Adagrasib: a novel inhibitor for KRAS(G12C)-mutated non-small-cell lung cancer

Adagrasib is a recently US FDA-approved novel KRAS(G12C) targeted therapy with clinical efficacy in patients with advanced, pretreated KRAS(G12C)-mutated non-small-cell lung cancer. KRYSTAL-I reported an objective response rate of 42.9% with median duration of response of 8.5 months. Treatment-related adverse events were primarily gastrointestinal and occurred in 97.4% of patients, with grade 3+ treatment-related adverse events occurring in 44.8% of patients. This review details the preclinical and clinical data for adagrasib in the treatment of non-small-cell lung cancer. We also outline practical clinical administration guidelines for this novel therapy, including management of toxicities. Finally, we discuss the implications of resistance mechanisms, summarize other KRAS(G12C) inhibitors currently in development and outline future directions for adagrasib-based combination therapies. Plain language summary Adagrasib for the treatment of non-small-cell lung cancerAdagrasib is a new oral (taken by mouth) treatment option for patients with non-small-cell lung cancer (NSCLC) with KRAS(G12C) mutations. KRAS is a gene that regulates signaling pathways, which are responsible for cell growth and division. A mutation in KRAS can cause cells to multiply and cause cancer. Clinical trials have shown that adagrasib causes cancer reduction or resolution in 42.9% of people with NSCLC with KRAS(G12C) mutations who receive the drug. Side effects of adagrasib are primarily gastrointestinal (nausea, vomiting, diarrhea). This review outlines guidelines for the management of side effects. New studies are looking at how adagrasib can be safely combined with other therapies to better treat NSCLC with KRAS(G12C) mutations. Tweetable abstractAdagrasib is a novel KRASG12C targeted therapy. In this review, we summarize data supporting adagrasib use in KRAS(G12C)-mutated non-small-cell lung cancer and provide expert summary for clinical administration, toxicity management and future directions.