Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 3
Start date: May 24, 2024
Planned enrollment: 600
MK-1084 is an investigational oral inhibitor targeting the KRAS G12C mutation, a prevalent alteration in various cancers, notably non-small cell lung cancer (NSCLC). (cancernetwork.com)
MK-1084 selectively binds to the KRAS G12C protein in its inactive GDP-bound state, preventing its activation and subsequent downstream signaling pathways that promote tumor growth. (targetedonc.com)
In a phase 1 trial, MK-1084 demonstrated promising efficacy:
Monotherapy: Among 55 patients with previously treated solid tumors harboring KRAS G12C mutations, MK-1084 achieved an objective response rate (ORR) of 29% and a disease control rate (DCR) of 82%. (onclive.com)
Combination Therapy: In 27 treatment-naïve NSCLC patients with PD-L1 expression ≥1%, MK-1084 combined with pembrolizumab resulted in an ORR of 70% and a DCR of 85%. (onclive.com)
MK-1084 exhibited an acceptable safety profile:
Monotherapy: Treatment-related adverse events (TRAEs) occurred in 60% of patients, with 7% experiencing grade 3 and 2% grade 4 TRAEs. No dose-limiting toxicities (DLTs) were observed. (onclive.com)
Combination Therapy: In the combination arm, 87% of patients experienced TRAEs, including 39% with grade 3 and 3% with grade 4 events. One patient experienced DLTs characterized by grade 3 elevations in liver enzymes. (onclive.com)
Pembrolizumab/MK-1084 Combo Is the Focus of Phase 3 Trial in KRAS G12C+ Metastatic NSCLC
Preliminary Data of MK-1084 +/- Pembrolizumab in Solid Tumors and NSCLC
Last updated: Apr 2025
Goal: To evaluate whether the combination of MK-1084 and pembrolizumab improves progression-free survival (PFS) and overall survival (OS) compared to pembrolizumab plus placebo as first-line therapy in patients with KRAS G12C-mutant, metastatic non-small cell lung cancer (NSCLC) with PD-L1 tumor proportion score (TPS) ≥50%.
Patients: Adults with histologically or cytologically confirmed newly diagnosed stage IV NSCLC, measurable disease per RECIST 1.1, KRAS G12C mutation, and PD-L1 TPS ≥50%, with ECOG performance status 0-1 and adequate organ function. Key exclusions include prior systemic therapy for metastatic NSCLC, active CNS metastases, active autoimmune or infectious disease requiring systemic therapy, and significant cardiovascular, autoimmune, or ophthalmologic conditions.
Design: Randomized, double-blind, multicenter, placebo-controlled, phase 3 trial. Patients are randomized to receive either MK-1084 plus pembrolizumab or placebo plus pembrolizumab.
Treatments: The experimental arm receives pembrolizumab 200 mg IV every 21 days (up to 35 cycles) plus MK-1084 oral tablets once daily. MK-1084 is a selective KRAS G12C inhibitor that covalently binds to the mutant protein in its GDP-bound state; in phase 1 trials, MK-1084 demonstrated manageable safety and high response rates when combined with pembrolizumab, especially in patients with high PD-L1 expression. The control arm receives pembrolizumab plus matching oral placebo.
Outcomes: The primary outcomes are progression-free survival (PFS) and overall survival (OS). Secondary outcomes include objective response rate (ORR), duration of response (DOR), adverse event rates, discontinuation due to adverse events, and multiple health-related quality of life metrics using EORTC QLQ-C30 and LC13 questionnaires, with time to deterioration assessed for several domains including global health, physical and role functioning, dyspnea, cough, and chest pain.
Burden on patient: Overall patient burden is moderate and in line with typical phase 3 oncology trials. Required tumor tissue for biomarker analysis must be provided at screening, but no mention is made of protocol-mandated serial biopsies. Treatment delivery involves an oral agent plus standard IV infusions every three weeks, aligning with standard-of-care schedules. Follow-up includes regular imaging and quality of life assessments but should not require substantially more frequent visits or tests compared to standard care. Adverse event monitoring and questionnaire completion may require additional attention but are not expected to significantly increase travel or procedural burden.
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.
Caba, Buenos Aires, C1019ABS, Argentina
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