Despite recent advances, treating advanced pancreatic cancer remains challenging, especially after progression on first- and second-line treatment. So far, no late-line therapies have shown a survival benefit in pancreatic cancer. Genetic alterations are common in this disease and approximately 90% of pancreatic cancers harbor KRAS mutations, of which 1-2% are KRAS G12C. Treatments targeting KRAS G12C have been developed recently. Sotorasib, a selective and irreversible KRAS G12C inhibitor, has been evaluated in previously treated patients with KRAS G12C-mutated solid tumors (including pancreatic cancer) in the single arm phase I/II CodeBreaK100 trial. Based on its efficacy (objective response rate [ORR] by independent review) and favorable safety profile in the lung cancer cohort, sotorasib received regulatory approval for patients with NSCLC who harbor this mutation. Data from the pancreatic cancer cohort from this study were presented at the February 2022 ASCO Plenary Session.

In total, 38 patients with stage IV pancreatic cancer were enrolled in the study. Most patients were heavily pretreated and had received ≥ 2 lines of therapy. Sotorasib was given orally at a dose of 960 mg once daily. The ORR was 21%, with 8 patients achieving a confirmed partial response. The disease control rate was 84.2%. The median duration of response was 5.7 months. At a median follow-up of 16.8 months, the median progression-free survival was 4.0 months, and median overall survival was 6.9 months. Sotorasib was well-tolerated and most treatment-related adverse events were grade 2 or less, and were manageable. The incidence of all-grade treatment-related adverse events (TRAEs) was 42%, and 16% of patients experienced grade 3 TRAEs. Investigators observed no grade 4 or fatal TRAEs, nor any that led to the discontinuation of sotorasib.

The authors concluded that sotorasib showed clinically meaningful anticancer activity and good tolerability in patients with heavily pretreated KRAS G12C-mutated advanced pancreatic cancer; they noted that the data support the further exploration of sotorasib in this patient population with a high unmet medical need.’  “KRAS G12C inhibition is really here to stay,” said discussant E. Gabriela Chiorean, MD, of the Fred Hutchinson Cancer Research Center. “The presented data are a steppingstone for future combination approaches with sotorasib. We also need to bring these approaches earlier in the disease treatment stage. Earlier lines of therapy will enable more patients to have access to treatment, because very few patients survive to reach the third line of therapy.’’ She noted that the efficacy seen in pancreatic cancer with sotorasib, as well as with other KRAS G12C inhibitors, such as adagrasib is ‘’remarkable for the refractory setting.’’ Furthermore, she pointed out that molecular and genomic profiling should be performed in all patients, and they should be encouraged to participate in clinical trials.

Reference:
Strickler JH, et al. J Clin Oncol. 2022;40(suppl 36): Abstract 360490.