Sotorasib for Lung Cancers with KRAS p.G12C Mutation.
Sotorasib for Lung Cancers with KRAS p.G12C Mutation.
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Sotorasib用于KRAS p.G12C突变的肺癌。
DOI：
10.1056/nejmoa2103695
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发表时间：
2021-06-24
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在一项1期研究中，Sotorasib在KRAS p.G12C突变的晚期实体瘤患者中显示了抗癌活性，特别是在非小细胞肺癌(NSCLC)患者亚组中观察到了特别有前景的抗癌活性。在一项单组2期试验中，我们调查了口服剂量为960 mg的Sotorasib在KRAS p.G12C突变的晚期NSCLC患者中的活性，这些患者以前曾接受标准治疗。根据独立的中央审查，主要终点是客观反应(完全或部分反应)。关键的次要终点包括反应持续时间、疾病控制(定义为完全反应、部分反应或稳定的疾病)、无进展存活率、总存活率和安全性。对探索性生物标记物与索托拉西治疗反应的相关性进行评估。在126名登记的患者中，大多数(81.0%)以前接受过铂类化疗和程序性死亡抑制物1(PD-1)或程序性死亡配体1(PD-L1)。根据中央审查，124名患者在基线时有可测量的疾病，并接受了反应评估。客观应答46例(37.1%，95%可信区间28.6~46.2)，其中完全应答4例(3.2%)，部分应答42例(33.9%)。中位有效时间为11.1个月(95%可信区间，6.9%无法评估)。疾病控制100例(80.6%；95%CI，72.6~87.2)。中位无进展生存期6.8个月(95%CI，5.1~8.2)，中位总生存期12.5个月(95%CI，10.0~无法评估)。126例患者中有88例发生与治疗相关的不良事件(69.8%)，其中3级事件25例(19.8%)，4级事件1例(0.8%)。根据PD-L1表达、肿瘤突变负荷和STK11、Keap1或TP53的共生突变定义的亚组中观察到反应。在这项2期试验中，sotorasib治疗导致了持久的临床益处，而没有新的安全信号出现在先前治疗过的KRAS p.G12C突变的非小细胞肺癌患者身上。(由安进和美国国立卫生研究院资助；CodeBreaK100 ClinicalTrials.gov编号，NCT03600883。)
Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non–small-cell lung cancer (NSCLC). In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C–mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C–mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)