A Clinical Study of MK-1084 With Other Treatments for Non-small Cell Lung Cancer (MK-3475-01F)

KEYMAKER-U01 Substudy 01F: A Phase 1b/2 Umbrella Study With Rolling Arms of Investigational Agents for Previously Treated Participants With Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With KRAS G12C Mutations

Researchers want to learn if MK-1084, the study medicine, can treat advanced or metastatic non-squamous NSCLC. MK-1084 is a targeted therapy, which is a treatment that works to control how specific types of cancer cells grow and spread. The goals of this study are to learn:

• About the safety of MK-1084 and if people tolerate it when taken with other treatments
• How many people have the cancer respond (get smaller or go away) to the treatments

Study Overview

• Status: Recruiting
• Conditions: Lung Neoplasm Malignant
• Intervention / Treatment: Drug: MK-1084; Biological: Sacituzumab tirumotecan; Biological: Patritumab deruxtecan; Drug: Rescue Medications; Biological: Cetuximab

Detailed Description

This is a substudy of the master protocol MK-3475-U01 (KEYMAKER-U01) - NCT04165798.

• Study Type: Interventional
• Enrollment (Estimated): 190
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Toll Free Toll Free Number; Phone Number: 1-888-577-8839; Email: Trialsites@msd.com

Study Locations

• Brazil
  • São Paulo
    • Barretos, São Paulo, Brazil, 14784-400
      • Recruiting
      • Fundação Pio XII - Hospital de Câncer de Barretos ( Site 0282)
      • Contact: Study Coordinator; Phone Number: +551733216637
    • São José do Rio Preto, São Paulo, Brazil, 15090-000
      • Recruiting
      • Fundação Faculdade Regional de Medicina de São José do Rio Preto ( Site 0286)
      • Contact: Study Coordinator; Phone Number: +551732015000
    • São Paulo, São Paulo, Brazil, 01321001
      • Recruiting
      • Hospital Paulistano ( Site 0280)
      • Contact: Study Coordinator; Phone Number: 55 11 31411083
• Chile
  • Region M. de Santiago
    • Santiago, Region M. de Santiago, Chile, 7500921
      • Recruiting
      • FALP ( Site 0161)
      • Contact: Study Coordinator; Phone Number: 56229490970
    • Santiago, Region M. de Santiago, Chile, 8420383
      • Recruiting
      • Bradfordhill ( Site 0160)
      • Contact: Study Coordinator; Phone Number: +56229490970
    • Santiago, Region M. de Santiago, Chile, 7500653
      • Recruiting
      • Centro de Estudios Clínicos SAGA-CECSAGA ( Site 0162)
      • Contact: Study Coordinator; Phone Number: +56991612199
• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510120
      • Recruiting
      • Guangdong Provincial People s Hospital ( Site 0300)
      • Contact: Study Coordinator; Phone Number: 02083525210
• Greece
  • Attica
    • Athens, Attica, Greece, 115 27
      • Recruiting
      • THORACIC GENERAL HOSPITAL OF ATHENS "I SOTIRIA" ( Site 0204)
      • Contact: Study Coordinator; Phone Number: +30210 7763100
    • Athens, Attica, Greece, 115 28
      • Recruiting
      • Alexandra General Hospital of Athens-ONCOLOGY DEPT. ( Site 0205)
      • Contact: Study Coordinator; Phone Number: +302132162543
• Hong Kong
  • Hong Kong, Hong Kong, 000000
    • Recruiting
    • Queen Mary Hospital ( Site 0230)
    • Contact: Study Coordinator; Phone Number: +85222551727
• Israel
  • Jerusalem, Israel, 9103102
    • Recruiting
    • Shaare Zedek Medical Center ( Site 0186)
    • Contact: Study Coordinator; Phone Number: +97226555999
  • Ramat Gan, Israel, 5265601
    • Recruiting
    • Sheba Medical Center ( Site 0180)
    • Contact: Study Coordinator; Phone Number: +97235303030
• South Korea
  • Seoul, South Korea, 03722
    • Recruiting
    • Severance Hospital, Yonsei University Health System ( Site 0080)
    • Contact: Study Coordinator; Phone Number: +82222280880
• Spain
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clinic de Barcelona ( Site 0092)
    • Contact: Study Coordinator; Phone Number: 34 932275402
  • Seville, Spain, 41009
    • Recruiting
    • Hospital Universitario Virgen Macarena ( Site 0093)
    • Contact: Study Coordinator; Phone Number: +34 671560092
  • Barcelona
    • Hospitalet, Barcelona, Spain, 08908
      • Recruiting
      • Institut Català d'Oncologia - L'Hospitalet ( Site 0090)
      • Contact: Study Coordinator; Phone Number: 0034932607744
• United States
  • Florida
    • Clermont, Florida, United States, 34711
      • Recruiting
      • Clermont Oncology Center ( Site 0041)
      • Contact: Study Coordinator; Phone Number: 386-538-3169
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • University of Illinois Hospital & Health Sciences System ( Site 0044)
      • Contact: Study Coordinator; Phone Number: 312-996-9272

