KRAS mutations exist in many cancers including pancreatic, colorectal and lung. 1 Of these isoforms, KRAS is the most common, making up 85–90% of all RAS proteins.
Rat sarcoma viral oncogene ( RAS) is the oldest driver mutation identified in 1982 and consists of three isoforms: KRAS, HRAS, and NRAS. Here, we explore in further detail the development of sotorasib, its efficacy, mechanism of resistance, and strategies to overcome these resistances. Many proposals have been made to address this, such as the use of combination therapy for synthetic lethality, which are producing encouraging results.
While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, resistance mutations to sotorasib are increasingly common. The most common adverse events were elevations in LFTs, which down-trended upon dose reduction and steroid treatment.
In both phases, grade 4 adverse events occurred in only one patient. Both phase I and phase II had similar progression-free survival, in 6.3 months and 6.8 months, respectively. The Phase II portion, which used 960mg daily dosing resulted in 37.1% of patients with confirmed response and 80.6% of patients with disease control. About 91.2% of patients who received the highest dose of 960mg daily achieved disease control.
The Phase I portion of the clinical trial produced 32% confirmed response with 56% of patients with stable disease. Based on promising results in both preclinical and clinical trials, sotorasib, a novel KRAS G12C inhibitor, was given conditional approval by the FDA in May 2021. Developing targeted therapies against KRAS G12C mutation has proven to be challenging due to the abundance of GTP in the cytoplasm, rapid hydrolysis of GTP, and difficulty designing small molecules to achieve sufficient concentration for KRAS inhibition. Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung cancer patients.