Although KRAS was long considered "undruggable," recent advances have been promising, suggesting that appropriate patient stratification and identification of subgroup mutations may improve outcomes. In May 2021, the US Food and Drug Administration approved sotorasib, a RAS GTPase family inhibitor, for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic NSCLC. Approval was based on results from the phase 2 CodeBreaK 100 trial, which showed deep responses, durable clinical benefit, and a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C. Sotorasib is being studied for use in the first-line setting.
Clinical benefit has also been shown in patients with KRAS-mutated NSCLC treated with ICI therapy. In a subgroup analysis of the KEYNOTE-042 trial, the population with KRAS-mutated NSCLC, treatment with the ICI pembrolizumab resulted in an ORR of 56.7% vs 18.0% with chemotherapy in patients with any KRAS mutation. In patients with KRAS G12C mutations, treatment with the ICI pembrolizumab resulted in an ORR of 66.7% vs an ORR of 23.5% for those treated with chemotherapy. The median PFS was comparable between any KRAS mutation and KRAS G12C, but a significantly smaller ORR was seen in patients with KRAS wild-type disease. Additional studies are needed to determine the benefit of ICI therapy in patients with KRAS-mutated NSCLC.
For additional information, refer to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Non–Small Cell Lung Cancer and the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines: Lung and Chest Tumours.
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Cite this: Winston W. Tan. Fast Five Quiz: KRAS Mutations in Non-Small Cell Lung Cancer - Medscape - Aug 17, 2021.