Matching-Adjusted Indirect Comparison of Sotorasib Versus Adagrasib in Previously Treated Advanced/Metastatic Non-Small Cell Lung Cancer Harboring KRAS G12C Mutation

Abstract

Introduction: Sotorasib and adagrasib are the only treatments approved in the USA and Europe for advanced/metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC). In the absence of head-to-head trials, a matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy and safety of sotorasib versus adagrasib using phase 3 trials. Methods: Patient-level data from CodeBreaK 200 were reweighted to match the baseline characteristics reported in KRYSTAL-12. The analysis evaluated progression free-survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAE). Age, sex, region, prior treatment, brain metastases, and liver metastases were selected for adjustment in the primary analysis per clinical guidance, using an unanchored approach (no common comparator). We conducted sensitivity analyses including additional covariates or anchoring the analysis via common comparator (docetaxel). Additional subgroup analysis was performed in patients with baseline brain metastases, assessing systemic PFS. Results: Following adjustment, the reweighted patient characteristics from CodeBreaK 200 and KRYSTAL-12 were well balanced. In the primary analysis, sotorasib and adagrasib showed similar efficacy: PFS (HR [hazard ratio] 0.93; 95% confidence interval [CI] 0.70-1.22; p = 0.589) and ORR (odds ratio 0.86; 95% CI 0.53-1.38; p = 0.524). Among patients with brain metastases, sotorasib demonstrated a 39% reduced risk of progression compared with adagrasib (HR 0.61; 95% CI 0.38-0.98; p = 0.040). Sotorasib also demonstrated a more favorable safety profile than adagrasib, with lower odds of TRAEs, TRAEs leading to dose reduction or dose interruption, and all eight individual TRAEs evaluated. Sensitivity analyses supported the robustness of base-case results. Conclusion: In this MAIC, sotorasib and adagrasib showed comparable efficacy in previously treated advanced KRAS G12C-mutated NSCLC. Among patients with baseline brain metastases, PFS point estimates favored sotorasib. Sotorasib also demonstrated a favorable overall safety profile. These findings may help inform payer decisions and clinical practice in the treatment of KRAS G12C-mutated NSCLC.