Merck has initiated a phase 3 clinical trial evaluating MK-1084, an investigational oral selective KRAS G12C inhibitor, in combination with pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor KRAS G12C mutations and express PD-L1 with a tumor proportion score of ≥50%.
The decision to advance to phase 3 follows encouraging preliminary data from an ongoing phase 1 trial (NCT05067283) that demonstrated promising anti-tumor activity and a manageable safety profile for the combination therapy.
Phase 1 Trial Results Drive Advancement
Data from the phase 1 trial, previously presented at the 2023 European Society for Medical Oncology Congress, showed an overall response rate (ORR) of 47% (7/15 patients) among those who received MK-1084 plus pembrolizumab in arm 2, compared to 19% (8/42 patients) for MK-1084 monotherapy in arm 1. All observed responses consisted of partial responses.
Safety data from the phase 1 trial revealed no dose-limiting toxicities across both treatment arms. Any-cause adverse effects affected 84% and 87% of patients in arms 1 and 2, respectively, while treatment-related adverse events occurred in 51% and 73% of patients.
"Based on early evidence showing MK-1084 in combination with [pembrolizumab] had a manageable safety profile and promising anti-tumor activity, we are now proceeding to a larger phase 3 trial to evaluate this combination in certain patients with metastatic [NSCLC]," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development at Merck Research Laboratories.
Phase 3 Trial Design and Endpoints
The randomized, double-blind, multicenter phase 3 trial (NCT06345729) will enroll approximately 600 patients globally. Participants will receive pembrolizumab at 200 mg intravenously on day 1 of each 21-day cycle for up to 35 cycles plus either MK-1084 orally once daily or matched placebo.
The study operates under two primary hypotheses: that MK-1084 plus pembrolizumab will demonstrate superior efficacy compared to placebo plus pembrolizumab with respect to progression-free survival (PFS), and that the combination will yield improvements in overall survival (OS). The primary endpoints include PFS per RECIST v1.1 criteria and OS, while secondary endpoints encompass objective response rate, duration of response, adverse events, treatment discontinuation due to adverse events, and quality of life.
Patient Population and Eligibility
The trial targets patients 18 years and older with histologically or cytologically confirmed NSCLC and newly diagnosed stage IV disease based on American Joint Committee on Cancer Staging Manual, Version 8 guidelines. Additional eligibility criteria include measurable disease per RECIST v1.1 guidelines, PD-L1 expression in at least 50% of tumor cells, tumor tissue harboring a KRAS G12C mutation, a minimum life expectancy of 3 months, and an ECOG performance status of 0 or 1 within 7 days prior to randomization.
Exclusion criteria include small cell lung cancer, active inflammatory bowel disease requiring immunosuppressive medication, prior or active neurologic paraneoplastic syndrome, active infection requiring systemic therapy, uncontrolled cardiovascular disease, prior systemic anticancer therapy for metastatic NSCLC, recent radiotherapy within 2 weeks, active central nervous system metastases, or prior allogeneic tissue or solid organ transplant.
Addressing a Significant Unmet Need
KRAS mutations represent among the most prevalent mutations in cancer, with KRAS G12C being the most common KRAS mutation in NSCLC patients. The KRAS G12C mutation occurs in approximately 14% of non-small cell lung cancers, specifically adenocarcinomas. Despite decades of research recognizing the therapeutic importance of targeting KRAS, developing small molecule inhibitors targeting KRAS mutations has proven challenging.
MK-1084 is being developed through a collaboration with Taiho Pharmaceutical Co. Ltd and Astex Pharmaceuticals (UK), a wholly owned subsidiary of Otsuka Pharmaceutical Co., Ltd., announced in January 2020. The compound is designed as a potent and specific KRAS G12C covalent inhibitor.
Lung Cancer Burden and Treatment Landscape
Lung cancer remains the leading cause of cancer death worldwide, with approximately 2.4 million new cases and 1.8 million deaths recorded globally in 2022. Non-small cell lung cancer accounts for about 80% of all lung cancer cases. The overall five-year survival rate for patients diagnosed with lung cancer is 25% in the United States as of 2024, with improvements attributed to earlier detection, screening advances, smoking reduction, diagnostic and surgical procedure improvements, and new therapy introductions.
Early detection and screening remain important unmet needs, as 44% of lung cancer cases are not discovered until they reach advanced stages. Merck's research portfolio in lung cancer includes nearly 200 clinical trials evaluating more than 36,000 patients worldwide, with pembrolizumab currently holding six approved U.S. indications for NSCLC and approval for advanced disease in more than 95 countries.
