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Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer
John H Strickler1, Hironaga Satake1, Thomas J George1
1From Duke University Medical Center, Durham, NC (J.H.S.); Kansai Medical University, Shinmachi, Hirakata (H.S.), and St. Marianna University School of Medicine, Kawasaki (Y.S.) - both in Japan; University of Florida, Gainesville (T.J.G.); Memorial Sloan Kettering Cancer Center, New York (R.Y.); Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif (A.H.), and Marseille University Hospital, Marseille (L.D.) - both in France; Huntsman Cancer Institute, University of Utah, Salt Lake City (I.G.-L.); West German Cancer Center, University Hospital Essen, Essen (M.S.); University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh (T.F.B.); Fred Hutchinson Cancer Center, University of Washington, Seattle (A.L.C.); Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); London Regional Cancer Program, London, ON, Canada (M.V.); University Hospitals Cleveland Medical Center, Cleveland (D.B.); Yonsei Cancer Center, Seoul, South Korea (S.-Y.R.); Scientia Clinical Research and Prince of Wales Clinical School, University of New South Wales, Sydney (C.L.); Massachusetts General Cancer Center, Boston (D.J.); Amgen, Thousand Oaks, CA (M.R., G.N., P.J., Q.T.); and University of Texas M.D. Anderson Cancer Center, Houston (D.S.H.).
Background:
KRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C-mutated pancreatic cancer are unknown.
Methods:
We conducted a single-group, phase 1-2 trial to assess the safety and efficacy of sotorasib treatment in patients with KRAS p.G12C-mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed.
Results:
The pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation.
Conclusions:
Sotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C-mutated advanced pancreatic cancer who had received previous treatment. (Funded by Amgen and others; CodeBreaK 100 ClinicalTrials.gov number, NCT03600883.).
Insights
Sotorasib demonstrated anticancer activity in patients with KRAS G12C-mutated pancreatic cancer. The drug showed an acceptable safety profile in previously treated individuals, offering a new option for this patient group.
Area of Science:
- Oncology
- Medical Genetics
Background:
- KRAS p.G12C mutations are found in 1-2% of pancreatic cancers.
- The efficacy and safety of sotorasib, a KRAS G12C inhibitor, in previously treated pancreatic cancer patients were previously unknown.
Purpose of the Study:
- To assess the safety and efficacy of sotorasib in patients with KRAS p.G12C-mutated pancreatic cancer who have undergone prior systemic therapy.
- To determine the recommended dose for phase 2 and evaluate objective response, duration of response, time to response, disease control, progression-free survival, and overall survival.
Main Methods:
- A single-group, phase 1-2 trial was conducted.
- Patients received sotorasib 960 mg orally once daily.
- Safety and efficacy endpoints were assessed in a pooled population of 38 patients with metastatic disease and prior chemotherapy.
Main Results:
- An objective response was observed in 21% of patients (8/38).
- Median progression-free survival was 4.0 months, and median overall survival was 6.9 months.
- Treatment-related adverse events occurred in 42% of patients, with 16% experiencing grade 3 events; no events were fatal or led to discontinuation.
Conclusions:
- Sotorasib exhibits anticancer activity in advanced pancreatic cancer with KRAS p.G12C mutations.
- The drug has an acceptable safety profile in patients previously treated with chemotherapy.
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