KRAS G12C Inhibition in Advanced NSCLC: MRTX849


Alexander Drilon, MD: There are various KRAS G12C direct inhibitors beyond AMG 510. MRTX849 is another one of these. It was explored in a phase 1 trial that looked at the safety and activity of this drug, and while we've seen fewer patients with lung cancer with KRAS G12C mutations, we've certainly seen proof of concept that the drug is active. We've seen responses in 3 out of 5 patients in the last presentation for an objective response rate of 60%, recognizing that we would need to see more patients treated with this drug moving forward, but certainly, it's very exciting. It also shows that the strategy of direct inhibition of a specific mutated KRAS protein works across different molecules that target this mutated protein.

Jonathan Riess, MD, MS: In terms of MRTX849, it's being studied in several clinical trials, including the KRYSTAL-1 trial, which is a phase 1/2 study with expansion cohorts looking at the direct KRAS G12C inhibitor MRTX849 stratified by histology, whether colorectal cancer, non–small cell lung cancer, or pancreatic adenocarcinoma. It's also looking at combination studies in certain histologic subsets that may have activity in combination, such as the PD-1 antibody pembrolizumab in non–small cell lung cancer, the EGFR TKI [tyrosine kinase inhibitor] afatinib in non–small cell lung cancer, and cetuximab in colorectal cancer. MRTX849 is a covalent G12C inhibitor that binds to the GDP downstate of KRAS, and in this trial there were some adverse events but, generally, it appeared to be well tolerated. Adverse events included mostly grade 1 toxicities, the most common being diarrhea and nausea. Two patients had grade 3 or higher toxicities in the initial clinical trial, including fatigue and decreased appetite. Overall, the drug was well tolerated with a low incidence of grade 3 and 4 toxicities.

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