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Adagrasib Induces Response in KRASG12C-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 KRASG12C mutations. KRAS had long been considered an “undruggable” target until the FDA approved sotorasib in 2021 for previously treated KRASG12C-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 KRASG12C mutation who had previously been treated with platinum-based chemotherapy and checkpoint inhibitor therapy received the KRASG12C 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.
Adagrasib, like the recently approved drug sotorasib, is a selective covalent inhibitor of KRASG12C that leads to a clinically significant and durable reduction in tumor burden. In addition, adagrasib has been optimized for favorable properties, including a long half-life and the ability to penetrate the central nervous system, and this is a very promising therapy for patients.
Jänne PA et al.
Title: Adagrasib in non–small-cell lung cancer harboring a KRASG12C mutation.
Source: N Engl J Med 2022 Jul 14; [e-pub]. (Abstract/FREE Full Text)