Merck Reports Encouraging Early Data for Investigational KRAS G12C Inhibitor MK-1084 in Phase 1 Trial for Advanced Colorectal and Lung Cancers
Merck known as MSD outside the United States and Canada, has announced promising early results from its ongoing KANDLELIT-001 Phase 1 clinical trial evaluating MK-1084, a novel investigational KRAS G12C inhibitor. The compound is being studied both as a standalone therapy and in combination with other treatment agents, including Merck’s blockbuster immunotherapy KEYTRUDA (pembrolizumab), in patients with advanced or metastatic solid tumors harboring KRAS G12C mutations, particularly colorectal cancer (CRC) and non-small cell lung cancer (NSCLC).
The preliminary findings, presented by Merck, show that MK-1084 demonstrated antitumor activity in patients with KRAS G12C-mutated tumors and was associated with a manageable safety profile, either as a monotherapy or in combination regimens. These results offer new hope for patients with cancers driven by the KRAS G12C mutation, one of the most common oncogenic mutations across multiple tumor types and historically considered difficult to target therapeutically.
Overview of the KANDLELIT-001 Study
KANDLELIT-001 is a first-in-human, open-label, dose-escalation and dose-expansion Phase 1 trial. It is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of MK-1084, both as a monotherapy and in various combinations. In this study, patients with advanced solid tumors harboring the KRAS G12C mutation, such as those with colorectal cancer or non-small cell lung cancer, were enrolled following progression on standard therapies.
The trial includes multiple arms, with some patients receiving MK-1084 alone and others receiving MK-1084 alongside combination therapies, including immunotherapies like KEYTRUDA and potentially other novel agents in Merck’s oncology pipeline.
Dr. Marjorie Green, senior vice president and head of oncology global clinical development at Merck Research Laboratories, emphasized the significance of the early findings. “We are encouraged by the promising early data from the KANDLELIT-001 study and look forward to further researching the potential for MK-1084, as monotherapy or in combinations, including with KEYTRUDA in certain settings in patients with KRAS mutations,” said Dr. Green. “KRAS mutations are among the most prevalent mutations in cancer. We are committed to evaluating innovative approaches that can improve outcomes for more patients with cancer, and these results reflect the growing strength of our differentiated and robust oncology pipeline.”
KRAS G12C Mutations: A Difficult Target in Oncology
The KRAS gene encodes a GTPase that acts as a molecular switch regulating cell proliferation. Mutations in KRAS are found in approximately 25% of all human cancers, with the G12C variant representing a particularly common and aggressive subtype found in lung, colorectal, and pancreatic cancers. Historically, KRAS has been considered an “undruggable” target due to its structure and the nature of its binding pocket.
However, the emergence of new-generation KRAS G12C inhibitors, like MK-1084, has shifted this paradigm. By irreversibly binding to the mutant cysteine residue unique to the G12C mutation, these compounds selectively inhibit KRAS-driven signaling pathways in tumor cells, leading to tumor shrinkage or disease stabilization in certain patients.
Several KRAS G12C inhibitors have entered clinical development over the past five years, and a few have received regulatory approval for select indications. However, issues such as drug resistance, limited durability of response, and the need for better combinatorial strategies remain challenges. Merck’s MK-1084 aims to improve upon the current landscape through enhanced potency, optimized pharmacokinetics, and a design amenable to combination regimens.
KEYTRUDA: A Key Combination Partner
In this study, Merck is also exploring MK-1084 in combination with KEYTRUDA (pembrolizumab), its leading PD-1 inhibitor that has become a cornerstone therapy in many cancers, including NSCLC and certain gastrointestinal malignancies.
KEYTRUDA works by blocking the interaction between PD-1 on immune cells and its ligands (PD-L1/PD-L2) expressed on tumor cells or within the tumor microenvironment. This blockade restores immune surveillance and enables T cells to recognize and destroy cancer cells. When paired with targeted therapies like KRAS G12C inhibitors, immunotherapies like KEYTRUDA may help sustain longer and more durable responses by stimulating the immune system to eliminate residual tumor cells that escape targeted inhibition.
However, KEYTRUDA is also associated with a spectrum of immune-mediated adverse reactions that may affect multiple organ systems, sometimes severely or fatally. These events can occur during or after treatment and may involve the lungs (pneumonitis), liver (hepatitis), endocrine glands (thyroiditis, hypophysitis, adrenal insufficiency), skin (rash, dermatitis), or other tissues.
Healthcare providers are advised to closely monitor patients for any symptoms suggestive of immune-related toxicity and conduct appropriate diagnostic evaluations. Baseline and periodic laboratory assessments of liver enzymes, thyroid function, and renal function are recommended. In the event of suspected immune-related adverse events, corticosteroid therapy and potential immunosuppressants should be initiated promptly, and KEYTRUDA should be withheld or permanently discontinued depending on the severity of the reaction.
In the context of the KANDLELIT-001 trial, no new safety signals were reported when MK-1084 was combined with KEYTRUDA. The combination showed a manageable safety profile, and immune-related adverse events were consistent with what has previously been reported for KEYTRUDA alone.
Future Directions and Broader Implications
The early results from the KANDLELIT-001 trial mark a potentially important advance in the treatment of KRAS G12C-mutated cancers. With both safety and preliminary efficacy signals supporting further development, Merck plans to continue advancing MK-1084 into later-phase clinical trials, including studies that evaluate more refined dosing schedules and additional combination strategies.
The company also sees potential for MK-1084 to be used across a broad array of solid tumors with KRAS G12C mutations. This may eventually include pancreatic cancer, which remains among the most lethal malignancies and is known to be driven in part by KRAS mutations, though other variants like G12D are more common in pancreatic disease.
In parallel, Merck is continuing to invest in next-generation immuno-oncology agents, antibody-drug conjugates, and bispecific antibodies as part of a diversified oncology pipeline aimed at targeting cancer from multiple biological angles. The company’s strategic approach includes leveraging KEYTRUDA as an immunotherapy backbone in combination with a wide array of novel agents, including MK-1084.
Merck’s unveiling of early data from its Phase 1 KANDLELIT-001 trial highlights the company’s commitment to addressing one of the most stubborn targets in oncology—KRAS G12C. The investigational agent MK-1084 has shown encouraging antitumor activity and a tolerable safety profile in patients with heavily pretreated advanced colorectal and non-small cell lung cancers. When combined with immunotherapy such as KEYTRUDA, MK-1084 may enhance the immune system’s ability to fight cancer and potentially overcome resistance mechanisms that limit the effectiveness of monotherapy KRAS inhibitors.
While these are early findings, they signal a potential new treatment avenue for a population of patients with limited options. Further clinical development will be essential to validate the efficacy and safety of MK-1084, but for now, Merck’s progress with this promising compound offers renewed hope for patients facing KRAS-driven cancers.
