Divarasib

Divarasib is a covalent inhibitor that specifically targets the KRAS G12C mutant protein, which is found in approximately 13% of non-small cell lung cancer (NSCLC) cases and 1-3% of colorectal cancer cases. This enhanced potency is attributed to its optimized binding to the switch II pocket of the KRAS G12C protein. ==Clinical development==

Phase I studies The safety and efficacy of divarasib were first evaluated in a phase I dose-escalation study (NCT04449874) in patients with advanced or metastatic solid tumors harboring KRAS G12C mutations. Additional combination studies are ongoing, including trials with pembrolizumab, an PD-1 inhibitor, for the treatment of NSCLC (NCT05789082), and with experimental SHP2 inhibitors to address potential resistance mechanisms. Phase II and III studies Divarasib is currently being evaluated in phase II and phase III clinical trials as both monotherapy and in combination with other agents for various tumor types. The Krascendo-170 Lung study is evaluating divarasib in combination with pembrolizumab and platinum-based chemotherapy in treatment-naïve patients with advanced NSCLC. ==Efficacy==

In the phase I study, divarasib demonstrated notable antitumor activity across multiple solid tumor types. ==Adverse effects==

Divarasib has demonstrated a manageable safety profile in clinical trials. The most frequently reported treatment-related adverse events include gastrointestinal toxicities such as nausea (45% of patients), diarrhea (42%), and vomiting (25%). Other common adverse events include fatigue, decreased appetite, and skin-related toxicities. Grade 3 or higher treatment-related adverse events occurred in approximately 38% of patients, with the most common being gastrointestinal disorders and laboratory abnormalities. Treatment discontinuation due to adverse events was relatively uncommon, occurring in less than 10% of patients in most studies. ==Regulatory status==

As of 2024, divarasib remains an investigational agent and has not yet received regulatory approval from the FDA or other major regulatory agencies. The drug is currently being developed through multiple phase II and phase III clinical trials across various tumor types and treatment settings. == See also ==