At the 2022 ESMO congress, results from the CodeBreak 200 trial were reported. CodeBreaK 200 is the first phase 3 trial of a KRAS G12C inhibitor in non-small cell lung cancer. In patients with NSCLC harboring KRAS G12C mutations, the KRAS G12C inhibitor sotorasib was shown to double the rate of 12-month progression-free survival and reduce the risk of disease progression and death by 34% compared to the standard second-line treatment, docetaxel. Sotorasip was granted accelerated approval by the U.S. FDA in May 2021 based on results from the CodeBreaK100 Phase 1/2 trial.

The CodeBreaK200 study enrolled 345 patients with metastatic or locally advanced, unresectable NSCLC harboring the KRAS G12C mutation. Thirty-six percent of patients assigned to the Sotorasip arm received follow-up treatment with docetaxel, compared to 42% of patients assigned to the docetaxel arm, and 34% of patients in the docetaxel arm subsequently received KRAS G12C inhibitor treatment.

Patients were randomized to the Sotorasib arm (n=171) and the docetaxel arm (n=174) to receive either Sotorasib 960 mg daily or docetaxel 7 mg/m^2 every 3 weeks. All patients had received prior concurrent or sequential platinum-based anticancer agents and immune checkpoint inhibitors.

Among treatment outcomes, median progression-free survival was 5.6 months and 4.5 months for Sotorasib and docetaxel, respectively. Overall survival was 10.6 months and 11.3 months for Sotorasib and docetaxel, respectively, with no significant difference. Objective response rates were 82.5% and 60.3% for Sotorasib and docetaxel, respectively, with tumor shrinkage seen in 80% of the Sotorasib arm compared to 62.8% of the docetaxel arm.

Safety and quality of life also favored SOTORASIP. Treatment-related adverse events occurred in 9.5% and 11.3% of patients in the SOTORASIP and docetaxel arms, respectively, with diarrhea, the most common adverse event, being higher in the SOTORASIP arm (33.7% vs 18.5% in the SOTORASIP and docetaxel arms, respectively), while fatigue was higher in the docetaxel arm (6.5% vs 25.2%). In terms of grade 3 or higher treatment-related adverse events, SOTORASIP (33.1%) was superior to docetaxel (40.4%).

The Phase 1/2 CodeBreaK 101 trial is currently investigating the combination of Sotorasib. In addition, the Phase 3 CodeBreaK 300 study is testing the efficacy of the combination of Sotorasib and panitumumab in patients with colorectal cancer harboring the KRAS G12C mutation. This study is significant because it is the first Phase 3 trial of a KRAS G12C inhibitor in non-small cell lung cancer, and the researchers expect Sotorasib to perform well when combined with MAP kinase, EGFR, and PD-L1 inhibitors.