Sotorasib Demonstrates Clinical Benefit in Patients with NSCLC Harboring KRASᴳ¹²ᶜ

Lung cancer is a leading cause of cancer-related deaths worldwide contributing to 1.6 million deaths per year.¹ The disease has a poor survival rate with approximately 20% of patients surviving to 5 years after diagnosis.¹ Of all lung cancer cases, 85% of patients have non–small-cell lung cancer (NSCLC). Among patients with NSCLC, the KRAS mutation is one of the most common mutated genes found during gene sequencing.¹ Among the mutations, the KRAS G12C mutation accounts for 13% of total NSCLC cases.¹ Targeting this mutation with sotorasib, an oral KRAS G12C inhibitor, was the goal of the single-arm, phase 2 CodeBreaK 100 trial.² The trial results were presented recently at the 2021 American Society of Clinical Oncology Annual Meeting by Skoulidis and colleagues.

Trial participants (N = 124) who had advanced NSCLC previously treated with standard therapies harboring the KRAS G12C mutation were given 960 mg of sotorasib once a day. There were 59 patients aged ≥65 years in the study and 65 patients aged <65 years. All participants had an Eastern Cooperative Oncology Group performance status of 0 (n = 37) or 1 (n = 87). Most patients (n = 120) had metastatic disease. Prior lines of therapy were ≥2 for 71 participants, and prior anti–PD-1 or PD-L1 therapy was administered to 113 participants.

The primary study end point was the objective response rate to sotorasib, which was found to be 37.1%. Secondary end points were also evaluated during the study, but the results of these end points remain immature. The median progression-free survival was 6.8 months. The tumor mutational burden levels were low (<10 mut/MB) in 69 patients and high (≥10 mut/MB) in 15 patients.

Co-mutation subgroup analysis was also performed, and sotorasib demonstrated a response across all patient subgroups. Next-generation sequencing using tissue and/or plasma samples was used to determine mutational status. Across these patient subgroups, sotorasib had a clinical benefit even in those harboring the STK11 co-mutation, a driver of poor clinical outcomes. In this subgroup, patients with the wild-type mutation (n = 69) had an objective response rate of 39.1%.

References

1. Uras IZ, Moll HP, Casanova E. Targeting KRAS mutant non-small-cell lung cancer: past, present and future. Int J Mol Sci. 2020;21(12):4325. doi:10.3390/ijms21124325.
2. Skoulidis F, Li BT, 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(15)9003. doi:10.1200/JCO.2021.39.15.