Sotoracib (AMG 510) belongs to the first generation of targeted drugs and its clinical application status

Sotorasib (R&D code AMG 510) is the first KRAS G12C inhibitor developed by Amgen to be approved for marketing. KRAS mutations are highly common in a variety of tumors, but have long been regarded as "undruggable" targets. The successful research and development of sotoracib broke through this problem and became an important milestone in the field of precision tumor treatment. Strictly speaking, it is not a "first-generation /second-generation /third-generation" targeted drug based on common generational methods such as EGFR and ALK, but KRAS The first-in-class drug targeting the target can be regarded as the first generation of KRAS inhibitors.

The core mechanism of sotorasiib is to irreversibly bind to the switch pocket of KRAS G12C mutant protein, fixing it in an inactive state, thereby blocking the continued activation of downstream signaling pathways (such as MAPK, PI3K) and inhibiting the growth of tumor cells. This "precise blocking" mechanism determines its specificity, that is, it mainly targets KRAS G12C mutant tumors, but does not work on other types of KRAS mutations. This design method created a new idea for targeted drug development and became the blueprint for the subsequent development of many KRAS inhibitors.

Currently, sotoraxib has been approved in the United States FDA and Europe EMA for patients with KRAS G12C who have received at least one systemic therapy in the past. Patients with mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). In the II phase CodeBreaK 100 study, sotoraxib demonstrated an objective response rate (ORR) of approximately 37% and maintained longer-lasting responses in some patients. Although the efficacy is still limited, as the first KRAS The launch of target drugs has brought new treatment options to a large group of patients and filled the clinical gap.

Sotorasiib is currently regarded as the "icebreaker" for KRAS target therapy, establishing the status of KRAS inhibitors in tumor treatment. Its application scope is gradually expanding from lung cancer to colorectal cancer, pancreatic cancer and other KRAS G12C mutation-related tumors. At the same time, clinical trials of combined immunotherapy, EGFR inhibitors or other targeted drugs are being carried out in order to improve efficacy and overcome resistance problems. From the clinical positioning point of view, sotoracib is the beginning of KRAS target precision treatment. It belongs to the first generation of KRAS G12C targeted drugs. In the future, it is likely to work with the new generation or combination regimen to build a more complete treatment system.

Reference link:https://www.drugs.com