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

• Has histologically or cytologically confirmed diagnosis of advanced or metastatic non-squamous non-small cell lung cancer (NSCLC)
• Has tumor tissue or circulating tumor deoxyribonucleic acid (ctDNA) that demonstrates the presence of Kirsten rat sarcoma viral oncogene (KRAS) mutation of glycine to cysteine at codon 12 (G12C) mutations
• Has documented disease progression after receiving 1-2 prior lines of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy and platinum-based chemotherapy
• Provides archival tumor tissue sample of a tumor lesion not previously irradiated
• Has provided tissue prior to treatment allocation/randomization from a newly obtained biopsy of a tumor lesion not previously irradiated
• Participants with human immunodeficiency virus (HIV) infection must have well-controlled HIV on antiretroviral therapy (ART) per protocol

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

• Has a diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements
• Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
• Has evidence of any leptomeningeal disease
• Has uncontrolled or significant cardiovascular disorder or cerebrovascular disease prior to allocation/randomization
• Has one or more of the following ophthalmological conditions: a) Clinically significant corneal disease b) history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Has received previous treatment with an agent targeting KRAS
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
• Has known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has history of (noninfectious) pneumonitis/ interstitial lung disease (ILD) that required steroids or has current pneumonitis/ILD
• Has an active infection requiring systemic therapy
• Have not adequately recovered from major surgery or have ongoing surgical complications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MK-1084 + Patritumab deruxtecan (HER3-DXd); Participants will receive MK-1084 and HER3-DXd until discontinuation due to toxicity, adverse event (AE) or at the discretion of an investigator.	Drug: MK-1084; Oral administration; Biological: Patritumab deruxtecan; IV infusion; Other Names: U3-1402; HER3-DXd; MK-1022
Experimental: MK-1084 + Sacituzumab tirumotecan (Sac-TMT); Participants will receive MK-1084 and sac-TMT until discontinuation due to toxicity, AE or at the discretion of an investigator.	Drug: MK-1084; Oral administration; Biological: Sacituzumab tirumotecan; IV Infusion; Other Names: SKB264; MK-2870; Sac-TMT; Drug: Rescue Medications; Participants receive rescue medication at the investigator's discretion, per approved product label. Recommended rescue medications are histamine -1 (H1) receptor agonist, histamine-2 (H2) receptor antagonist, acetaminophen or equivalent, dexamethasone or equivalent infusion, or steroid mouthwash (dexamethasone or equivalent) for prevention of chemotherapy induced nausea and vomiting.
Experimental: MK-1084 + Cetuximab; Participants will receive MK-1084 and cetuximab until discontinuation due to toxicity, AE or at the discretion of an investigator.	Drug: MK-1084; Oral administration; Biological: Cetuximab; IV Infusion; Other Names: C225; Erbitux

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experience a Dose Limiting Toxicity (DLT)	DLT will be defined as any drug-related AE observed during the DLT evaluation period (up to 42 days) that results in a change to a given dose or a delay in initiating the next treatment.	Up to 42 days
Number of Participants Who Experience an Adverse Event (AE)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants that experience AEs will be reported.	Up to approximately 65 months
Number of Participants Who Discontinue Study Treatment Due to an AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants that discontinue study intervention due to an AE will be reported.	Up to approximately 64 months
Objective Response Rate (ORR)	ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.	Up to approximately 65 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.	Up to approximately 65 months
Progression-Free Survival (PFS)	PFS is defined as the time from randomization to the first documented PD or death due to any cause, whichever occurs first as assessed by RECIST 1.1. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.	Up to approximately 124 months
Area Under the Curve From Time 0 to the End of the Dosing Interval (AUC tau)	Blood samples will be collected at multiple time points to estimate AUC tau.	Predose and at designated time points post-dose (up to approximately 65 months)
Maximum Plasma Concentration (Cmax)	Blood samples will be collected at multiple time points to estimate Cmax.	Predose and at designated time points post-dose (up to approximately 65 months)
Minimum Observed Concentration (Ctrough)	Blood samples will be collected at multiple time points to estimate Ctrough.	Predose and at designated time points post-dose (up to approximately 65 months)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: Daiichi Sankyo
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2026
• Primary Completion (Estimated): August 11, 2031
• Study Completion (Estimated): May 6, 2037

Study Registration Dates

• First Submitted: November 17, 2025
• First Submitted That Met QC Criteria: December 12, 2025
• First Posted (Actual): December 16, 2025

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab; patritumab deruxtecan
• Other Study ID Numbers: 3475-01F; MK-3475-01F (Other Identifier: MSD); 2024-512248-47-00 (Registry Identifier: EU CT); U1111-1304-4707 (Registry Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No