索托拉西布联合帕尼单抗治疗携带 G12C 突变的难治性结直肠癌。

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated G12C.

机构信息

From Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), and Amgen, Thousand Oaks (E.C., J.C., Y.S., Q.T.) - both in California; Oncologia Medica, Università Cattolica del Sacro Cuore, and Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome (L.S.), the Oncology Department, Fondazione Poliambulanza Istituto Ospedaliero, Brescia (F.M.), the Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa (C.C.), and the Medical Oncology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan (F.P.) - all in Italy; the Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka (T.E.), and the Experimental Therapeutics and GI Oncology Department, National Cancer Center Hospital East, Kashiwa (Y.K.) - both in Japan; the Medicine Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin (D.P.M.); the Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona (D.P.L.-B.); Université Paris Cité, Site de Recherche Intégrée sur le Cancer, Cancer Research for Personalized Medicine Comprehensive Cancer Center, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges-Pompidou, Paris (J.T.); the Department of Biological Chemistry, National and Kapodistrian University of Athens-School of Medicine, Athens (M.V.K.); Gastrointestinal Oncology Department and Translational Medicine Laboratory, Instituto Nacional de Cancerologia, Mexico City (E.R.-G.); the Oncology Department, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea (T.W.K.); the Medicine Department, Royal Marsden Hospital, London (D.C.); and the Department of Oncology, National Taiwan University Hospital, and the Graduate Institute of Oncology, National Taiwan University College of Medicine - both in Taipei (K.H.Y.).

出版信息

N Engl J Med. 2023 Dec 7;389(23):2125-2139. doi: 10.1056/NEJMoa2308795. Epub 2023 Oct 22.

DOI:10.1056/NEJMoa2308795

PMID:37870968

Abstract

BACKGROUND

G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy.

METHODS

In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response.

RESULTS

After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab.

CONCLUSIONS

In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.).

摘要

背景

G12C 是约 3%至 4%转移性结直肠癌患者中发生的突变。KRAS G12C 抑制剂的单药治疗仅产生适度疗效。联合 KRAS G12C 抑制剂索托拉西布和表皮生长因子受体 (EGFR) 抑制剂帕尼单抗可能是一种有效的策略。

方法

在这项 3 期、多中心、开放标签、随机试验中，我们将未接受过 KRAS G12C 抑制剂治疗的化疗耐药转移性结直肠癌且携带突变 G12C 的患者随机分配接受 960 mg 索托拉西布每日一次加帕尼单抗（53 例）、240 mg 索托拉西布每日一次加帕尼单抗（53 例）或研究者选择的替匹嘧啶-三氟尿苷或瑞戈非尼（标准治疗；54 例）。主要终点是根据实体瘤反应评估标准 1.1 进行的盲法独立中心评估的无进展生存期。关键次要终点是总生存期和客观缓解。

结果

中位随访 7.8 个月（范围，0.1 至 13.9）后，960 mg 索托拉西布-帕尼单抗组和 240 mg 索托拉西布-帕尼单抗组的中位无进展生存期分别为 5.6 个月（95%CI，4.2 至 6.3）和 3.9 个月（95%CI，3.7 至 5.8），而标准治疗组为 2.2 个月（95%CI，1.9 至 3.9）。与标准治疗组相比，960 mg 索托拉西布-帕尼单抗组疾病进展或死亡的风险比为 0.49（95%CI，0.30 至 0.80；P=0.006），240 mg 索托拉西布-帕尼单抗组的风险比为 0.58（95%CI，0.36 至 0.93；P=0.03）。总生存期数据正在成熟。客观缓解率分别为 26.4%（95%CI，15.3 至 40.3）、5.7%（95%CI，1.2 至 15.7）和 0%（95%CI，0.0 至 6.6），960 mg 索托拉西布-帕尼单抗组、240 mg 索托拉西布-帕尼单抗组和标准治疗组分别为 35.8%、30.2%和 43.1%。≥3 级的治疗相关不良事件分别发生在 35.8%、30.2%和 43.1%的患者中。与索托拉西布-帕尼单抗相关的皮肤毒性和低镁血症是最常见的不良事件。

结论

在这项针对化疗耐药转移性结直肠癌患者的 KRAS G12C 抑制剂加 EGFR 抑制剂的 3 期试验中，与标准治疗相比，两种剂量的索托拉西布联合帕尼单抗均可延长无进展生存期。两种药物的毒性作用与单独使用时一致，导致治疗中断的情况很少。（由 Amgen 资助；CodeBreaK 300 临床试验.gov 编号，NCT05198934。）