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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02717-6

摘要内容如下：

目前ras突变转移性结直肠癌的三线（及以上）治疗方案疗效有限。在研究开始时，假设Sotorasib（一种KRAS（Kirsten大鼠肉瘤病毒致癌基因同系物）-G12C抑制剂）和帕尼单抗（一种表皮生长因子受体（EGFR）抑制剂）的组合可克服治疗诱导的耐药性。CodeBreak 101主方案的1B期子研究评估了Sotorasib联合帕尼单抗治疗化疗难治性KrasG12C突变转移性结直肠癌患者的疗效。在此，我们报告了剂量探索队列和剂量扩展队列的结果。患者接受索托拉西（960mg，每日一次）联合帕尼单抗（6mgkg-1，每2周一次）治疗。主要终点是安全性和耐受性。次要终点包括疗效和药代动力学。评估基线时的探索性生物标志物。48名患者（剂量探索队列，n=8；剂量扩展队列，n=40）进行治疗。45例（94%）和13例（27%）患者分别发生了任何级别和≥3级的治疗相关不良事件。在剂量扩展队列中，证实的客观缓解率为30.0%（95%可信区间（CI）为16.6%，46.5%）。中位无进展生存期为5.7个月（95%CI 4.2，7.7个月）。中位总生存期为15.2个月（95%CI 12.5个月，无法估计）。常见的基因组共改变包括APC（84%）、TP53（74%）、Smad4（33%）、PIK3CA（28%）和EGFR（26%）。Sotorasib-帕尼单抗在化疗难治性KrasG12C突变的转移性结直肠癌中显示出可接受的安全性和有希望的疗效。ClinicalTrials.gov标识符：NCT04185883。

英文原文如下：

Abstracts

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .

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