A Study of Investigational Agents in Participants With Previously Treated Stage IV Nonsquamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-01H/KEYMAKER-U01)

May 21, 2026 updated by: Merck Sharp & Dohme LLC

KEYMAKER-U01 Substudy 01H: A Phase 2, Randomized, Umbrella Study With Rolling Arms of Investigational Agents in Participants With Previously Treated Stage IV Nonsquamous Non-small Cell Lung Cancer (NSCLC)

Researchers are looking for new ways to treat metastatic nonsquamous non-small cell lung cancer (NSCLC) that has been treated before. Metastatic means the cancer has spread to other parts of the body. Nonsquamous means the cancer did not start in squamous cells, which are flat cells that line the inside of the lungs.

Standard treatment (usual treatment) for NSCLC is surgery, then immunotherapy with or without chemotherapy after surgery. Immunotherapy is a treatment that helps the immune system fight cancer. Chemotherapy is a medicine that works to destroy cancer cells or stop them from growing.

However, standard treatment may not work or may stop working for some people. Researchers want to know if 2 antibody drug conjugates (ADCs) can help treat metastatic nonsquamous NSCLC that did not respond (get smaller or go away) to treatment. An ADC attaches to specific targets on cancers cells and delivers treatment to destroy those cells.

Researchers will compare 2 different ADCs (the study treatments) to chemotherapy in this study. The goals of this study are to learn:

  • About the safety of the study treatments and if people tolerate them
  • How many people have the cancer respond to the study treatments

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The master screening protocol is MK-3475-U01 (KEYMAKER-U01) - NCT04165798

Study Type

Interventional

Enrollment (Estimated)

