Background: In the single-arm phase 1/2 CodeBreaK 100 study (NCT03600883) evaluating sotorasib monotherapy in KRAS G12C-mutated mCRC patients whose disease progressed on or after fluoropyrimidine, oxaliplatin, and irinotecan treatment, the overall response rate was 12%, and the median progression-free survival (PFS) and overall survival (OS) was 4.2 and 13.4 months, respectively (data cutoff March 2021, n = 91). To compare the efficacy and safety of sotorasib with standard of care (SOC) T/T and regorafenib as monotherapy treatments, MAICs were performed. Methods: Clinical outcomes and adverse events (AEs) were compared from representative studies in mCRC patients who received sotorasib 960 mg once daily in CodeBreaK 100, T/T in the phase 3 RECOURSE study (NCT01607957, n = 534), and regorafenib in the phase 3 CORRECT study (NCT01103323, n = 505). By weighting individual patient-level data from CodeBreak 100, differences in available baseline characteristics considered to be prognostic factors, including age, race, sex, type of cancer (colon vs. rectum), ECOG performance status, time from diagnosis of metastatic disease, number of metastatic sites, number of prior lines of therapy, and prior bevacizumab treatment, were adjusted with the MAIC. MAICs compared sotorasib with T/T and regorafenib separately. Odds ratios (ORs) were estimated for objective response rates, hazard ratios (HRs) were used for PFS and OS. AEs were compared descriptively. Results: The effective sample size of sotorasib with matched characteristics consisted of 29 and 56 patients in the T/T and regorafenib comparison, respectively. The MAIC results showed that treatment with sotorasib increases the likelihood of response to treatment, with an adjusted OR of 8.5 vs T/T and 16.1 vs regorafenib. Sotorasib decreased the risk of progression or death by 41% vs T/T and 45% vs regorafenib (Table). Grade 3+ treatment-emergent AEs occurred in 37%, 69%, and 78% of sotorasib-, T/T-, and regorafenib-treated patients, respectively. Conclusions: The analyses suggest that sotorasib monotherapy is associated with a statistically significant and clinically meaningful improvement in response rates, PFS and OS vs. T/T and regorafenib in heavily pretreated chemorefractory KRAS G12C-mutated mCRC patients. The analyses are limited by the decreased sample size for sotorasib, the lack of KRAS G12C-specific data in SOC studies, and the impact of differences in post-progression treatments on OS across studies.

* Per central review for sotorasib, per investigator assessment for comparators CI: confidence interval.