From the University of Texas M.D. Anderson Cancer Center, Houston (F.S.), and U.S. Oncology Research, the Woodlands (A. Spira) - both in Texas; Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (B.T.L.) and Thoracic Medical Oncology, Perlmutter Cancer Center, New York University (V.V.), New York, and Roswell Park Cancer Institute, Buffalo (G.K.D.) - all in New York; the Queen Elizabeth Hospital and University of Adelaide, Woodville, SA, Australia (T.J.P.); Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), the West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen (M.S.), and the German Cancer Consortium, Heidelberg (M.S.) - all in Germany; the Early Phase Trials and Sarcoma Units, Bergonie Cancer Institute, Bordeaux (A.I.), and Gustave Roussy Institute, Villejuif (F.B., B.B.) - both in France; Fox Chase Cancer Center, Philadelphia (H.B.); Kanagawa Cancer Center, Yokohama (T.K.), and the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka (T.T.) - both in Japan; the Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland (A.C.-F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A. Sacher); Virginia Cancer Specialists, Fairfax (A. Spira); Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore (A. Spira); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); Amgen, Thousand Oaks, CA (A. Anderson, A. Ang, Q.T., O.M., H.H., G.N., G.F.); and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis (R.G.).
N Engl J Med. 2021 Jun 24;384(25):2371-2381. doi: 10.1056/NEJMoa2103695. Epub 2021 Jun 4.
BACKGROUND: Sotorasib showed anticancer activity in patients with 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). METHODS: 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 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. RESULTS: 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 , , or . CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
背景：在一项 1 期研究中，索托拉西布在携带 p.G12C 突变的晚期实体瘤患者中显示出抗癌活性，在非小细胞肺癌（NSCLC）亚组患者中观察到特别有前景的抗癌活性。
方法：在一项单组、2 期试验中，我们研究了索托拉西布（每天口服 960mg）在先前接受过标准治疗的携带 p.G12C 突变的晚期 NSCLC 患者中的活性。主要终点是独立中心评估的客观缓解（完全或部分缓解）。关键次要终点包括缓解持续时间、疾病控制（完全缓解、部分缓解或稳定疾病）、无进展生存期、总生存期和安全性。探索性生物标志物用于评估其与索托拉西布治疗反应的相关性。
结果：在 126 名入组患者中，大多数（81.0%）既往接受过铂类化疗和程序性死亡 1（PD-1）或程序性死亡配体 1（PD-L1）抑制剂治疗。根据中心评估，基线时有可测量疾病的 124 名患者接受了缓解评估。46 名患者（37.1%；95%置信区间 [CI]，28.6 至 46.2）观察到客观缓解，包括 4 名（3.2%）完全缓解和 42 名（33.9%）部分缓解。缓解持续时间的中位数为 11.1 个月（95%CI，6.9 至 15.3 个月），无法评估。疾病控制发生在 100 名患者（80.6%；95%CI，72.6 至 87.2）中。无进展生存期的中位数为 6.8 个月（95%CI，5.1 至 8.2），总生存期的中位数为 12.5 个月（95%CI，10.0 至 无法评估）。126 名患者中有 88 名（69.8%）发生与治疗相关的不良事件，包括 25 名（19.8%）患者发生 3 级事件和 1 名（0.8%）患者发生 4 级事件。根据 PD-L1 表达、肿瘤突变负荷以及 、 或 中共同发生的突变，在亚组中观察到缓解。
结论：在这项 2 期试验中，索托拉西布治疗在先前治疗的携带 p.G12C 突变的 NSCLC 患者中导致持久的临床获益，无新的安全性信号。（由 Amgen 和美国国立卫生研究院资助；CodeBreaK100 临床试验.gov 编号，NCT03600883。）
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