KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors

被引:1237
作者
Hong, David S. [1 ]
Fakih, Marwan G. [2 ]
Strickler, John H. [5 ]
Desai, Jayesh [6 ]
Durm, Gregory A. [10 ]
Shapiro, Geoffrey I. [11 ]
Falchook, Gerald S. [12 ]
Price, Timothy J. [7 ,8 ]
Sacher, Adrian [13 ]
Denlinger, Crystal S. [14 ]
Bang, Yung-Jue [16 ]
Dy, Grace K. [19 ]
Krauss, John C. [22 ]
Kuboki, Yasutoshi [23 ]
Kuo, James C. [9 ]
Coveler, Andrew L. [24 ]
Park, Keunchil [17 ]
Kim, Tae Won [18 ]
Barlesi, Fabrice [25 ]
Munster, Pamela N. [3 ]
Ramalingam, Suresh S. [26 ]
Burns, Timothy F. [15 ]
Meric-Bernstam, Funda [1 ]
Henary, Haby [4 ]
Ngang, Jude [4 ]
Ngarmchamnanrith, Gataree [4 ]
Kim, June [4 ]
Houk, Brett E. [4 ]
Canon, Jude [4 ]
Lipford, J. Russell [4 ]
Friberg, Gregory [4 ]
Lito, Piro [20 ,21 ]
Govindan, Ramaswamy [27 ]
Li, Bob T. [20 ,21 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase I Clin Trials Program, Houston, TX 77030 USA
[2] City Hope Comprehens Canc Ctr, Dept Med Oncol & Expt Therapeut, Duarte, CA USA
[3] Univ Calif San Francisco, San Francisco, CA 94143 USA
[4] Amgen Inc, Thousand Oaks, CA USA
[5] Duke Univ, Med Ctr, Durham, NC USA
[6] Royal Melbourne Hosp, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia
[7] Queen Elizabeth Hosp, Woodville South, SA, Australia
[8] Univ Adelaide, Woodville South, SA, Australia
[9] Scientia Clin Res, Randwick, NSW, Australia
[10] Indiana Univ Sch Med, Dept Med, Div Hematol Oncol, Indianapolis, IN 46202 USA
[11] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA
[12] HealthONE, Sarah Cannon Res Inst, Denver, CO USA
[13] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada
[14] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA
[15] Univ Pittsburgh, Med Ctr, Hillman Canc Ctr, Pittsburgh, PA USA
[16] Seoul Natl Univ, Coll Med, Seoul, South Korea
[17] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea
[18] Univ Ulsan, Coll Med, Dept Oncol, Asan Med Ctr, Seoul, South Korea
[19] Roswell Pk Canc Inst, Buffalo, NY USA
[20] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA
[21] Weill Cornell Med, New York, NY 10065 USA
[22] Univ Michigan, Ann Arbor, MI 48109 USA
[23] Natl Canc Ctr Hosp East, Dept Expt Therapeut, Kashiwa, Chiba, Japan
[24] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA
[25] Aix Marseille Univ, CNRS, INSERM, Ctr Rech Cancerol Marseille,Assistance Publ Hop M, Marseille, France
[26] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA
[27] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 14263 USA
关键词
METASTATIC COLORECTAL-CANCER; KRAS CODON 12; MUTATION; CETUXIMAB; SURVIVAL; THERAPY; TAS-102; PLACEBO; TRIAL; NRAS;
D O I
10.1056/NEJMoa1917239
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 KRAS(G12C). 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.
引用
收藏
页码:1207 / 1217
页数:11
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