[Development of Therapies Targeting Non-G12C KRAS Mutations (Focusing on G12D and Pan-RAS)]

Sotorasib and adagrasib, which are KRAS G12C inhibitors, have shown favorable clinical results mainly in non-small cell lung cancer (NSCLC) and have already been introduced into clinical practice. However, for patients with non-G12C mutations that account for the majority, such as G12D, G12V, and G13D, effective targeted therapies have still not been established. Setidegrasib (ASP3082) is a first-in-class proteolysis-targeting chimera molecule (PROTAC) that targets the KRAS G12D mutation. Phase Ⅰ trial targeting previously treated patients with advanced solid tumors harboring KRAS G12D mutations has been initiated, and the latest results were reported in the N Engl J Med in March 2026. Daraxonrasib (RMC-6236) is a pan-RAS inhibitor that targets all ON-state RAS (KRAS, NRAS, HRAS) by forming a specific pocket spanning the Switch Ⅰand Switch Ⅱ regions of KRAS through a mechanism called tri-complex/molecular glue. Currently, multiple international collaborative phase Ⅲ trials on RMC-6236, mainly focusing on PDAC and NSCLC, are underway. The development of new drugs targeting molecules other than KRAS G12C is progressing rapidly, and in KRAS mutation-positive solid cancers where prognosis was difficult to improve with conventional chemotherapy, there is a high possibility that the existing standard treatments will be significantly revised.