Sotorasib for Lung Cancers with KRAS p.G12C Mutation
Ferdinandos Skoulidis1, Bob T Li1, Grace K Dy1
1From 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-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.).
Background:
Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC).
Methods:
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-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-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
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