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KRAS is one of the most commonly mutated genes in non−small-cell lung cancer (NSCLC) and G12C mutation accounts for 13% of all NSCLC. The industry-funded, single-arm, phase 2 CodeBreaK-100 trial evaluated the activity of the oral tyrosine kinase inhibitor sotorasib (960 mg once daily) in patients with KRAS p.G12C mutated NSCLC who had progression after treatment with other therapies.
Of 126 patients enrolled, 81% had been treated with anti–PD-1 or anti–PD-L1 immunotherapy, platinum-based combination chemotherapy, or both, and 22.2% had received at least three lines of prior therapy. During a median follow-up of 15.3 months, objective response — the primary endpoint — occurred in 37.1% of patients, with 4 patients (3.2%) experiencing a complete response. Median duration of response was 11.1 months, median progression free survival was 6.8 months, and median overall survival was 12.5 months. No new safety issues were identified.
Skoulidis F et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021 Jun 24; 384:2371. (https://doi.org/10.1056/NEJMoa2103695)
Comment
These results are immediately practice changing and establish a new standard of care in management of metastatic NSCLC harboring a KRAS G12C mutation. In addition, these results underscore the importance of next generation gene sequencing in patients with metastatic non-squamous NSCLC at initial diagnosis. The current FDA approval for sotorasib, which was based on this trial, is for second-line treatment and beyond, and patients with KRAS G12C mutant NSCLC should still be treated with upfront immunotherapy, either alone or in combination with chemotherapy based on PDL1 status.