Background: Mutations in KRAS are one of the most prevalent oncogene mutations in human cancers, among which KRAS G12C mutations are one of the most frequently occurring. KRAS G12C inhibitors can slow tumor growth via attenuation of the KRAS signaling pathway. MK-1084, a selective KRAS G12C inhibitor, has demonstrated promising antitumor activity in preclinical studies. This phase 1, open-label, multicenter study (ClinicalTrials.gov, NCT05067283) is the first MK-1084 clinical study and aims to evaluate it as monotherapy and combination therapy in patients (pts) with advanced solid tumors. Findings from the initially enrolled study arms (Rojas et al. ESMO 2023; Abs 3156) indicated antitumor activity in pts with solid tumors receiving oral MK-1084 monotherapy QD or BID (25 to 800 mg total daily; arm 1) and pts with previously untreated non–small-cell lung cancer (NSCLC) with PD-L1 tumor proportion score ≥1% receiving MK-1084 from 25 to 400 mg total daily dose plus pembrolizumab 200 mg IV Q3W (arm 2). Toxicity was manageable during dose escalation of these 2 arms. Based on these initial findings, the study design has been updated to assess an alternate MK-1084 formulation and MK-1084 in combination with other therapies in KRAS G12C–mutated tumors. We present the study design for the new arms that include patients with gastrointestinal cancers. Methods: Eligible pts are aged ≥18 years with measurable disease per RECIST version 1.1 by investigator, ECOG performance status 0/1, adequate organ function, and advanced solid tumors (arm 3), or metastatic CRC with progression on 1 or 2 lines of prior therapy (arm 5), or previously untreated metastatic CRC (arm 6), all with KRAS G12C mutation. Pts in arm 3 receive the alternate MK-1084 formulation. Pts in arms 5 and 6 receive MK-1084 with one of the following: cetuximab 500 mg/m² IV Q2W (arm 5); or cetuximab 500 mg/m² IV Q2W, oxaliplatin 85 mg/m², leucovorin 400 mg/m², and 5-fluorouracil per label IV Q2W (arm 6). Each arm has a safety run-in prior to expansion. The primary objective is to assess the safety and tolerability of MK-1084 as monotherapy and in combination with these other agents. Secondary endpoints include objective response and duration of response. AEs will be evaluated from baseline through 30 days after cessation of study treatment (90 days for serious AEs). Tumor imaging by CT or MRI will be performed at baseline, every 6 weeks up to week 18, every 9 weeks for the remainder of the first year, and then every 12 weeks. Response is assessed per RECIST version 1.1 by investigators. Analyses include pts who receive ≥1 dose of study treatment. Study enrollment began in December 2021. Clinical trial information: NCT05067283.