Phase 2 olomorasib KRAS G12C covalent inhibitor + pembrolizumab PD‑1 blockade in 1L NSCLC.

This UNC Lineberger Comprehensive Cancer Center study (NCT07639242) tests first-line olomorasib plus pembrolizumab in locally advanced/metastatic NSCLC with a KRAS G12C mutation and PD-L1 TPS 1–49%. Olomorasib (Eli Lilly) is an oral, selective next-generation KRAS G12C covalent inhibitor designed to lock KRAS G12C in an inactive state; pembrolizumab (Merck/MSD) is an anti–PD‑1 monoclonal antibody that restores T-cell anti-tumor activity. The goal is to estimate progression-free survival, with additional endpoints including response rate, duration of response, overall survival, safety, and exploratory biomarker work; the protocol also emphasizes tougher-to-study groups such as patients with brain metastases and less favorable ECOG performance status. Scientifically, the key angle is whether a better-tolerated, “next-gen” KRAS G12C inhibitor can be combined up front with PD‑1 therapy—an approach historically limited by overlapping toxicities seen with some KRAS inhibitor + immunotherapy combinations. Today, many PD‑L1 1–49% KRAS G12C NSCLC patients start with pembrolizumab plus platinum-doublet chemotherapy, with KRAS G12C inhibitors typically used after progression.