96

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Chile
    • Region M. de Santiago
      • Santiago, Region M. de Santiago, Chile, 7500653
        • Recruiting
        • Centro de Estudios Clínicos SAGA ( Site 0161)
        • Contact:
          • Study Coordinator
          • Phone Number: +5690556961
      • Santiago, Region M. de Santiago, Chile, 7500921
        • Recruiting
        • FALP ( Site 0160)
        • Contact:
          • Study Coordinator
          • Phone Number: 56227128000
      • Santiago, Region M. de Santiago, Chile, 8420383
        • Recruiting
        • Bradfordhill ( Site 0162)
        • Contact:
          • Study Coordinator
          • Phone Number: +56229490970
  • Germany
      • Berlin, Germany, 13353
        • Recruiting
        • Charite-Universitaetsmedizin Berlin ( Site 0191)
        • Contact:
          • Study Coordinator
          • Phone Number: +49 30 450 553 044
    • Baden-Wurttemberg
      • Tübingen, Baden-Wurttemberg, Germany, 72076
        • Recruiting
        • Universitaetsklinik Tuebingen ( Site 0192)
        • Contact:
          • Study Coordinator
          • Phone Number: +4970712982795
  • Greece
      • Thessaloniki, Greece, 570 01
        • Recruiting
        • European Interbalkan Medical Center ( Site 0205)
        • Contact:
          • Study Coordinator
          • Phone Number: 0030 2310400213
    • Attica
      • Athens, Attica, Greece, 115 27
        • Recruiting
        • THORACIC GENERAL HOSPITAL OF ATHENS "I SOTIRIA"-3rd Dept of Internal Medicine and Laboratory, Oncol ( Site 0204)
        • Contact:
          • Study Coordinator
          • Phone Number: 0030 2107700220
  • Hungary
    • Bács-Kiskun county
      • Kecskemét, Bács-Kiskun county, Hungary, 6000
        • Recruiting
        • Bacs-Kiskun Varmegyei Oktatokorhaz ( Site 0063)
        • Contact:
          • Study Coordinator
          • Phone Number: +3676516700
    • Győr-Moson-Sopron
      • Győr, Győr-Moson-Sopron, Hungary, 9024
        • Recruiting
        • Petz Aladar Egyetemi Oktato Korhaz ( Site 0062)
        • Contact:
          • Study Coordinator
          • Phone Number: +3696507900
    • Jász-Nagykun-Szolnok
      • Szolnok, Jász-Nagykun-Szolnok, Hungary, 5000
        • Recruiting
        • Jasz-Nagykun-Szolnok Varmegyei Hetenyi Geza Korhaz-Rendelointezet ( Site 0061)
        • Contact:
          • Study Coordinator
          • Phone Number: +3656503603
  • Israel
      • Haifa, Israel, 3109601
        • Recruiting
        • Rambam Health Care Campus ( Site 0076)
        • Contact:
          • Study Coordinator
          • Phone Number: +972-4-7776234
      • Jerusalem, Israel, 9103102
        • Recruiting
        • Shaare Zedek Medical Center ( Site 0075)
        • Contact:
          • Study Coordinator
          • Phone Number: +972-2-6555768
      • Kfar Saba, Israel, 4428164
        • Recruiting
        • Meir Medical Center ( Site 0071)
        • Contact:
          • Study Coordinator
          • Phone Number: +97297472414
      • Petah Tikva, Israel, 4941492
        • Recruiting
        • Rabin Medical Center ( Site 0074)
        • Contact:
          • Study Coordinator
          • Phone Number: +97239378101
      • Ramat Gan, Israel, 5265601
        • Recruiting
        • Sheba Medical Center ( Site 0070)
        • Contact:
          • Study Coordinator
          • Phone Number: +97235307032
      • Tel Aviv, Israel, 6423906
        • Recruiting
        • Sourasky Medical Center ( Site 0077)
        • Contact:
          • Study Coordinator
          • Phone Number: +972-3-6973082
  • Italy
      • Florence, Italy, 50134
        • Recruiting
        • Azienda Ospedaliera Universitaria Careggi ( Site 0173)
        • Contact:
          • Study Coordinator
          • Phone Number: +393209225506
      • Milan, Italy, 20132
        • Recruiting
        • Ospedale San Raffaele. ( Site 0171)
        • Contact:
          • Study Coordinator
          • Phone Number: +390223903829
      • Roma, Italy, 00168
        • Recruiting
        • Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore ( Site 0174)
        • Contact:
          • Study Coordinator
          • Phone Number: +390630156318
    • Lombardy
      • Milan, Lombardy, Italy, 20133
        • Recruiting
        • Fondazione IRCCS Istituto Nazionale dei Tumori ( Site 0175)
        • Contact:
          • Study Coordinator
          • Phone Number: 390223902190
  • Poland
    • Greater Poland Voivodeship
      • Poznan, Greater Poland Voivodeship, Poland, 60-569
        • Recruiting
        • Wielkopolskie Centrum Pulmonologii i Torakochirurgii ( Site 0153)
        • Contact:
          • Study Coordinator
          • Phone Number: +48616654242
    • Masovian Voivodeship
      • Warsaw, Masovian Voivodeship, Poland, 02-781
        • Recruiting
        • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie ( Site 0151)
        • Contact:
          • Study Coordinator
          • Phone Number: +48225463066
    • Pomeranian Voivodeship
      • Gdansk, Pomeranian Voivodeship, Poland, 80-214
        • Recruiting
        • Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 0150)
        • Contact:
          • Study Coordinator
          • Phone Number: +48585844466
    • West Pomeranian Voivodeship
      • Koszalin, West Pomeranian Voivodeship, Poland, 75-581
        • Recruiting
        • Szpital Wojewódzki im. Mikoaja Kopernika w Koszalinie ( Site 0152)
        • Contact:
          • Study Coordinator
          • Phone Number: +48943488930
  • Spain
      • Madrid, Spain, 28223
        • Recruiting
        • Hospital Universitario Quiron Madrid ( Site 0091)
        • Contact:
          • Study Coordinator
          • Phone Number: 34914521987
    • Barcelona
      • L'Hospitalet de Llobregat, Barcelona, Spain, 08908
        • Recruiting
        • Institut Català d'Oncologia - L'Hospitalet ( Site 0090)
        • Contact:
          • Study Coordinator
          • Phone Number: 0034932607744
  • Turkey (Türkiye)
      • Adana, Turkey (Türkiye), 01250
        • Recruiting
        • Baskent University Dr. Turgut Noyan Research and Training Center-ONCOLOGY ( Site 0141)
        • Contact:
          • Study Coordinator
          • Phone Number: +90 322 344 44 44
      • Ankara, Turkey (Türkiye), 06230
        • Recruiting
        • Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 0140)
        • Contact:
          • Study Coordinator
          • Phone Number: +90 312 305 43 36
      • Ankara, Turkey (Türkiye), 06800
        • Recruiting
        • Ankara Bilkent Şehir Hastanesi. ( Site 0142)
        • Contact:
          • Study Coordinator
          • Phone Number: +905555306271
      • Istanbul, Turkey (Türkiye), 34098
        • Recruiting
        • I. U. Cerrahpasa Tip Fakultesi ( Site 0144)
        • Contact:
          • Study Coordinator
          • Phone Number: +902124143000
  • United States
    • Kentucky
      • Lexington, Kentucky, United States, 40536-0293
        • Recruiting
        • University of Kentucky Chandler Medical Center ( Site 0019)
        • Contact:
          • Study Coordinator
          • Phone Number: 859-257-1000
    • Maryland
      • Baltimore, Maryland, United States, 21237
        • Recruiting
        • MedStar Franklin Square Medical Center ( Site 0033)
        • Contact:
          • Study Coordinator
          • Phone Number: 443-777-7147

