Substudy 01I: A Study of Investigational Agents in Participants With Previously Treated Stage IV Squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-01I/KEYMAKER-U01I)

Phase 2

Recruiting

• Conditions: Lung Neoplasm
• Interventions: Biological: R-DXD; Biological: I-DXD; Drug: Docetaxel

• Registration Number: NCT06780098
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

Researchers are looking for other ways to treat metastatic squamous non-small cell lung cancer (NSCLC). Squamous NSCLC is cancer that starts in squamous cells, which are flat cells that line the inside of the airways in the lungs. Metastatic means the cancer has spread to other parts of the body.

Standard treatment (usual treatment) for metastatic squamous NSCLC is immunotherapy with or without chemotherapy. Immunotherapy is a treatment that helps the immune system fight cancer. Chemotherapy is medicine that destroys cancer cells or stops them from growing. However, standard treatment may not work or may stop working to treat metastatic squamous NSCLC.

Researchers want to learn if study treatments that are antibody drug conjugates (ADCs) can treat metastatic squamous NSCLC that did not respond (get smaller or go away) to standard treatment. An ADC attaches to a protein on cancer cells and delivers treatment to destroy those cells.

The main goals of this study are to learn about:

* The cancer response to the study treatments compared to chemotherapy

* The safety of the study treatments and if people tolerate them

This study is one of the substudies being conducted under one pembrolizumab umbrella master protocol (MK-3475-U01/KEYMAKER-U01).

Detailed Description

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

Study Timeline

• Study First Submitted: 2025-01-13
• Study First Submitted QC: 2025-01-13
• Study First Posted: 2025-01-17
• Study Start: 2025-05-28
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-09
• Last Update Posted: 2025-09-10
• Primary Completion: 2032-03-02
• Study Completion: 2032-03-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 144

Inclusion Criteria

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

• Histologically or cytologically confirmed diagnosis of Stage IV squamous non-small cell lung cancer (NSCLC)
• Has documented disease progression per Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1), as assessed by investigator after receiving an anti-programmed cell death protein 1 (anti-PD-1)/programmed cell death ligand 1 (PD-L1) treatment and platinum-based chemotherapy for Stage IV disease
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)
• Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load
• Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable

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
• Has uncontrolled or significant cardiovascular disorder
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc), or any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc), or prior pneumonectomy
• Participants who have adverse events (AEs) (other than alopecia) due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline
• Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection (including HIV infection)
• Has clinically significant corneal disease
• 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
• Evidence of any leptomeningeal disease
• History of (noninfectious) pneumonitis/Interstitial Lung Disease (ILD) that required steroids or has current pneumonitis/ILD, and/or suspected ILD/pneumonitis
• Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed
• Active infection requiring systemic therapy
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea)
• Known history of, or active, neurologic paraneoplastic syndrome
• History of allogeneic tissue/solid organ transplant
• Has not adequately recovered from major surgery or have ongoing surgical complications

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1: Raludotatug deruxtecan (R-DXD)	R-DXD	Participants receive 5.6 mg/kg of R-DXD, every 3 weeks (Q3W) (Day 1 of every 21-day cycle) via intravenous (IV) infusion until progressive disease (PD) or discontinuation.
Arm 2: Infinatamab deruxtecan (I-DXD) High Dose	I-DXD	Participants receive 12 mg/kg of I-DXD, Q3W (Day 1 of every 21-day cycle) via IV infusion until PD or discontinuation.
Arm 3: I-DXD Low Dose	I-DXD	Participants receive 8 mg/kg of I-DXD, Q3W (Day 1 of every 21-day cycle) via IV infusion until PD or discontinuation.
Arm 4: Docetaxel	Docetaxel	Participants receive 75 mg/m\^2 of Docetaxel, Q3W (Day 1 of every 21-day cycle) via IV infusion until PD or discontinuation.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to approximately 81 months	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) as assessed per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). ORR will be assessed by Blinded Independent Central Review (BICR). The percentage of participants who experience CR or PR as assessed by the investigator will be presented.
Number of participants who experience one or more adverse events (AEs)	Up to approximately 81 months	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 who experience an AE will be reported.
Number of participants who discontinue study intervention due to an AE	Up to approximately 81 months	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 who discontinue study treatment due to an AE will be reported.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Up to approximately 81 months	OS is defined as time from randomization to death due to any cause.
Duration of Response (DOR)	Up to approximately 81 months	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 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.
Progression-free Survival (PFS)	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.

Trial Locations

Locations (9)

University of Kentucky Chandler Medical Center ( Site 0019); 🇺🇸 Lexington, Kentucky, United States

Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 0150); 🇵🇱 Gdansk, Pomeranian Voivodeship, Poland

MedStar Franklin Square Medical Center ( Site 0033); 🇺🇸 Baltimore, Maryland, United States

Rambam Health Care Campus ( Site 0076); 🇮🇱 Haifa, Israel

Shaare Zedek Medical Center ( Site 0075); 🇮🇱 Jerusalem, Israel

Meir Medical Center ( Site 0071); 🇮🇱 Kfar Saba, Israel

Rabin Medical Center ( Site 0074); 🇮🇱 Petah Tikva, Israel

Sheba Medical Center ( Site 0070); 🇮🇱 Ramat Gan, Israel

Sourasky Medical Center ( Site 0077); 🇮🇱 Tel Aviv, Israel