Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 3
Start date: July 16, 2025
Planned enrollment: 477
MK-1084 is an investigational, oral, covalent inhibitor of KRAS G12C being developed by Merck (MSD). Early-phase clinical results (Phase 1, KANDLELIT-001; NCT05067283) have shown antitumor activity in KRAS G12C–mutated colorectal cancer (CRC) and non–small cell lung cancer (NSCLC). Randomized Phase 3 trials are ongoing in first-line KRAS G12C–mutated NSCLC (KANDLELIT-004; NCT06345729) and in first-line KRAS G12C–mutated CRC (KANDLELIT-012; NCT06997497). (merck.com)
MK-1084 is a selective, covalent KRAS G12C inhibitor that binds the inactive GDP-bound state of KRAS G12C. Its discovery leveraged structure-based design to create a macrocyclic scaffold optimized for potency and oral exposure; an X‑ray co‑crystal structure of MK-1084 bound to KRAS G12C (PDB 8S8C) corroborates target engagement. (pubs.acs.org)
MK‑1084 + cetuximab + mFOLFOX6 in metastatic CRC with 0–1 prior lines (n=29): confirmed ORR 38% (95% CI 21–58%); unconfirmed ORR 66% (follow‑up 4.6 months). (merck.com)
Non–small cell lung cancer (Phase 1, KANDLELIT‑001; ASCO 2025):
Earlier dose‑escalation updates presented at ESMO 2023 and ESMO TAT 2024 also showed preliminary activity of MK‑1084 monotherapy and of MK‑1084 plus pembrolizumab in KRAS G12C–mutated tumors, supporting continued development. (oncologypro.esmo.org)
Across KANDLELIT‑001 arms presented at ASCO 2025, treatment‑related adverse events (TRAEs) occurred in 58% with MK‑1084 monotherapy, 94% with MK‑1084+pembrolizumab, 93% with MK‑1084+pembrolizumab+chemotherapy, 95% with MK‑1084+cetuximab, and 97% with MK‑1084+cetuximab+mFOLFOX6; the overall safety profile was characterized as manageable. Reported TRAEs in earlier updates included transaminase elevations and diarrhea with monotherapy/IO combinations, consistent with KRAS G12C inhibitor and checkpoint inhibitor class effects. (merck.com)
Notes: MK‑1084 remains investigational; no regulatory approvals to date. Reported Phase 1 outcomes are early and from nonrandomized cohorts; ongoing Phase 3 trials will clarify comparative efficacy and safety in first‑line settings. (merck.com)
Last updated: Oct 2025
Goal: Evaluate whether adding the KRAS G12C inhibitor MK-1084 plus cetuximab to standard mFOLFOX6 improves outcomes and maintains acceptable safety compared with mFOLFOX6 with or without bevacizumab as first-line therapy for unresectable locally advanced or metastatic KRAS G12C–mutant colorectal cancer.
Patients: Adults with histologically confirmed colorectal adenocarcinoma that is unresectable Stage III or Stage IV per AJCC 8th edition and harbors a KRAS G12C mutation. Part 2 enrolls treatment-naive patients in the metastatic/unresectable setting. Key exclusions include active IBD requiring immunosuppression, significant uncontrolled cardiovascular/cerebrovascular disease, known DPD deficiency, active CNS metastases or leptomeningeal disease, recent other malignancies needing treatment, recent major surgery without recovery, active infections, and conditions precluding bevacizumab. Controlled HIV, HBV on antivirals with undetectable load, and cured/controlled HCV are allowed.
Design: Phase 3, randomized, open-label, multicenter study with two parts, allocating participants to experimental triplet therapy versus control. Approximately 477 participants will be randomized. Safety run-in in Part 1 assesses dose-limiting toxicities and tolerability, followed by efficacy-focused Part 2.
Treatments: Experimental arm: MK-1084 orally plus cetuximab every 2 weeks and mFOLFOX6 (oxaliplatin, leucovorin or levofolinate, and 5-fluorouracil) every 2 weeks until discontinuation criteria. Control arm: mFOLFOX6 every 2 weeks with optional bevacizumab per investigator discretion, until discontinuation criteria. MK-1084 is an investigational, selective covalent inhibitor of KRAS G12C that targets the GDP-loaded form via binding to the switch II pocket cysteine, aiming to lock KRAS G12C in an inactive state. Early-phase data in solid tumors, notably NSCLC, show single-agent activity (approximately 22% response rate) and enhanced responses when combined with pembrolizumab in first-line NSCLC, with a generally manageable safety profile characterized by elevated transaminases and diarrhea; grade 3–4 events were more frequent in combination settings. Cetuximab is an anti-EGFR antibody used off-label in RAS wild-type mCRC; here it is combined with KRAS G12C inhibition and chemotherapy to potentially overcome adaptive EGFR-mediated feedback signaling seen with KRAS G12C inhibitors.
Outcomes: Primary endpoints include dose-limiting toxicity during Part 1, overall safety and discontinuations due to adverse events in Part 1, and progression-free survival in Part 2. Key secondary endpoints are objective response rate by BICR per RECIST 1.1, overall survival, duration of response, comprehensive safety in Part 2, and patient-reported outcomes using EORTC QLQ-C30 (global health status/quality of life, physical and role functioning, appetite loss) and QLQ-CR29 bloating, including time to first deterioration analyses.
Burden on patient: Moderate. Participants receive biweekly intravenous chemotherapy and cetuximab infusions with associated infusion times, laboratory monitoring, and toxicity assessments, which are comparable to standard first-line mFOLFOX6 ± bevacizumab schedules. The addition of an oral daily MK-1084 and a biologic (cetuximab) may increase clinic time and dermatologic and electrolyte monitoring, particularly early in treatment. Part 1 may include closer safety assessments to capture dose-limiting toxicities. Imaging for response assessment is expected at regular intervals typical for metastatic CRC trials. No intensive pharmacokinetic schedules or mandatory serial biopsies are specified, suggesting burden above standard care primarily due to the extra infusion and monitoring rather than additional procedures or travel frequency beyond Q2W visits.
Last updated: Nov 2025
Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
* Has a histologically confirmed diagnosis of locally advanced unresectable or metastatic (unresectable Stage III or Stage IV as defined by American Joint Committee on Cancer \[AJCC\] eighth edition) colorectal adenocarcinoma
* Part 2 only: Has not received systemic anticancer therapy for locally advanced unresectable or metastatic colorectal cancer
* Tumor tissue demonstrates presence of a Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation
* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)
* Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy and have undetectable HBV viral load
* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable
Exclusion Criteria:
The main exclusion criteria include but are not limited to the following:
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, chronic diarrhea)
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
* Has known dihydropyrimidine dehydrogenase (DPD) deficiency
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization
* Has 1 or more conditions that, in the opinion of the investigator, make the participant ineligible for treatment with bevacizumab
* Has known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease
* Has active infection requiring systemic therapy
* Has not adequately recovered from major surgery or have ongoing surgical complications
* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
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