KANDLELIT-012: Phase 3 study of MK-1084 (a KRAS G12C inhibitor) plus cetuximab and mFOLFOX6 with or without bevacizumab for KRAS G12C -mutant colorectal cancer.

TPS267 Background: KRAS G12C is an oncogenic driver mutation observed in 3-4% of metastatic colorectal cancer (mCRC) cases. Globally available first-line therapy for RAS -mutated unresectable microsatellite stable or proficient DNA mismatch repair (pMMR) mCRC consists of FOLFOX with or without a monoclonal anti-vascular endothelial growth factor (VEGF) antibody. MK-1084 is a potent KRAS G12C inhibitor that has shown encouraging antitumor activity as monotherapy or when combined with cetuximab with or without chemotherapy in the phase 1 KANDLELIT-001 study. The randomized, open-label, multicenter, phase 3 KANDLELIT-012 study (NCT06997497) is designed to evaluate the safety and efficacy of MK-1084 plus cetuximab, and mFOLFOX6 versus mFOLFOX6 with or without bevacizumab as first-line treatment of participants with KRAS G12C -mutant mCRC. Methods: The study will comprise a safety lead-in phase (Part 1) followed by the main study (Part 2). Eligible adults (≥18 years) must have locally advanced unresectable or metastatic colorectal adenocarcinoma, locally confirmed pMMR/non-microsatellite instability high (non‒MSI-H) status, measurable disease per RECIST v1.1, no prior systemic therapy for advanced or metastatic disease (Part 2 only), presence of KRAS G12C mutation, have an ECOG PS of 0 or 1 and be eligible for cetuximab-, fluoropyrimidine- and oxaliplatin-based therapies. One prior non-oxaliplatin containing therapy with or without anti-VEGF therapy (Part 1) or ≤2 cycles of mFOLFOX6 or 1 cycle of CAPOX before or during screening (Part 2) is permitted. In Part 1, 15 participants will receive MK-1084 PO plus cetuximab 500 mg IV Q2W and mFOLFOX6 Q2W (oxaliplatin: 85 mg/m 2 IV; leucovorin: 400 mg/m 2 IV; 5-fluorouracil: 400 mg/m 2 bolus on day 1, then 1200 mg/m 2 /day for 2 days IV). In Part 2, approximately 462 participants will be randomly assigned (1:1) to receive MK-1084 plus cetuximab and mFOLFOX6 (arm A) or mFOLFOX6 with or without bevacizumab 5 mg IV Q2W (arm B). The primary objective of Part 1 is to evaluate safety and tolerability of treatment. The primary end point of Part 2 is progression-free survival per RECIST 1.1 by blinded independent central review (BICR). Secondary end points include objective response rate and duration of response per RECIST v1.1 by BICR, overall survival, and safety. This study is currently enrolling. Clinical trial information: NCT06997497 .