Wednesday, September 23, 2020

KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

David S. Hong, M.D., Marwan G. Fakih, M.D., John H. Strickler, M.D., Jayesh Desai, M.D., Gregory A. Durm, M.D., Geoffrey I. Shapiro, M.D., Ph.D., Gerald S. Falchook, M.D., Timothy J. Price, M.B., B.S., D.Hlth.Sc., Adrian Sacher, M.D., M.M.Sc., Crystal S. Denlinger, M.D., Yung-Jue Bang, M.D., Ph.D., Grace K. Dy, M.D., John C. Krauss, M.D., Yasutoshi Kuboki, M.D., James C. Kuo, M.D., Andrew L. Coveler, M.D., Keunchil Park, M.D., Ph.D., Tae Won Kim, M.D., Ph.D., Fabrice Barlesi, M.D., Ph.D., Pamela N. Munster, M.D., Suresh S. Ramalingam, M.D., Timothy F. Burns, M.D., Ph.D., Funda Meric-Bernstam, M.D., Haby Henary, M.D., Jude Ngang, Pharm.D., Gataree Ngarmchamnanrith, M.D., June Kim, Ph.D., Brett E. Houk, Ph.D., Jude Canon, Ph.D., J. Russell Lipford, Ph.D., Gregory Friberg, M.D., Piro Lito, M.D., Ph.D., Ramaswamy Govindan, M.D., and Bob T. Li, M.D., M.P.H

N. Engl. J. Med. 2020; 383:1207-1217

DOI: 10.1056/NEJMoa1917239 



No therapies for targeting KRAS mutations in cancer have been approved. The KRASp.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.


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.


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.


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. (Funded by Amgen and others; CodeBreaK100 number, NCT03600883. opens in new tab.)

Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry

Roman C. Sarott, Inchul You, Yen-Der Li, Sean T. Toenjes, Katherine A. Donovan, Pooreum Seo, Martha Ordonez, Woong Sub Byun, Muhammad Murtaz...