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KRASG12C抑制剂Sotorasib治疗晚期实体瘤效果让人惊喜

发布日期:2021-05-13 16:17:16   来源 : unknown    作者 :unknown    浏览量 :58
unknown unknown 发布日期:2021-05-13 16:17:16  
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美国德克萨斯大学安德森癌症中心David S. Hong联合斯隆·凯特林纪念癌症中心Bob T. Li团队研究了KRASG12C抑制剂Sotorasib治疗晚期实体瘤的疗效。2020年9月20日,该研究发表在《新英格兰医学杂志》上。

针对KRAS突变的癌症,尚未有批准疗法。KRAS p.G12C突变发生在13%的非小细胞肺癌(NSCLC)和1-3%的大肠癌和其他癌症中。Sotorasib是一个选择性且不可逆靶向KRASG12C的小分子。

针对KRAS p.G12C突变的晚期实体瘤患者,研究组进行了一项关于sotorasib的1期试验。患者每日口服一次sotorasib。主要终点是安全性,关键次要终点是药代动力学和客观缓解。

剂量递增和扩展队列共包括129例患者,其中59例NSCLC、42例大肠癌和28例其他癌症。患者先前平均接受过3种转移性疾病抗癌治疗。未观察到剂量限制的毒副作用或与治疗有关的死亡。共有73例患者(56.6%)发生治疗相关不良事件;15名患者(11.6%)发生了3或4级不良事件。

在NSCLC亚组中,32.2%的患者(19例)客观缓解(完全或部分缓解),88.1%(52例)疾病控制(客观缓解或病情稳定),中位无进展生存期为6.3个月。在大肠癌亚组中,7.1%的患者(3例)客观缓解,73.8%(31例)疾病控制,中位无进展生存期为4.0个月。在胰腺癌、子宫内膜癌、阑尾癌和黑色素瘤患者中也观察到了缓解。

总之,Sotorasib对先前治疗过的、KRAS p.G12C突变的晚期实体瘤患者显示出令人鼓舞的抗癌活性,但具有一定的毒副作用。


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附:英文原文

Title: KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors | NEJM

Author: David S. Hong, M.D.,, Marwan G. Fakih, M.D.,, John H. Strickler, M.D.,, Jayesh Desai, M.D.,, Gregory A. Durm, M.D.,, Geoffrey I. Shapiro, M.D., Ph.D.,, Gerald S. Falchook, M.D.,, Timothy J. Price, M.B., B.S., D.Hlth.Sc.,, Adrian Sacher, M.D., M.M.Sc.,, Crystal S. Denlinger, M.D.,, Yung-Jue Bang, M.D., Ph.D.,, Grace K. Dy, M.D.,, John C. Krauss, M.D.,, Yasutoshi Kuboki, M.D.,, James C. Kuo, M.D.,, Andrew L. Coveler, M.D.,, Keunchil Park, M.D., Ph.D.,, Tae Won Kim, M.D., Ph.D.,, Fabrice Barlesi, M.D., Ph.D.,, Pamela N. Munster, M.D.,, Suresh S. Ramalingam, M.D.,, Timothy F. Burns, M.D., Ph.D.,, Funda Meric-Bernstam, M.D.,, Haby Henary, M.D.,, Jude Ngang, Pharm.D.,, Gataree Ngarmchamnanrith, M.D.,, June Kim, Ph.D.,, Brett E. Houk, Ph.D.,, Jude Canon, Ph.D.,, J. Russell Lipford, Ph.D.,, Gregory Friberg, M.D.,, Piro Lito, M.D., Ph.D.,, Ramaswamy Govindan, M.D.,, and Bob T. Li, M.D., M.P.H.

Issue&Volume: 2020-09-20

Abstract:

Background

No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non–small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.

Methods

We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Results

A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.

Conclusions

Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients.

DOI: 10.1056/NEJMoa1917239

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