KRAS is the first human oncogene discovered in 1983; however, no any approved KRAS target therapy till now. The challenges are protein itself lack of known allosteric regulatory sites and binding affinity to GTP/GDP, thus directly targeting oncogenic KRAS with small molecules in the nucleotide-binding site has been difficult. Adagrasib (MRTX849) is a covalent tyrosine kinase inhibitor (TKI) specific binding to KRASG12C in its inactive-GDP state, which brings a glimmer of hope to around 10% of KRASG12C mutant NSCLC patients. In the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutic, the phase 1/2 study, KRYSTAL-1, demonstrated adagrasib 600 mg BID achieved 45% objective response rate (ORR) and 96% of disease control rate. It was noted that mainly pre-treated and smoking history patients were included, which was typically considered with limited outcomes. As for the safety profile, adagrasib was tolerated with 30% ≥3 TRAEs, and the most common AEs were nausea(54%) and diarrhea(51%). Preliminary exploratory correlative analysis of co-mutations genes and response rates showed that 64% ORR in patients with STK11 and KRASG12C co-mutations; however, with no apparent trend with KEAP1, TP53, or other common co-mutations. To further investigate the efficacy of KRASG12C TKI and immunotherapy, adagrasib combine with pembrolizumab is ongoing in phase 1b expansion arm. Overall, these results indicated that adagrasib is a promising KRASG12C inhibitor with good efficacy and safety, and further results should be expected.
Pasi A. Jänne, et al. EORTC-NCI-AACR 2020