Phase III Trial to Evaluate Novel KRAS G12C Covalent Inhibitor Plus Keytruda for NSCLC

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Merck is launching a Phase III clinical trial to analyze the investigational therapy MK-1084 plus Keytruda (pembrolizumab) in certain patients with metastatic non-small cell lung cancer (NSCLC) with tumors that carry KRAS G12C mutations and express PD-L1.¹ MK-1084 is a potent and specific KRAS G12C covalent inhibitor, whereas Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which leads to the activation of T lymphocytes that could affect tumor and healthy cells.

The randomized, double-blind, multicenter trial (NCT06345729) will enroll approximately 600 patients globally to compare once daily MK-1084 plus Keytruda administered once every three weeks vs. Keytruda plus placebo in previously untreated patients with KRAS G12C-mutated metastatic NSCLC with a PD-L1 TPS ≥50%. The trial’s primary endpoints are progression-free survival and overall survival, with key secondary endpoints that include objective response rate and duration of response.

KRAS mutations are highly prevalent across cancer types, most frequently occurring in NSCLC, pancreatic, urogenital, and colorectal cancers. Further, KRAS G12C mutations are the most common KRAS mutations, found in approximately 14% of NSCLC cases.

“KRAS is among the most prevalent mutations in cancer and KRAS G12C is the most common KRAS mutation in patients with non-small cell lung cancer,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, said in a press release. “Based on early evidence showing MK-1084 in combination with Keytruda had a manageable safety profile and promising anti-tumor activity, we are now proceeding to a larger Phase III trial to evaluate this combination in certain patients with metastatic non-small cell lung cancer.”¹

To date, more than 1600 trials are evaluating Keytruda across a range of cancer types and treatment settings. Keytruda also has approved indications in melanoma; non-small cell lung cancer; head and neck squamous cell cancer; classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma; urothelial carcinoma; gastric cancer; microsatellite instability-high or mismatch repair deficient cancer; microsatellite instability-high or mismatch repair deficient colorectal cancer; esophageal cancer; cervical cancer; hepatocellular carcinoma; Merkel cell carcinoma; renal cell carcinoma; endometrial carcinoma; tumor mutational burden-high cancer; cutaneous squamous cell carcinoma; and triple-negative breast cancer.

A Phase I, open-label multicenter clinical trial (NCT05067283) is also currently evaluating the safety, tolerability, pharmacokinetics, and efficacy of MK-1084 monotherapy and in combination with various other therapies that treat KRAS G12C mutant advanced solid tumors.

MK-1084 is in development via a collaboration between Merck with Taiho Pharmaceutical Co. Ltd and Astex Pharmaceuticals.²

As per the agreement reached between the companies in 2020, Merck, Taiho, and Astex will combine preclinical candidates and data from the respective research programs. Merck gained exclusive global license for Taiho’s and Astex’s small molecule inhibitor candidates for an aggregate upfront payment of $50 million with the potential for approximately $2.5 billion contingent upon achieving preclinical, clinical, regulatory, and sales milestones for multiple products included in the agreement.²

“Taiho has used its unique and proprietary drug discovery platform to generate a number of small molecule inhibitors,” Teruhiro Utsugi, PhD, managing director at Taiho, said in a press release. “This alliance builds on our KRAS research up to now and together with Merck, allows us to combine our expertise to significantly accelerate the global research, development, and commercialization of a number of our mutant KRAS programs by accessing external talent and resources.”²

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. Merck. News release. April 4, 2024. Accessed April 5, 2024. https://www.merck.com/news/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-met/

2. Merck Establishes Strategic Oncology Collaboration with Taiho and Astex. Merck. News release. January 6, 2020. Accessed April 5, 2024. https://www.merck.com/news/merck-establishes-strategic-oncology-collaboration-with-taiho-and-astex/