Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 2
Start date: Dec. 19, 2025
Planned enrollment: 130
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: To evaluate the safety, tolerability, and preliminary antitumor activity of adding the investigational KRAS G12C inhibitor MK-1084 (with or without cetuximab) to pembrolizumab-based first-line therapy for advanced/metastatic nonsquamous NSCLC harboring KRAS G12C mutations, and to estimate response rates with these regimens.
Patients: Adults with histologically/cytologically confirmed advanced or metastatic nonsquamous NSCLC with a documented KRAS G12C mutation in tumor tissue or ctDNA, who are systemic therapy–naïve for advanced/metastatic disease and can provide archival or newly obtained (non-irradiated) tumor tissue. Key exclusions include prior KRAS-targeted therapy, prior systemic therapy for metastatic disease, active CNS metastases/carcinomatous meningitis, significant uncontrolled cardiovascular disease, active autoimmune disease requiring recent systemic treatment, active IBD requiring immunosuppression, and history of steroid-requiring pneumonitis/ILD.
Design: Randomized, phase 2, umbrella substudy with three experimental arms in the first-line setting. Safety is assessed early for dose-limiting toxicities, with longer-term follow-up for adverse events and efficacy endpoints; tumor response assessments are performed per RECIST 1.1 with blinded independent central review.
Treatments: Arm 1 receives standard first-line chemoimmunotherapy with pembrolizumab 400 mg every 6 weeks plus carboplatin every 3 weeks plus pemetrexed 500 mg/m^2 every 3 weeks. Arm 2 evaluates pembrolizumab 400 mg every 6 weeks combined with MK-1084. Arm 3 evaluates pembrolizumab 400 mg every 6 weeks plus MK-1084 combined with cetuximab 500 mg/m^2 every 2 weeks. MK-1084 is an investigational selective KRAS G12C-GDP inhibitor that covalently binds the switch II pocket cysteine of KRAS G12C in its GDP-bound state to suppress oncogenic signaling. In early clinical testing, MK-1084 monotherapy produced an overall response rate of about 22% in previously treated solid tumors, and in first-line NSCLC combined with pembrolizumab showed high response rates (approximately 71% overall, with higher activity reported in PD-L1–high disease). Common toxicities observed to date have included transaminase elevations and diarrhea, with higher rates of grade 3–4 events in combination regimens than with monotherapy.
Outcomes: Primary endpoints are dose-limiting toxicities within approximately the first 21 days, overall incidence of adverse events over extended follow-up, discontinuation due to adverse events, and objective response rate by RECIST 1.1 per blinded independent central review. Secondary endpoints include duration of response, progression-free survival, and overall survival, as well as pharmacokinetics of MK-1084 (AUC, Cmax, and trough concentrations).
Burden on patient: Moderate-to-high. Participants must undergo molecular confirmation of KRAS G12C and provide archival or newly obtained tumor tissue, which may require an additional biopsy if adequate archival tissue is unavailable. Treatment involves frequent infusion visits (every 2 weeks in the cetuximab-containing arm and every 3 weeks for carboplatin/pemetrexed during induction) in addition to pembrolizumab every 6 weeks, plus standard serial imaging for RECIST assessments. The MK-1084 arms add pharmacokinetic blood sampling at multiple early timepoints (up to roughly the first 44 days) and continued long-term safety follow-up, increasing clinic time and procedure burden beyond standard first-line care.
Last updated: Jan 2026
Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
* Has histologically or cytologically confirmed diagnosis of advanced or metastatic nonsquamous Non-Small Cell Lung Cancer (NSCLC)
* Has tumor tissue or circulating tumor deoxyribonucleic acid (ctDNA) that demonstrates the presence of Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutations
* Can provide an archival tumor tissue sample or newly obtained core, incisional, excisional biopsy of a tumor lesion not previously irradiated
* Has recovered to ≤Grade 1 or baseline from any Adverse events (AEs) due to previous anticancer therapies and/or ≤Grade 2 neuropathy and/or endocrine-related AEs adequately treated with hormone replacement
* Has well controlled human immunodeficiency virus (HIV) on antiretroviral therapy (ART) if HIV-infected
* Has undetectable hepatitis B (HBV) viral load and have received HBV antiviral therapy for at least 4 weeks if hepatitis B surface antigen (HBsAg) positive
* Has undetectable hepatitis C (HCV) viral load if HCV-infected
Exclusion Criteria:
The main exclusion criteria include but are not limited to the following:
* Has a diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements
* Has HIV-infection with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease
* Has uncontrolled, clinically significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of corrected QT interval corrected for heart rate by Fridericia's formula (QTcF) interval to \>470 ms, and/or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention
* Has received prior systemic anticancer therapy for advanced or metastatic NSCLC
* Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE) (except endocrine disorders that can be treated with replacement therapy) or was discontinued from that treatment due to Grade 2 myocarditis or recurrent Grade 2 pneumonitis
* Has received previous treatment with an agent targeting KRAS
* Has received prior systemic anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) and has not recovered to grade ≤ 1 or baseline from AE associated with anticancer therapy before allocation/randomization
* Has received radiation therapy to the lung that is \>30 Gray within 6 months of start of study intervention
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has a known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed
* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
* Has a history of stem cell/solid organ transplant
* Has not adequately recovered from major surgery or has ongoing surgical complications
Vinnitsya, Vinnytsia Oblast, 21029, Ukraine
No email / 380953105783
Status: Recruiting
Clermont, Florida, 34711, United States
No email / 386-538-3169
Status: Recruiting