordance with the PRISMA 2020 guidelines. A systematic search was conducted in PubMed, Web of Science, and ClinicalTrials.gov for studies published between January 2020 and July 2026. Two studies met the inclusion criteria and were analyzed: the Phase 1-2 RMC-6236-001 (n = 168) and the Phase 3 RASolute 302 trial (n = 500), involving a total of 668 patients. The risk of bias was assessed using the Cochrane RoB 2.0 tool for the randomized trial and the Methodological Index for Non-Randomized Studies (MINORS) tool. Results: In the RASolute 302 trial, daraxonrasib out performed investigator-selected chemotherapy in a population of patients with the RAS G12 mutation, improving median overall survival (13.2 vs. 6.6 months; HR 0.40), progression-free survival (7.3 vs. 3.5 months; HR 0.45), and objective response rate (33.2% vs. 11.8%; all p < 0.001), and also delayed the onset of pain and deterioration in quality of life. These results were consistent with the earlier RMC-6236-001 study (objective response rate [ORR] 35%, median overall survival [OS] 13.1 months in patients with RAS G12 mutation treated in the second-line setting). Daraxonrasib exhibited a predictable toxicity profile, consisting mainly of Grade 1-2 dermatologic and gastrointestinal symptoms, with lower rates of hematologic toxicity and treatment discontinuation than with chemotherapy. Conclusions: Daraxonrasib demonstrates clinically relevant and statistically significant efficacy with an acceptable safety profile in previously treated patients with metastatic RAS G12-mutated PDAC, the population for which the strongest randomized evidence is currently available. These findings support its potential as a promising new treatment option in this setting. Further studies are needed regarding rare RAS gene variants and forms of the disease with wild-type RAS.