CodeBreaK 100: Efficacy Results from a Phase 2 Trial in Pretreated KRAS G12C–Mutated NSCLC

CodeBreaK 100 was a registrational phase 2 trial of sotorasib in patients with pretreated KRAS G12C–mutated non–small-cell lung cancer (NSCLC), and demonstrated an objective response rate (ORR) of 37% (95% confidence interval [Cl], 29%-46%) and a median progression-free survival (PFS) of 6.8 months (95% Cl, 5.1-8.2 months).¹ Patients bearing co-mutations in STK11, a driver of poor clinical outcomes with standard of care, were observed for tumor response. Efficacy data for an extended set of patient subgroups described by key baseline characteristics and biomarkers were reported at ASCO 2021.¹

In CodeBreaK 100, sotorasib was given at 960 mg once daily orally to patients who had advanced NSCLC harboring KRAS G12C and had received prior standard therapies. The majority of patients were previously treated with platinum-based chemotherapy (89.7%), PD-1 or PD-L1 inhibitors (91.3%), or with both (81.0%). The primary end point was ORR assessed by central review, and key secondary end points included disease control rate (DCR), PFS, overall survival (OS), and safety.¹

Using tissue samples and next-generation sequencing (NGS), KRAS G12C–mutated allele frequency and tumor mutational burden were analyzed. Individual gene mutational status was determined by NGS using tissue and/or plasma samples. KRAS G12C–mutated allele frequency, tumor mutational burden, or co-mutations were correlated to responses in subsets of patients who had available results.¹

The ORR associated with sotorasib was 37.1% (95% CI, 28.6-46.2) with a DCR of 80.6% (95% CI, 72.6-87.2) and was independent of KRAS G12C–mutated allele frequency in the study population (odds ratio, 1.11; 95% CI, 0.88-1.39). Median OS was 12.5 months (95% CI, 10.0-not evaluable). Treatment was well-tolerated, with most adverse events (AEs) grade 1 or 2 and no grade 5 AEs. The most common treatment-related AEs of any grade were diarrhea (31.7%), nausea (19.0%), and ALT/AST increase (15.1%/15.1%).¹

The clinical benefit of sotorasib was observed across KRAS G12C patient subgroups in exploratory analyses, including the elderly, heavily pretreated patients, and those who had progressed on checkpoint inhibitor therapy within 3 months. Responses were consistently beneficial across molecular subgroups, including genomic alterations in TP53, STK11, and KEAP1, which are associated with poorer outcomes across a variety of treatments.

Reference

1. 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. American Society of Clinical Oncology (ASCO), June 2021; Abstract 9003.