TY - JOUR
T1 - KrAsG12C inhibition with sotorasib in advanced solid tumors
AU - Hong, David S.
AU - Fakih, Marwan G.
AU - Strickler, John H.
AU - Desai, Jayesh
AU - Durm, Gregory A.
AU - Shapiro, Geoffrey I.
AU - Falchook, Gerald S.
AU - Price, Timothy J.
AU - Sacher, Adrian
AU - Denlinger, Crystal S.
AU - Bang, Yung Jue
AU - Dy, Grace K.
AU - Krauss, John C.
AU - Kuboki, Yasutoshi
AU - Kuo, James C.
AU - Coveler, Andrew L.
AU - Park, Keunchil
AU - Kim, Tae Won
AU - Barlesi, Fabrice
AU - Munster, Pamela N.
AU - Ramalingam, Suresh S.
AU - Burns, Timothy F.
AU - Meric-Bernstam, Funda
AU - Henary, Haby
AU - Ngang, Jude
AU - Ngarmchamnanrith, Gataree
AU - Kim, June
AU - Houk, Brett E.
AU - Canon, Jude
AU - Russell Lipford, J.
AU - Friberg, Gregory
AU - Lito, Piro
AU - Govindan, Ramaswamy
AU - Li, Bob T.
N1 - Funding Information:
Supported by Amgen; also supported in part by a Cancer Prevention Research Institute of Texas Precision Oncology Decision Support Core grant (RP150535)and Comprehensive Cancer Center Core Grants (P30 CA016672 and P30 CA008748) at Memorial Sloan Kettering Cancer Center from the National Institutes of Health (NIH). Dr. Denlinger is supported in part by a Comprehensive Cancer Center Core Grant (P30 CA006927) at Fox Chase Cancer Center from the NIH, and Dr. Lito is supported in part by grants (1R01CA23074501 and 1R01CA23026701A1) from the NIH National Cancer Institute, by the Pew Charitable Trusts, and by the Damon Runyon Cancer Research Foundation.
Publisher Copyright:
Copyright © 2020 Massachusetts Medical Society.
PY - 2020/9/24
Y1 - 2020/9/24
N2 - 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 KRASG12C. 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.
AB - 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 KRASG12C. 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.
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U2 - 10.1056/NEJMoa1917239
DO - 10.1056/NEJMoa1917239
M3 - Article
C2 - 32955176
AN - SCOPUS:85091570541
SN - 0028-4793
VL - 383
SP - 1207
EP - 1217
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 13
ER -