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Histologically or cytologically confirmed diagnosis of Stage IV nonsquamous non-small cell lung cancer (NSCLC)
  • Documented disease progression per RECIST 1.1 after receiving an anti-programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) treatment and platinum-based chemotherapy
  • Confirmation per local test report that epidermal growth factor receptor negative (EGFR-), anaplastic lymphoma kinase negative (ALK-), c ros oncogene 1 negative (ROS1-), or other directed therapy is not indicated as primary therapy
  • Measurable disease per RECIST 1.1 as assessed by investigator and verified by BICR
  • Life expectancy of at least 3 months
  • An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 7 days before randomization
  • Is an individual of any sex/gender who is at least 18 years of age at the time of providing the informed consent
  • Has adequate organ function
  • If capable of producing sperm refrains from donating sperm plus either abstains from penile-vaginal intercourse or uses a penile/external condom, with contraceptive use consistent with local regulations
  • Participant/participants of childbearing potential (POCBP) is not pregnant and has a negative highly sensitive pregnancy test; and is not breastfeeding and uses a highly effective contraceptive method
  • Archival tumor tissue sample of a tumor lesion not previously irradiated has been provided
  • Has provided tissue prior to treatment randomization from a newly obtained formalin-fixed sample from a new biopsy
  • Human Immunodeficiency Virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)
  • Participants who are hepatitis B surface antigen (HBsAg) positive have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization
  • Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening

Exclusion Criteria:

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

  • Diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements
  • Received radiation therapy to the lung
  • Has uncontrolled or significant cardiovascular disorder prior to randomization
  • Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
  • Participants who have adverse events (AEs) (other than alopecia) due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline
  • Has known severe hypersensitivity (≥Grade 3) to study intervention and/or any of its excipients
  • Has clinically significant corneal disease
  • Has received prior radiotherapy within 2 weeks of start of study intervention, or radiation related toxicities, requiring corticosteroids
  • Has inadequate washout period prior to randomization
  • Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
  • Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
  • Has previously received docetaxel as monotherapy or in combination with other therapies
  • Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
  • Has known additional malignancy that is progressing or has required active treatment within the past 3 years
  • Has known untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Has evidence of any leptomeningeal disease
  • Has history of interstitial lung disease (ILD)/pneumonitis, current diagnosis of ILD, and/or suspected ILD
  • Has active autoimmune disease that has required systemic treatment in the past 2 years
  • Has active infection requiring systemic therapy
  • HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
  • Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease
  • Has known history of, or active, neurologic paraneoplastic syndrome
  • Has history of allogeneic tissue/solid organ transplant
  • Have not adequately recovered from major surgery or have ongoing surgical complications

