Pembrolizumab/MK-1084 Combo Is the Focus of Phase 3 Trial in KRAS G12C+ Metastatic NSCLC

Treatment with MK-1084 is also currently under evaluation as a treatment for patients with advanced solid tumors harboring KRAS G12C mutations as part of an open-label, multicenter phase 1 trial (NCT05067283).

Investigators have launched a phase 3 trial (NCT06345729) that will evaluate the novel selective KRAS G12C inhibitor MK-1084 plus pembrolizumab (Keytruda) as frontline therapy for those with metastatic KRAS G12C–mutated, PD-L1–positive non–small cell lung cancer (NSCLC), according to a press release from Merck, the developers of both agents.¹

Treatment with MK-1084 is currently under evaluation as a treatment for patients with advanced solid tumors harboring KRAS G12C mutations as part of an open-label, multicenter phase 1 trial (NCT05067283). Investigators previously presented data from this trial at the 2023 European Society for Medical Oncology Congress (ESMO).

Findings from the phase 1 trial highlighted an overall response rate (ORR) of 19% (n = 8/42) among patients who received MK-1084 monotherapy in arm 1 and 47% (n = 7/15) among those who received MK-1084 plus pembrolizumab in arm 2.² All observed responses consisted of partial responses.

Regarding safety, investigators reported no dose-limiting toxicities across both treatment arms. In arm 1 and arm 2, respectively, any-cause adverse effects affected 84% and 87% of patients, and treatment-related AEs occurred in 51% and 73%.

“KRAS is among the most prevalent mutations in cancer and KRAS G12C is the most common KRAS mutation in patients with [NSCLC],” Marjorie Green, MD, senior vice president and head of oncology, Global Clinical Development at Merck Research Laboratories, said in the press release.¹ “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].”

In the double-blind, multicenter, phase 3 trial, approximately 600 patients will be assigned to receive pembrolizumab at 200 mg intravenously on day 1 of each 21-day cycle for up to 35 cycles plus MK-1084 orally or matched placebo once a day.³

The study has 2 primary hypotheses. First, it is believed that MK-1084 plus pembrolizumab is more effective compared with placebo plus pembrolizumab with respect to progression-free survival (PFS). Additionally, investigators hypothesize that the MK-1084 combination will yield improvements in overall survival (OS).

The trial’s primary end points include PFS per RECIST v1.1 criteria and OS. Secondary end points include ORR, duration of response, AEs, treatment discontinuation due to AEs, and quality of life.

Patients 18 years and older with histologically or cytologically confirmed NSCLC and newly diagnosed stage IV disease based on American Joint Committee on Cancer (AJCC) Staging Manual, Version 8 guidelines can enroll on the trial. Additional eligibility criteria include having 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.

Those with small cell lung cancer, active inflammatory bowel disease that needs to be managed with immunosuppressive medication, prior or active neurologic paraneoplastic syndrome, or an active infection requiring management with systemic therapy are unable to enroll on the trial. Patients are also unsuitable for enrollment if they have uncontrolled and significant cardiovascular disease, received prior systemic anticancer therapy for metastatic NSCLC, received prior radiotherapy within 2 weeks of study entry, have known active central nervous system metastases and/or carcinomatous meningitis, or had a prior allogeneic tissue or solid organ transplant.

References

1. Merck initiates phase 3 clinical trial of MK-1084, an investigational oral KRAS G12C inhibitor, in combination with KEYTRUDA® (pembrolizumab) for first-line treatment of certain patients with metastatic non-small cell lung cancer. News release. Merck. April 4, 2024. Accessed April 4, 2024. https://tinyurl.com/ydv898tp
2. Rojas C, Lugowska I, Juergens R, et al. Safety and preliminary efficacy of the KRAS G12C inhibitor MK-1084 in solid tumors and in combination with pembrolizumab in NSCLC. Ann Oncol. 2023;34(suppl 2):S466-S467. doi:10.1016/j.annonc.2023.09.1849
3. A study of MK-1084 plus pembrolizumab (MK-3475) in participants with KRAS G12C mutant, metastatic non-small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% (MK-1084-004). ClinicalTrials.gov. Accessed April 4, 2024. https://tinyurl.com/3wf62bc3