Phase 3 zoldonrasib (RMC-9805) KRAS G12D-selective RAS(ON) inhibitor + pembrolizumab chemo in NSCLC

Revolution Medicines is running RASolve 308, a randomized, double-blind, placebo-controlled Phase 3 trial testing whether adding zoldonrasib (RMC-9805)—a KRAS G12D-selective, active-state “RAS(ON)” small-molecule inhibitor—to first-line pembrolizumab plus platinum/pemetrexed improves outcomes in metastatic non-squamous NSCLC with a confirmed RAS/KRAS G12D mutation and known PD-L1 status. Participants receive zoldonrasib or placebo with pembrolizumab (Merck/MSD’s PD-1 antibody) and pemetrexed (an antifolate that inhibits thymidylate synthase–dependent DNA synthesis) plus a platinum agent (carboplatin or cisplatin, DNA crosslinking chemotherapy). The key angle is “genotype-first” intensification of the current chemo-immunotherapy backbone in a KRAS G12D-defined population, where targeted options are far less established than for KRAS G12C. Today’s care for treatment-naive metastatic non-squamous NSCLC without other actionable drivers is typically pembrolizumab + pemetrexed + platinum, followed by later-line docetaxel ± ramucirumab or antibody–drug conjugates depending on biomarker eligibility.