Sotorasib Demonstrates Clinical Benefit in Patients with NSCLC Harboring KRASᴳ¹²ᶜ

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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.

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