Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 3
Start date: May 24, 2024
Planned enrollment: 600
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 determine whether adding the selective KRAS G12C inhibitor MK-1084 to pembrolizumab improves progression-free survival and overall survival versus pembrolizumab plus placebo as first-line therapy for metastatic KRAS G12C–mutant NSCLC with high PD-L1 expression (TPS ≥50%).
Patients: Adults with histologically or cytologically confirmed stage IV NSCLC harboring a KRAS G12C mutation and PD-L1 TPS ≥50%, measurable disease by RECIST 1.1, ECOG 0–1, and adequate organ function. Key exclusions include prior systemic therapy for metastatic disease, active CNS metastases, active autoimmune disease requiring systemic therapy, clinically significant cardiovascular disease, uncontrolled infections, prior recent radiotherapy, and conditions affecting oral drug absorption.
Design: Multicenter, randomized, double-blind, placebo-controlled Phase 3 trial. Approximately 600 participants randomized to pembrolizumab plus MK-1084 or pembrolizumab plus placebo. Stratification and blinded independent central review used for efficacy assessments; first-line setting.
Treatments: Experimental arm: Pembrolizumab 200 mg IV Q3W for up to 35 cycles plus oral MK-1084 once daily until discontinuation criteria are met. Control arm: Pembrolizumab 200 mg IV Q3W for up to 35 cycles plus matching oral placebo. MK-1084 is an investigational, selective covalent inhibitor of KRAS G12C that binds the GDP-loaded form at the switch II pocket cysteine, aiming to lock KRAS G12C in an inactive state and suppress downstream signaling. In a Phase 1 study, MK-1084 monotherapy produced a 22% overall response rate in previously treated solid tumors; in combination with pembrolizumab in first-line NSCLC, ORR was 71% overall and 86% in PD-L1 TPS ≥50%. The safety profile has been manageable; common adverse events include transaminase elevations and diarrhea, with grade 3–4 events more frequent in combination therapy but generally manageable, and a low incidence of dose-limiting hepatotoxicity reported.
Outcomes: Primary endpoints: PFS by BICR per RECIST 1.1 and overall survival. Secondary endpoints: ORR and DOR by BICR, safety and tolerability (AEs and treatment discontinuations due to AEs), and patient-reported outcomes using EORTC QLQ-C30 (global health/QoL, physical and role functioning, dyspnea) and EORTC QLQ-LC13 (cough and chest pain), including time to deterioration analyses. Follow-up up to approximately 42–56 months depending on endpoint.
Burden on patient: Moderate. Visits every 3 weeks for IV pembrolizumab align with standard first-line immunotherapy schedules. Additional burden includes daily oral dosing, baseline tumor tissue provision for biomarker confirmation (KRAS G12C and PD-L1; typically from existing biopsy), periodic imaging for BICR-based RECIST assessments likely every 6–9 weeks early on, and routine labs to monitor for immune-related adverse events and MK-1084-associated hepatotoxicity. No intensive pharmacokinetic sampling or mandated serial biopsies are described. Travel and time commitments are driven mainly by Q3W infusion visits and scheduled imaging; adverse event monitoring may necessitate occasional extra visits if transaminase elevations or immune-related toxicities occur.
Last updated: Oct 2025
The main inclusion and exclusion criteria include but are not limited to the following:
Inclusion Criteria:
* Has a histologically or cytologically confirmed diagnosis of NSCLC
* Has newly diagnosed Stage IV NSCLC by American Joint Committee on Cancer (AJCC) Staging Manual, Version 8
* Has measurable disease based on RECIST 1.1
* Has provided tumor tissue that demonstrates PD-L1 expression in ≥50% of tumor cells
* Has provided tumor tissue that demonstrates presence of KRAS G12C mutation
* Has life expectancy of at least 3 months
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days before randomization
* For participant assigned male sex at birth: If capable of producing sperm, participant must agree to the following during the study treatment period and for at least 10 days after the last dose of oral intervention: Either be abstinent or must agree to use male condom plus additional contraceptive method.
* For participant assigned female sex at birth: Either be a person of nonchildbearing potential (PONCBP) or must agree to follow contraceptive guidance during the study treatment period and for at least 10 days after the last dose of oral intervention and 120 days after the last dose of pembrolizumab. Must abstain from breastfeeding during the study intervention period and for at least 120 days after study intervention.
* 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 for at least 4 weeks and have undetectable HBV viral load before randomization
Exclusion Criteria:
* Diagnosis of small cell lung cancer
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease
* Has a known history of, or active, neurologic paraneoplastic syndrome
* Has an active infection requiring systemic therapy
* Has uncontrolled, 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 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
* Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome.
* Has one or more of the following ophthalmological findings/conditions: intraocular diagnosis of central serous retinopathy, retinal vein occlusion, or retinal artery occlusion, diagnosis of retinal degenerative disease pressure \>21 mm Hg and/or any diagnosis of glaucoma
* Is unable to swallow orally administered medication, or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, or malabsorption)
* Received prior systemic anticancer therapy for their metastatic NSCLC
* Received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor within 12 months before diagnosis of metastatic NSCLC
* Has received radiotherapy within 2 weeks of start of study intervention
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* 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
* Active autoimmune disease that has required systemic treatment in the past 2 years
* History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* History of allogeneic tissue/solid organ transplant
* Has not fully recovered from any effects of major surgical procedure. Surgical procedures that required general anesthesia must be completed at least 2 weeks before first study intervention administration.
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Lviv, Lviv Oblast, 79059, Ukraine
No email / +380506749772
Status: Recruiting
Rivne, Rivne Oblast, 33010, Ukraine
No email / +380362633075
Status: Recruiting
Vinnytsia, Vinnytsia Oblast, 21029, Ukraine
No email / 1-888-577-8839
Status: Recruiting
Lutsk, Volyn Oblast, 43018, Ukraine
No email / +380503782998
Status: Recruiting
Beverly Hills, California, 90211, United States
No email / 310-432-8955
Status: Recruiting
Bakersfield, California, 93309, United States
No email / 888-577-8839
Status: Recruiting
Miami Beach, Florida, 33140, United States
No email / 888-577-8839
Status: Recruiting
Skokie, Illinois, 60077, United States
No email / 224-534-7580
Status: Recruiting
Springfield, Missouri, 65807, United States
No email / 417-875-3000
Status: Recruiting
Kansas City, Missouri, 64108, United States
No email / 816-404-4093
Status: Recruiting
Billings, Montana, 59102, United States
No email / 888-577-8839
Status: Recruiting
Morristown, New Jersey, 07960, United States
No email / 973-275-7788
Status: Recruiting
Albany, New York, 12206, United States
No email / 888-577-8839
Status: Recruiting
Kettering, Ohio, 45429, United States
No email / 888-577-8839
Status: Recruiting
Cincinnati, Ohio, 45219, United States
No email / 888-577-8839
Status: Recruiting
Houston, Texas, 77030, United States
No email / 713-600-0900
Status: Recruiting
Madison, Wisconsin, 53715, United States
No email / 888-577-8839
Status: Recruiting
CABA, Buenos Aires, C1019ABS, Argentina
No email / No phone
Status: Completed
Rivne, Rivne Oblast, 33007, Ukraine
No email / No phone
Status: Completed