MK-1084, Merck’s investigational KRAS G12C inhibitor, showed a manageable safety profile along with antitumor activity in the Phase I KANDLELIT-001 study.
Early-phase trial design should anticipate combination therapy pathways, as seen with MK-1084 across multiple arms.
Safety and tolerability remain primary endpoints, even when exploring novel mutation-specific therapies like KRAS G12C inhibitors.
Operational planning must account for global scalability, with Phase III trials like KANDLELIT-004 aiming to enroll 600 patients worldwide.
Merck has shared positive outcomes from its Phase I KANDLELIT-001 study of MK-1084, an investigational KRAS G12C inhibitor, in patients with KRAS G12C-mutant solid tumors, including advanced colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). Across both patient populations, the inhibitor demonstrated a favorable safety profile and antitumor activity either as monotherapy or in combination. Merck will be sharing additional data from the study at this year’s American Society of Clinical Oncology (ASCO) meeting.1
For CRC patients, MK-1084 was evaluated as monotherapy and in combination with cetuximab with or without chemotherapy (oxaliplatin and leucovorin plus 5-fluorouracil [mFOLFOX6]). In NSCLC, MK-1084 was once again evaluated as monotherapy as well as in combination with Keytruda (pembrolizumab) with or without chemotherapy (carboplatin and pemetrexed).
In a press release, Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “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, which are among the most prevalent mutations in cancer. We are committed to evaluating the potential for innovative approaches to help even more patients with cancer and these results further demonstrate the potential of our robust and differentiated pipeline.”
KANDLELIT-001 is a Phase I, open-label, multicenter trial (NCT05067283). Its primary endpoints were safety and tolerability, as measured by the number of patients who experienced a dose-limiting toxicity, adverse events, and treatment discontinuations. The secondary endpoints included overall response rate (ORR) and duration of response (DoR).
MK-1084 showed a manageable safety profile across all arms of the KANDLELIT-001 trial. Treatment-related adverse events occurred in 58% of patients in the MK-1084 monotherapy arm, 94% of patients in the MK-1084 and Keytruda arm, 93% of patients in the MK-1084 in combination with Keytruda and chemotherapy arm, 95% of patients in the MK-1084 and cetuximab arm, and 97% of patients in the MK-1084 with cetuximab and mFOLFOX6 arm.
In April 2024, Merck announced it would be evaluating MK-1084 plus Keytruda for the treatment of NSCLC in a Phase III trial, now known as KANDLELIT-004 (NCT06345729).2
The randomized, double-blind, multicenter study plans to enroll approximately 600 patients globally to evaluate and compare once daily MK-1084 plus Keytruda administered once every three weeks versus Keytruda plus placebo in previously untreated patients with KRAS G12C-mutated metastatic NSCLC with PD-L1. Along with its primary endpoints of progression-free survival and overall survival, key secondary endpoints for the trial include ORR and DoR.
In a press release from the time, Green said: “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. 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.”
Outside of KANDLELIT-001 and KANDLELIT-004, Merck will be investigating MK-1084 in the Phase III KANDLELIT-012 study, which is evaluating MK-1084 in combination with cetuximab and mFOLFOX6 for the first-line treatment of certain patients with locally advanced unresectable or metastatic CRC who have KRAS G12C-mutated tumors.
MK-1084 is being developed under a collaboration between Merck, Taiho Pharmaceutical, and Astex Pharmaceuticals, which is a wholly owned subsidiary of Otsuka. The agreement was made official in January 2020.2
1. Merck Announces MK-1084, an Investigational KRAS G12C Inhibitor, Shows Antitumor Activity in Phase 1 Trial of Patients With Advanced Colorectal Cancer and Non-Small Cell Lung Cancer Whose Tumors Harbor KRAS G12C Mutations. News release. Merck. May 30, 2025. Accessed May 30, 2025. https://www.merck.com/news/merck-announces-mk-1084-an-investigational-kras-g12c-inhibitor-shows-antitumor-activity-in-phase-1-trial-of-patients-with-advanced-colorectal-cancer-and-non-small-cell-lung-cancer-whose-tumors-harbo/
2. Phase III Trial to Evaluate Novel KRAS G12C Covalent Inhibitor Plus Keytruda for NSCLC. Applied Clinical Trials. April 5, 2024. Accessed May 30, 2025. https://www.appliedclinicaltrialsonline.com/view/phase-iii-trial-to-evaluate-novel-kras-g12c-covalent-inhibitor-plus-keytruda-for-nsclc
Unifying Industry to Better Understand GCP Guidance
May 7th 2025In this episode of the Applied Clinical Trials Podcast, David Nickerson, head of clinical quality management at EMD Serono; and Arlene Lee, director of product management, data quality & risk management solutions at Medidata, discuss the newest ICH E6(R3) GCP guidelines as well as how TransCelerate and ACRO have partnered to help stakeholders better acclimate to these guidelines.
