The most common mutated oncogene in cancer is the RAS oncogene, with KRAS being the most frequently mutated RAS isoform.1 In cells, the KRAS protein cycles between an active form and an inactive form.1 The active form activates signaling pathways responsible for cell proliferation, cell-cycle regulation, and cell survival among other cellular functions.1 When KRAS becomes dysregulated, tumor growth occurs and cancer-cell survival, invasion, and migration are promoted.1 In lung cancer, KRAS accounts for approximately one-third of mutations, with G12C mutations being the most common type.1 Patients with non–small-cell lung cancer (NSCLC) with KRAS mutations generally have a poor treatment outcome, as these mutations are often associated with treatment resistance.1,2 Sotorasib is a small-molecule KRASG12C inhibitor that irreversibly traps KRASG12C in an inactive state.2
In the phase 2 CodeBreaK 100 trial, sotorasib demonstrated favorable efficacy in pretreated patients with KRASG12C NSCLC with an objective response rate (ORR) of 37.1% and a median progression-free survival of 6.8 months.3,4 Based on these results, the US Food and Drug Administration approved sotorasib in May 2021 for adult patients with NSCLC with the KRASG12C mutation and who had received ≥1 previous systemic therapies.3 In patients with STK11 co-mutations, tumor response was also observed.4 With standard treatment, the STK11 mutation is associated with poor clinical outcomes.4
At the 2021 American Society of Clinical Oncology Annual Meeting, researchers presented further overall survival and efficacy results across an extended set of patient subgroups from the phase 2 CodeBreaK 100 trial. In this trial, 960 mg of sotorasib was given to 124 patients with advanced KRASG12C mutation–positive NSCLC who had disease progression despite previous treatment.3,4 Nearly one-third (30.8%) of patients aged <65 years had an ORR, whereas 44.1% of patients aged ≥65 years had an ORR. The ORR was approximately 50% higher in patients aged ≥65 years. Two or more previous lines of therapy were found in 35.2% of the patients. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and the majority (N = 120) had metastatic disease. Adverse reactions led to permanent discontinuation of sotorasib in 9% of patients.3 The primary end point was ORR, and secondary end points were overall survival, progression-free survival, and safety. In patients with previous anti–PD-1 or PD-L1 treatment, the ORR was 36.3%; in patients without these previous treatments, the ORR was 45.5%. In patients with either TP53, STK11, or KEAP1 co-mutation, the ORR was approximately 40.0%. In this subanalysis of the CodeBreaK 100 trial, a clinical benefit with sotorasib was observed across all patients with KRASG12C mutation–positive subgroups.
- Reck M, Carbone DP, Garassino M, Barlesi F. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann Oncol. 2021;32:1101-1110.
- Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383:1207-1217.
- Goodman A. Sotorasib: subgroup analysis of phase II trial shows activity with breakthrough KRAS inhibitor in lung cancer. June 25, 2021. https://ascopost.com/issues/june-25-2021/subgroup-analysis-of-phase-ii-trial-shows-activity-with-breakthrough-kras-inhibitor-in-lung-cancer/. Accessed June 26, 2021.
- Skoulidis F, Li B, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(suppl 15):Abstract 9003.