Background: Soto, a KRAS^G12C inhibitor, had a 9.7% objective response rate (ORR) as monotherapy for chemorefractory patients (pts) with KRAS G12C-mutated mCRC. When combined with Pmab, a monoclonal anti-EGFR antibody, ORR increased to 30%, supporting the model that the doublet mitigates Soto-related feedback reactivation of the RAS-MAPK pathway and accumulation of activated EGFR. We hypothesize that Soto plus Pmab and FOLFIRI will further enhance Soto efficacy while maintaining a manageable safety profile. We report the first results for a KRAS^G12C inhibitor combined with an EGFR inhibitor and chemotherapy in pts with prior mCRC treatment. Methods: Pts included dose exploration and expansion cohorts from CodeBreaK 101 subprotocol H (NCT04185883) who received Soto (960 mg PO daily) plus Pmab (6 mg/kg IV Q2W) and standard-dose FOLFIRI (IV Q2W). Key eligibility criteria were KRAS G12C-mutated mCRC and ≥1 prior treatment for metastatic disease. Pts in dose expansion were KRAS^G12C inhibitor-naïve. The primary endpoint was safety. Secondary endpoints included efficacy and pharmacokinetics (PK). Results: As of November 30, 2022, 33 pts (median age: 53 years; 48% female) were treated (6 in dose exploration, 27 in dose expansion). Median prior lines of systemic therapy was 2 (range: 1-6), with 33% and 67% of pts receiving 1 or ≥ 2 prior lines, respectively; 97% had prior fluoropyrimidine and 73% had prior irinotecan. Two pts in dose exploration received prior Soto. None of the 6 pts in dose level 1 of dose exploration had dose limiting toxicities (DLTs) during DLT evaluation (first 28 days), and Soto (960 mg PO daily) plus Pmab (6 mg/kg IV Q2W) and FOLFIRI (IV Q2W) was the recommended phase 2 dose. Treatment-related adverse events (TRAEs) of any grade occurred in 32 (97.0%) pts; 1 pt discontinued the full regimen due to grade 3 ALT increase. Fifteen (45.5%) had grade ≥ 3 TRAEs (most commonly dermatologic; n = 5). There were no fatal TRAEs. Safety findings were consistent with known profiles of Soto, Pmab, and FOLFIRI. No clinically meaningful PK interaction was observed between Soto and irinotecan. Of 31 pts evaluable for response, confirmed ORR (all partial responses) was 58.1% (95% CI: 39.1, 75.5). The 2 pts with prior Soto achieved partial response (n = 1) and stable disease (n = 1). Disease control rate was 93.5% (95% CI: 78.6, 99.2). With median follow-up of 5.7 and 7.4 months, respectively, progression-free and overall survival data are not yet mature. Fully enrolled data will be presented. Conclusions: In the first ever data set for this novel combination, Soto plus Pmab and FOLFIRI showed promising safety and efficacy in pretreated KRAS G12C-mutated mCRC, with a confirmed ORR of 58.1%. Adverse events were manageable and consistent with the expected safety profile of the drugs used, and there was no clinically meaningful Soto and irinotecan PK interaction. Clinical trial information: NCT04185883.