Adagrasib Induces Response in KRAS^G12C-Mutated NSCLC

Mutations in KRAS occur in about one quarter of patients with non–small-cell lung cancer (NSCLC), and approximately 14% of lung adenocarcinomas and 0.5%–4% of squamous NSCLCs harbor KRAS^G12C mutations. KRAS had long been considered an “undruggable” target until the FDA approved sotorasib in 2021 for previously treated KRAS^G12C-mutant NSCLC based on a phase 2 trial showing a response rate of 37% (NEJM JW Onc Hem 2021 Sep and N Engl J Med 2021; 384:2371).

Now, in an industry-sponsored, phase 2 study, 115 patients with unresectable or metastatic NSCLC with a KRAS^G12C mutation who had previously been treated with platinum-based chemotherapy and checkpoint inhibitor therapy received the KRAS^G12C inhibitor, adagrasib (600 mg orally twice daily) until disease progression, unacceptable adverse events, withdrawal of consent, or death.

During a median follow-up of 13 months, the primary outcome — objective response — was noted in 43% of 112 patients with measurable disease at baseline. One patient had a complete response and 47 had a partial response. The median duration of response was 8.5 months. Furthermore, in a post hoc analysis of 33 patients with central nervous system (CNS) metastases at baseline, the rate of intracranial objective response was 33%.

Treatment-related adverse events occurred in nearly all patients, most commonly gastrointestinal events and fatigue. Just over half of treatment-related events were grade 1 or 2 in severity; 45% were grade 3 or higher.