The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target-a narrative review

Background and Objective: The genetic nature of cancer provides the rationale to support the need for molecular diagnosis and patient selection for individualised antineoplastic treatments that are the best in both tolerability and efficacy for each cancer patient, including non-small cell lung cancer (NSCLC) patients. Kirsten rat sarcoma viral oncogene (KRAS) mutations represent the prevalent oncogenic driver in NSCLC, being detected in roughly one-third of cases and KRAS G12C is the most frequent mutation found in approximately 13% of patients. Methods: This paper gives an overview of the numerous scientific efforts in recent decades aimed at KRAS inhibition. Key Content and Findings: Sotorasib is the first approved KRAS G12C inhibitor that has been shown to provide a durable clinical benefit in patients with pre-treated NSCLC with KRAS G12C mutation. Together with the development of new targeted drugs, the development of strategies to control resistance mechanisms is one of the major drivers of research that is exploring the use of KRAS inhibitors not only alone, but also in combination with other targeted therapies, chemotherapy and immunotherapy. Conclusions: This review will describe the major therapeutic developments in KRAS mutation-dependent NSCLC and will analyse future perspectives to maximise benefits for this group of patients.