[Pharmacological characteristics and clinical study results of the first RAS inhibitor sotorasib (LUMAKRAS®) for non-small cell lung cancer with KRAS G12C mutation]

Abstract

Sotorasib (LUMAKRAS^®) is the first RAS inhibitor that selectively binds to KRAS G12C and irreversibly inhibits the conformational change from the inactive to active form of KRAS. The gene mutation that produces KRAS G12C protein, which is the target of sotorasib, is one of the oncogenic drivers observed in non-small cell lung cancer (NSCLC), and the KRAS G12C mutation causes conformational changes to maintain KRAS in an active form enhancing downstream signals, leading to tumor cell proliferation and survival. Although the role of KRAS in human cancers has been known for decades, role of RAS in normal cells, the high affinity between RAS and GTP, high concentration of intracellular GTP, and the smooth surface of RAS protein makes it difficult to develop drugs targeting RAS mutation for a long time. However, the discovery of the Switch II pocket of KRAS in 2013 and the report of compounds that specifically bind to KRAS G12C led to the development of sotorasib. Sotorasib inhibited the growth of KRAS G12C positive cell lines and suppressed tumor growth in a mouse model implanted with the KRAS G12C positive cell line. In clinical trials, objective responses were seen in 37.4% of patients with KRAS G12C positive advanced NSCLC taking 960mg sotorasib orally per day. There were no dose-limiting toxicities and other adverse events were tolerable. Sotorasib was designated as an orphan drug in March 2021 and approved in January 2022 for KRAS G12C positive unresectable/recurrent NSCLC that has progressed after 1st line therapy in Japan.