Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer

Abstract

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.).

Figure 1.. Efficacy Analyses of Sotorasib Therapy.

Panel A shows the responses and the duration of treatment in all patients as assessed by blinded independent central review (which could be different from investigator-assessed timing of progressive disease). Five patients with a best objective response of progressive disease as assessed by blinded independent central review ended treatment within one cycle after the occurrence of progressive disease according to the decision of the investigator. Panel B shows the best percentage change from baseline in tumor burden (defined as the sum of the diameters of all target lesions). The upper dashed line indicates a 20% increase in tumor burden (progressive disease), and the lower dashed line indicates a 30% decrease in tumor burden (partial response). Progressive disease with less than a 20% increase (from nadir) in the sum diameter of target lesions was due to unequivocal progressive disease in the nontarget lesion or the presence of a new lesion. Panel C shows the Kaplan–Meier curve of progression-free survival; the dashed line indicates 50% progression-free survival probability. Panel D shows the Kaplan–Meier curve of overall survival; the dashed line indicates 50% overall survival probability. The vertical bars in Panels C and D indicate censored data.