OBJECTIVES: A new class of therapies targeting KRAS G12C has emerged in a/mNSCLC, with FDA approvals of sotorasib (May-2021) and adagrasib (December-2022). Adagrasib was investigated in KRYSTAL-1, a Phase 2, single-arm trial in a/mNSCLC patients pre-treated with chemoimmunotherapy. A MAIC evaluated efficacy and safety of adagrasib in KRYSTAL-1 versus sotorasib in CodeBreaK100, a Phase 2 single-arm trial in a/mNSCLC patients pretreated with chemotherapy and/or immunotherapy, and CodeBreaK200, a Phase 3 randomized controlled trial (RCT) in a/mNSCLC patients pretreated with chemoimmunotherapy.

METHODS: An unanchored MAIC was performed, adjusting adagrasib outcomes by matching KRYSTAL-1 patient-level data to the CodeBreaK trials. Matching variables included age, gender, and performance status. Efficacy analyses also incorporated smoking, metastases, and histology. Sensitivity analyses further evaluated differences in prior therapies and ethnicity. Efficacy outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety outcomes included treatment-related adverse events (TRAEs).

RESULTS: Against CodeBreaK200, adagrasib demonstrated an ORR benefit (Odds Ratio [OR]=2.22; 95%CI, 1.25-3.96). Additionally, estimates for PFS (hazard ratio [HR]=0.79; 95%CI, 0.55-1.12) and OS (HR=0.81; 95%CI, 0.55-1.17) also favored adagrasib but were not statistically significant. In the CodeBreaK100 comparison, adagrasib was numerically favorable for ORR (OR=1.46; 95% CI, 0.81-2.63) and PFS (HR=0.77; 95%CI, 0.52-1.14). OS was similar (HR=0.95; 95%CI, 0.63-1.42). Sensitivity analyses confirmed these findings. Grade ≥3 TRAEs estimates favored sotorasib in CodeBreaK200 and CodeBreaK100 (ORs=1.50; 95%CI, 0.87-2.57; 2.83; 95%CI, 1.56-5.12, respectively); however, discontinuation due to TRAEs appeared to favor adagrasib (ORs=0.69; 95%CI, 0.26-1.80; 0.98, 95%CI, 0.33-2.87, respectively). Effective sample size ranged 70.9-94.0 across analyses.

CONCLUSIONS: This MAIC suggests differences may exist between KRAS G12C inhibitors in a/mNSCLC with adagrasib demonstrating potential improvement over sotorasib in patients pretreated with standard-of-care chemoimmunotherapy. Additional data from RCTs and real-world studies will further inform the comparative effectiveness of adagrasib versus sotorasib and will also help inform treatment decisions.