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KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors – nejm.org

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List of authors.

  • 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.

Abstract

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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Funding and Disclosures

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.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Hong and Fakih and Drs. Lito, Govindan, and Li contributed equally to this article.

This article was published on September 20, 2020, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the patients for participating in the trial and their families, as well as Melissa Farley and Peter Alexander for study management, Bob Dawson and Brian Lanman for graphics assistance, Jonathan Aspe and Noella Vang for operational planning assistance, and Yang Li for medical writing assistance (all of Amgen).

Author Affiliations

From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) — all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) — all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana–Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) — all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) — all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.).

Address reprint requests to Dr. Hong at the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, or at [email protected]; or to Dr. Li at the Thoracic Oncology and Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY 10065, or at [email protected].

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