MK-1084

Shows activity

Cancer types include:

colon cancer non-small cell lung cancer rectal cancer sarcoma small cell lung cancer

HealthScout AI Analysis

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Overview

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)

Mechanism of action

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)

Efficacy

Colorectal cancer (Phase 1, KANDLELIT‑001; ASCO 2025):
MK‑1084 monotherapy in previously treated CRC (n=53): confirmed ORR 38% (95% CI 25–52%); unconfirmed ORR 43%. (merck.com)
MK‑1084 + cetuximab in previously treated CRC (n=39): confirmed ORR 46% (95% CI 30–63%); unconfirmed ORR 56%. Reported DCR 92% and median DOR 10.8 months (follow‑up 9.2 months). (merck.com)
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):
MK‑1084 monotherapy in previously treated NSCLC (n=21): confirmed ORR 38% (95% CI 18–62%). (merck.com)
MK‑1084 + pembrolizumab in untreated metastatic NSCLC with PD‑L1 TPS ≥1% (n=69): confirmed ORR 77% (95% CI 65–86%). (merck.com)
MK‑1084 + pembrolizumab + chemotherapy (carboplatin/pemetrexed) in untreated metastatic NSCLC (n=40): confirmed ORR 53% (95% CI 36–69%). (merck.com)

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)

Safety

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)

Ongoing/Planned studies

KANDLELIT‑004 (NCT06345729): Phase 3, randomized, double‑blind study of MK‑1084+pembrolizumab vs pembrolizumab in first‑line KRAS G12C–mutated, PD‑L1 TPS ≥50% NSCLC; coprimary endpoints PFS and OS (target n≈600). Status: recruiting (study start May 24, 2024). (merck.com)
KANDLELIT‑012 (NCT06997497): Phase 3, open‑label study of MK‑1084+cetuximab+mFOLFOX6 vs mFOLFOX6±bevacizumab in first‑line locally advanced unresectable or metastatic KRAS G12C–mutated CRC. Study start July 16, 2025. (ichgcp.net)

Active trials using MK-1084

Found 3 active trials using this drug:

A Phase 3, Randomized, Open-label, Multicenter Clinical Study to Evaluate the Safety and Efficacy of MK-1084 in Combination With Subcutaneous Pembrolizumab and Berahyaluronidase Alfa (MK-3475A) Versus MK-3475A in Combination With Pemetrexed/Platinum (Carboplatin or Cisplatin) Chemotherapy as First-line Treatment of Participants With KRAS G12C-Mutant, Advanced or Metastatic Nonsquamous NSCLC (KANDLELIT-007)

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 3 Start date: Oct. 8, 2025

HealthScout AI summary: Adults with treatment‑naive, advanced/metastatic nonsquamous NSCLC harboring KRAS G12C are randomized to MK‑1084 (a selective covalent KRAS G12C inhibitor) plus subcutaneous pembrolizumab with berahyaluronidase alfa versus subcutaneous pembrolizumab with berahyaluronidase alfa plus pemetrexed and platinum chemotherapy. Primary analysis focuses on PFS (BICR) in PD‑L1 TPS ≥1%, with key secondary endpoints including PFS/OS in all-comers and response outcomes.

ClinicalTrials.gov ID: NCT07190248

A Phase 3, Randomized, Open-label, Multicenter Clinical Study to Evaluate the Safety and Efficacy of MK-1084, Cetuximab, and mFOLFOX6 Versus mFOLFOX6 With or Without Bevacizumab as First-line Treatment of Participants With KRAS G12C-mutant, Locally Advanced Unresectable or Metastatic Colorectal Cancer (KANDLELIT-012)

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 3 Start date: July 16, 2025

HealthScout AI summary: Adults with unresectable locally advanced or metastatic colorectal adenocarcinoma harboring a KRAS G12C mutation, treatment-naive in the first-line metastatic setting, are randomized to mFOLFOX6 ± bevacizumab versus mFOLFOX6 plus cetuximab and MK-1084, a selective covalent KRAS G12C inhibitor that locks KRAS in its inactive GDP-bound state. Key exclusions include active CNS metastases, DPD deficiency, significant uncontrolled cardiovascular disease, and conditions precluding bevacizumab; controlled HIV/HBV and cured/controlled HCV are allowed.

ClinicalTrials.gov ID: NCT06997497

A Phase 3, Randomized, Double-blind, Multicenter Study of MK-1084 in Combination With Pembrolizumab Compared With Pembrolizumab Plus Placebo as Firstline Treatment of Participants With KRAS G12C-Mutant, Metastatic NSCLC With PD-L1 TPS ≥50%

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 3 Start date: May 24, 2024

HealthScout AI summary: This trial enrolls adults with newly diagnosed, metastatic KRAS G12C-mutant NSCLC and high PD-L1 expression (TPS ≥50%), randomizing them to pembrolizumab plus either MK-1084—a selective KRAS G12C inhibitor—or placebo as first-line treatment. Key exclusions include prior systemic therapy for metastatic disease, active CNS disease, and certain comorbidities.

ClinicalTrials.gov ID: NCT06345729