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Original ArticleFree Preview

Sotorasib for Lung Cancers with KRAS p.G12C Mutation

List of authors.
  • Ferdinandos Skoulidis, M.D., Ph.D.,
  • Bob T. Li, M.D., Ph.D., M.P.H.,
  • Grace K. Dy, M.D.,
  • Timothy J. Price, M.B., B.S., D.H.Sc.,
  • Gerald S. Falchook, M.D.,
  • J邦rgen Wolf, M.D.,
  • Antoine Italiano, M.D.,
  • Martin Schuler, M.D.,
  • Hossein Borghaei, D.O.,
  • Fabrice Barlesi, M.D., Ph.D.,
  • Terufumi Kato, M.D.,
  • Alessandra Curioni-Fontecedro, M.D.,
  • Adrian Sacher, M.D.,
  • Alexander Spira, M.D., Ph.D.,
  • Suresh S. Ramalingam, M.D.,
  • Toshiaki Takahashi, M.D., Ph.D.,
  • Benjamin Besse, M.D., Ph.D.,
  • Abraham Anderson, Ph.D.,
  • Agnes Ang, Ph.D.,
  • Qui Tran, Ph.D.,
  • Omar Mather, M.D.,
  • Haby Henary, M.D.,
  • Gataree Ngarmchamnanrith, M.D.,
  • Gregory Friberg, M.D.,
  • Vamsidhar Velcheti, M.D.,
  • and Ramaswamy Govindan, M.D.

Abstract

Background

Sotorasib showed anticancer activity in patients with KRAS p.G12C每mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non每small-cell lung cancer (NSCLC).

Methods

Download a PDF of the Research Summary.

In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C每mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy.

Results

Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53.

Conclusions

In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C每mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)

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Funding and Disclosures

Supported by Amgen and by a Cancer Center Core Grant (P30 CA008748, to Dr. Li) at Memorial Sloan Kettering Cancer Center from the National Institutes of Health.

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

Drs. Skoulidis and Li and Drs. Velcheti and Govindan contributed equally to this article.

This article was published on June 4, 2021, 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 and their families for participating in this trial and Yang Li (of Amgen) for medical writing assistance with an earlier version of the manuscript.

Author Affiliations

From the University of Texas M.D. Anderson Cancer Center, Houston (F.S.), and U.S. Oncology Research, the Woodlands (A. Spira) 〞 both in Texas; Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (B.T.L.) and Thoracic Medical Oncology, Perlmutter Cancer Center, New York University (V.V.), New York, and Roswell Park Cancer Institute, Buffalo (G.K.D.) 〞 all in New York; the Queen Elizabeth Hospital and University of Adelaide, Woodville, SA, Australia (T.J.P.); Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), the West German Cancer Center, University Hospital Essen, University Duisburg每Essen, Essen (M.S.), and the German Cancer Consortium, Heidelberg (M.S.) 〞 all in Germany; the Early Phase Trials and Sarcoma Units, Bergonie Cancer Institute, Bordeaux (A.I.), and Gustave Roussy Institute, Villejuif (F.B., B.B.) 〞 both in France; Fox Chase Cancer Center, Philadelphia (H.B.); Kanagawa Cancer Center, Yokohama (T.K.), and the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka (T.T.) 〞 both in Japan; the Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland (A.C.-F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A. Sacher); Virginia Cancer Specialists, Fairfax (A. Spira); Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore (A. Spira); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); Amgen, Thousand Oaks, CA (A. Anderson, A. Ang, Q.T., O.M., H.H., G.N., G.F.); and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis (R.G.).

Address reprint requests to Dr. Skoulidis at the Department of Thoracic and Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 432, Houston, TX 77030, or at ; or to Dr. Govindan at the Alvin J. Siteman Cancer Center, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8056, St. Louis, MO 63110, or at .