Of the 11 NSCLC patients enrolled, 3 (27%) had a confirmed partial response (PR) with 2 responses ongoing at data cutoff, and 7 (64%) had disease control. Of the 4 KRASG12C inhibitor-naïve patients with NSCLC who received the highest two doses of RMC-4630 in combination with sotorasib, 3 (75%) had a confirmed PR and 4 (100%) had disease control. One patient, whose NSCLC had progressed on prior sotorasib, achieved an unconfirmed PR at 24 weeks with progressive disease at 30 weeks; one patient with ovarian cancer had a confirmed PR with an 81% reduction in tumor burden; 5 of 6 patients with CRC achieved disease control including one patient achieving a 26% reduction in tumor burden. The combination of sotorasib with RMC-4630 was safe and tolerable in patients with KRAS p.G12C-mutated solid tumors. Promising clinical activity was observed in KRAS p.G12C-mutated NSCLC patients, most notably in those KRASG12C inhibitor-naïve.