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Investigational antibody–drug conjugates for previously treated stage IV squamous non-small cell lung cancer

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

PHASE2 · Merck Sharp & Dohme LLC · NCT06780098

This trial tests whether antibody–drug conjugates can shrink or control metastatic squamous non-small cell lung cancer in people whose cancer progressed after immunotherapy and platinum chemotherapy.

Quick facts

PhasePHASE2
Study typeInterventional
Enrollment144 (estimated)
Ages18 Years and up
SexAll
SponsorMerck Sharp & Dohme LLC (industry)
Drugs / interventionschemotherapy, radiation, pembrolizumab, immunotherapy
Locations40 sites (Lexington, Kentucky and 39 other locations)
Trial IDNCT06780098 on ClinicalTrials.gov

What this trial studies

This Phase 2 substudy within the KEYMAKER-U01 master protocol is testing ADC agents (including R‑DXD and I‑DXD) in participants with stage IV squamous NSCLC who progressed after anti–PD‑1/PD‑L1 therapy and platinum‑based chemotherapy. Participants receive investigational ADCs with standard supportive/rescue medications, and responses are measured by RECIST 1.1 criteria. The trial enrolls at select U.S. cancer centers and is sponsored by Merck in collaboration with Daiichi Sankyo. Safety and anti‑tumor activity (tumor shrinkage and duration of response) are the primary focuses of the substudy.

Who should consider this trial

Good fit: Ideal candidates are adults with histologically confirmed stage IV squamous NSCLC who have documented progression after anti‑PD‑1/PD‑L1 therapy plus platinum chemotherapy and meet infection control criteria (e.g., controlled HIV, treated HBV/HCV as specified).

Not a fit: Patients with non‑squamous lung cancer histology, those who have not received prior anti‑PD‑1/PD‑L1 and platinum therapy, or those with uncontrolled comorbid infections or severe organ dysfunction are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, these antibody–drug conjugates could provide a new treatment option that shrinks tumors or extends disease control for patients who no longer respond to current immunotherapy and chemotherapy.

How similar studies have performed: Antibody–drug conjugates have shown promising activity in other lung cancer subtypes and solid tumors in early‑phase trials, but their use specifically in previously treated squamous NSCLC remains under active study.

Eligibility criteria

Show full inclusion / exclusion criteria 
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
* Has clinically significant corneal disease
* Has previously received docetaxel as monotherapy or in combination with other therapies
* 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
* Has one or more of the following indicators of interstitial lung disease (ILD)/pneumonitis: any history of ILD/pneumonitis irrespective of steroid use (except for a history of radiation pneumonitis that did not require steroids), current diagnosis of ILD, clinical or radiographic suspicion of ILD
* 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

Where this trial is running

Lexington, Kentucky and 39 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.

View on ClinicalTrials.gov →

Conditions: Lung Neoplasm

Last reviewed 2026-05-15 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.