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KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

Publication ,  Journal Article
Hong, DS; Fakih, MG; Strickler, JH; Desai, J; Durm, GA; Shapiro, GI; Falchook, GS; Price, TJ; Sacher, A; Denlinger, CS; Bang, Y-J; Dy, GK ...
Published in: N Engl J Med
September 24, 2020

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. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

September 24, 2020

Volume

383

Issue

13

Start / End Page

1207 / 1217

Location

United States

Related Subject Headings

  • Pyrimidines
  • Pyridines
  • Proto-Oncogene Proteins p21(ras)
  • Piperazines
  • Neoplasms
  • Mutation
  • Middle Aged
  • Male
  • Lung Neoplasms
  • Humans
 

Citation

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Hong, D. S., Fakih, M. G., Strickler, J. H., Desai, J., Durm, G. A., Shapiro, G. I., … Li, B. T. (2020). KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med, 383(13), 1207–1217. https://doi.org/10.1056/NEJMoa1917239
Hong, David S., Marwan G. Fakih, John H. Strickler, Jayesh Desai, Gregory A. Durm, Geoffrey I. Shapiro, Gerald S. Falchook, et al. “KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.N Engl J Med 383, no. 13 (September 24, 2020): 1207–17. https://doi.org/10.1056/NEJMoa1917239.
Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020 Sep 24;383(13):1207–17.
Hong, David S., et al. “KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.N Engl J Med, vol. 383, no. 13, Sept. 2020, pp. 1207–17. Pubmed, doi:10.1056/NEJMoa1917239.
Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang Y-J, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020 Sep 24;383(13):1207–1217.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

September 24, 2020

Volume

383

Issue

13

Start / End Page

1207 / 1217

Location

United States

Related Subject Headings

  • Pyrimidines
  • Pyridines
  • Proto-Oncogene Proteins p21(ras)
  • Piperazines
  • Neoplasms
  • Mutation
  • Middle Aged
  • Male
  • Lung Neoplasms
  • Humans