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Matching-Adjusted Indirect Comparison of Sotorasib Versus Adagrasib in Previously Treated Advanced/Metastatic
Divyan Chopra1, Zhiyi Lan2, David M Waterhouse3
1Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
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.
Insights
Sotorasib and adagrasib show similar efficacy for KRAS G12C-mutated non-small cell lung cancer. Sotorasib demonstrated a better safety profile and improved progression-free survival in patients with brain metastases.
Area of Science:
- Oncology
- Medical Research
- Pharmacology
Background:
- Sotorasib and adagrasib are approved treatments for advanced/metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC).
- No head-to-head trials exist to compare these two therapies directly.
- A matching-adjusted indirect comparison (MAIC) was performed to evaluate their relative efficacy and safety.
Purpose of the Study:
- To compare the efficacy and safety of sotorasib versus adagrasib in patients with advanced/metastatic KRAS G12C-mutated NSCLC.
- To utilize a MAIC methodology using patient-level data from pivotal phase 3 trials.
Main Methods:
- Patient-level data from the CodeBreaK 200 trial were reweighted to match baseline characteristics of the KRYSTAL-12 trial.
- Key efficacy endpoints included progression-free survival (PFS) and objective response rate (ORR).
- Treatment-related adverse events (TRAEs) were assessed, with sensitivity analyses conducted to ensure robustness.
Main Results:
- The primary analysis revealed comparable efficacy between sotorasib and adagrasib for PFS (HR 0.93; 95% CI 0.70-1.22) and ORR (OR 0.86; 95% CI 0.53-1.38).
- Sotorasib showed a statistically significant 39% reduced risk of progression in patients with brain metastases (HR 0.61; 95% CI 0.38-0.98).
- Sotorasib exhibited a more favorable safety profile, with lower incidence of TRAEs and related dose modifications.
Conclusions:
- Sotorasib and adagrasib demonstrate comparable efficacy in previously treated patients with advanced KRAS G12C-mutated NSCLC.
- Sotorasib presents a potentially superior safety profile and improved PFS in the subgroup of patients with brain metastases.
- These findings can aid in clinical decision-making and formulary considerations for KRAS G12C-mutated NSCLC treatment.