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Raludotatug Deruxtecan
Participants receive raludotatug deruxtecan (R-DXd) 5.6 mg/kg via intravenous (IV) Infusion every 3 weeks (q3w) until disease progression or discontinuation criterion is met.
Biological: Raludotatug Deruxtecan
IV Infusion
Other Names:
  • R-DXd
  • DS-6000a
  • MK-5909
Drug: 5-hydroxytryptamine subtype 3 receptor antagonist
Administered as a rescue medication per approved product label before R-DXd or I-DXd infusion
Other Names:
  • 5-HT3 receptor antagonist
Drug: Neurokinin-1 receptor antagonist
Administered as a rescue medication per approved product label before R-DXd or I-DXd infusion
Other Names:
  • NK-1 receptor antagonist
Drug: Corticosteroid
Administered as a rescue medication per approved product label before R-DXd or I-DXd infusion, and for 3 days starting 1 day prior to docetaxel administration
Experimental: Ifinatamab Deruxtecan
Participants receive ifinatamab deruxtecan (I-DXd) 12 mg/kg via IV infusion q3w until disease progression or discontinuation criterion is met.
Biological: Ifinatamab Deruxtecan
IV Infusion
Other Names:
  • DS-7300a
  • I-DXd
  • MK-2400
Drug: 5-hydroxytryptamine subtype 3 receptor antagonist
Administered as a rescue medication per approved product label before R-DXd or I-DXd infusion
Other Names:
  • 5-HT3 receptor antagonist
Drug: Neurokinin-1 receptor antagonist
Administered as a rescue medication per approved product label before R-DXd or I-DXd infusion
Other Names:
  • NK-1 receptor antagonist
Drug: Corticosteroid
Administered as a rescue medication per approved product label before R-DXd or I-DXd infusion, and for 3 days starting 1 day prior to docetaxel administration
Active Comparator: Docetetaxel
Participants receive docetaxel 75mg/m2 via IV infusion q3w until disease progression or discontinuation criterion is met.
Drug: Docetetaxel
IV Infusion
Drug: Corticosteroid
Administered as a rescue medication per approved product label before R-DXd or I-DXd infusion, and for 3 days starting 1 day prior to docetaxel administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Who Discontinued Medication Due to an AE
Time Frame: Up to approximately 24 months
An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The percentage of participants who discontinue study intervention due to an AE will be reported.
Up to approximately 24 months
Objective Response Rate (ORR)
Time Frame: Up to approximately 81 months
ORR is defined as the percentage of participants with Complete Response (CR: Disappearance of all target lesions) or a 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 81 months
Percentage of Participants with at Least One Adverse Event (AE)
Time Frame: Up to approximately 81 months
An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The percentage of participants who experience an AE will be reported.
Up to approximately 81 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Duration of Response (DOR)
Time Frame: Up to approximately 81 months
For participants who demonstrate a confirmed CR (disappearance of all target lesions) or (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 millimeters (mm). The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.
Up to approximately 81 months
Progression-free Survival (PFS)
Time Frame: Up to approximately 81 months
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 81 months
Overall Survival (OS)
Time Frame: Up to approximately 81 months
OS is defined as the time from randomization to death due to any cause.
Up to approximately 81 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Merck Sharp & Dohme LLC

Collaborators

Daiichi Sankyo

Investigators

  • Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 13, 2025

Primary Completion (Estimated)

March 12, 2032

Study Completion (Estimated)

March 12, 2032

Study Registration Dates

First Submitted

January 13, 2025

First Submitted That Met QC Criteria

January 13, 2025

First Posted (Actual)

January 17, 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

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3475-01H
  • KEYMAKER-U01 (Other Identifier: MSD)
  • MK-3475-01H (Other Identifier: MSD)
  • U1111-1314-1785 (Registry Identifier: UTN)
  • 2024-518761-10-00 (Registry Identifier: EU CT)

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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