MK-1084 / Merck (MSD), Otsuka - LARVOL DELTA

MK-1084 for KRAS G12C-mutated (mut) metastatic non–small-cell lung cancer (mNSCLC): Results from KANDLELIT-001. (ASCO 2025) - P1 | "Pts with previously untreated nonsquamous mNSCLC received MK-1084 50-200 mg/d + pembro 200 mg, carboplatin, and pemetrexed Q3W in arm 4. In pts with KRAS G12C-mut mNSCLC, MK-1084 shows manageable safety and antitumor activity as monotherapy for previously treated disease and in combination with pembro ± chemo as first-line (1L) therapy. The >90% decrease from baseline in KRAS G12C VAF in ctDNA confirms MK-1084 target engagement. The phase 3 KANDLELIT-004 study is evaluating MK-1084 + pembro as 1L therapy for KRAS G12C-mut mNSCLC with PD-L1 TPS ≥50%."

IO biomarker • Metastases • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

The KRAS G12C inhibitor MK-1084 for KRAS G12C–mutated advanced colorectal cancer (CRC): Results from KANDLELIT-001. (ASCO 2025) - P1 | "Preliminary data suggest that MK-1084 monotherapy, MK-1084 + cetuximab, and MK-1084 + cetuximab + mFOLFOX6 have manageable safety profiles and show evidence of antitumor activity in pts with advanced, KRAS G12C-mutated CRC. Pts continue to be followed, and enrollment continues."

Metastases • Colorectal Cancer • Dermatitis • Dermatology • Febrile Neutropenia • Immunology • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study to Evaluate the Effect of Formulation and Food on MK-1084 in Healthy Adult Participants (MK-1084-011) (clinicaltrials.gov) - P1 | N=52 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open

Research on Novel Treatment Approaches and Scientific Advances From Merck’s Broad and Differentiated Oncology Portfolio and Pipeline to be Presented at ASCO 2025 (Merck (MSD) Press Release) - "New and updated data for MK-1084, an investigational KRAS G12C inhibitor, from the colorectal cancer and non-small cell lung cancer cohorts of the Phase 1 KANDLELIT-001 study will be presented; Zilovertamab vedotin and sacituzumab tirumotecan data to highlight progress in Merck’s pipeline of innovative antibody-drug conjugates; Follow-up data for KEYTRUDA (pembrolizumab) and WELIREG (belzutifan), as well as new and updated analyses for KEYTRUDA in earlier stages of cancer, add to the body of evidence supporting the role of these medicines."

Clinical data • Cervical Cancer • Clear Cell Renal Cell Carcinoma • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Melanoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Prostate Cancer • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Von Hippel-Lindau Syndrome

A Clinical Study of MK-1084 With Targeted Therapy and Chemotherapy in People With Colorectal Cancer (MK-1084-012/KANDLELIT-012) (clinicaltrials.gov) - P3 | N=477 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P3 trial • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • KRAS

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 (Gurufocus) - P1 | N=830 | KANDLELIT-001 (NCT05067283) | Sponsor: Merck Sharp & Dohme LLC | "Merck...has announced encouraging results from its Phase 1 KANDLELIT-001 trial involving MK-1084, an investigational KRAS G12C inhibitor....In the colorectal cancer cohort, MK-1084 was tested both as a standalone treatment and in combination with cetuximab and mFOLFOX6 chemotherapy. The overall response rate (ORR) for patients receiving MK-1084 in combination with cetuximab and mFOLFOX6 was particularly impressive, reaching 66% (46-82% CI) for unconfirmed responses. Meanwhile, the NSCLC cohort showed a remarkable 77% (65-86% CI) ORR in patients receiving MK-1084 combined with KEYTRUDA, especially those whose tumors express PD-L1 tumor proportion scores of 1% or higher."

P1 data • Colorectal Cancer

A Clinical Study of MK-1084 in Participants With Renal Impairment (MK-1084-010) (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Renal Disease

A Study to Evaluate the Effect of Formulation and Food on MK-1084 in Healthy Adult Participants (MK-1084-011) (clinicaltrials.gov) - P1 | N=52 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

A Study of MK-1084 in KRAS Mutant Advanced Solid Tumors (MK-1084-001) (clinicaltrials.gov) - P1 | N=830 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Aug 2027 ➔ Feb 2030 | Trial primary completion date: Aug 2027 ➔ Feb 2030

Monotherapy • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

A Clinical Study of MK-1084 in Participants With Renal Impairment (MK-1084-010) (clinicaltrials.gov) - P1 | N=30 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial • Renal Disease

MSD Pharmaceutical Gets CDSCO Panel Nod To study MK-1084 (Medical Dialogues) - "MSD Pharmaceutical has got approval from the Subject Expert Committee SEC functional under the Central Drug Standard Control Organisation (CDSCO) to conduct the phase 3 clinical study of the anti-cancer drug MK-1084. This came after MSD Pharmaceutical presented phase 3 clinical study protocol no. MK-1084-004 version 00 dated 15 December 2023. However, this nod is subject to the condition that the number of subjects shall be increased up to 50. Furthermore, the expert panel stated that more geographically distributed government sites shall be included in the study."

New P3 trial • Oncology

A Study of MK-1084 in KRAS Mutant Advanced Solid Tumors (MK-1084-001) (clinicaltrials.gov) - P1 | N=830 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Aug 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2026 ➔ Aug 2027

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

A Study of the Effect of Itraconazole and Phenytoin on MK-1084 in Healthy Adults (MK-1084-008) (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

CA43815: A Study of MK-1084 With Midazolam and Digoxin in Healthy Participants (MK-1084-009) (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study of MK-1084 Human Absorption, Distribution, Metabolism, and Excretion in Healthy Adult Participants (MK-1084-006) (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

Phase III study of pembrolizumab plus MK-1084 vs pembrolizumab plus placebo as first-line treatment for metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation and PD-L1 tumour proportion score (TPS) ≥50%: MK-1084-004 (ESMO 2024) - P3 | "Efficacy analyses will be evaluated in all randomized patients and safety analyses in patients who receive ≥1 dose of study treatment. The study is actively enrolling patients."

Clinical • IO biomarker • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

A Study to Evaluate the Effect of Food, Formulation, and a Proton Pump Inhibitor (PPI) on MK-1084 in Healthy Adult Participants (MK-1084-003) (clinicaltrials.gov) - P1 | N=56 | Completed | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

CA43815: A Study of MK-1084 With Midazolam and Digoxin in Healthy Participants (MK-1084-009) (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

CA43815: A Study of MK-1084 With Midazolam and Digoxin in Healthy Participants (MK-1084-009) (clinicaltrials.gov) - P1 | N=28 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study of MK-1084 With Midazolam and Digoxin in Healthy Participants (MK-1084-009) (clinicaltrials.gov) - P1 | N=28 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor. (PubMed, J Med Chem) - P1 | "Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability."

Journal • Oncology • KRAS

Study of MK-0472 in Participants With Advanced/Metastatic Solid Tumors (MK-0472-001) (clinicaltrials.gov) - P1 | N=178 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | N=100 ➔ 178

Enrollment change • Oncology • Solid Tumor

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) - P3 | N=600 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • IO biomarker • Metastases • Tumor proportion score • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study of MK-1084 in KRAS Mutant Advanced Solid Tumors (MK-1084-001) (clinicaltrials.gov) - P1 | N=830 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | N=450 ➔ 830

Combination therapy • Enrollment change • Metastases • Monotherapy • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

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) - P3 | N=600 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P3 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS