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Two antibody-drug conjugates for people with previously treated metastatic nonsquamous non-small cell lung cancer

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)

PHASE2 · Merck Sharp & Dohme LLC · NCT06780085

This trial tests whether two antibody-drug conjugates can help people with metastatic nonsquamous non-small cell lung cancer whose disease progressed after PD-1/PD-L1 immunotherapy and platinum chemotherapy.

Quick facts

PhasePHASE2
Study typeInterventional
Enrollment96 (estimated)
Ages18 Years and up
SexAll
SponsorMerck Sharp & Dohme LLC (industry)
Drugs / interventionschemotherapy, radiation, immunotherapy
Locations33 sites (Lexington, Kentucky and 32 other locations)
Trial IDNCT06780085 on ClinicalTrials.gov

What this trial studies

This is a phase 2, randomized comparison within a master screening protocol that enrolls adults with Stage IV nonsquamous NSCLC who progressed after prior PD-1/PD-L1 therapy and platinum-based chemotherapy. Participants must have measurable disease by RECIST 1.1, ECOG performance status 0–1, and no actionable driver mutation such as EGFR, ALK, or ROS1. The trial assigns participants to receive one of two investigational antibody-drug conjugates (ADCs) and includes standard supportive medications as needed; tumor response and safety will be measured during treatment. The protocol is sponsored by Merck in collaboration with Daiichi Sankyo and is open at several U.S. cancer centers.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed Stage IV nonsquamous NSCLC, measurable disease, prior progression after PD-1/PD-L1 therapy plus platinum chemotherapy, EGFR/ALK/ROS1-negative status, ECOG 0–1, and at least a 3-month life expectancy.

Not a fit: People with squamous histology, untreated disease, actionable driver mutations (EGFR/ALK/ROS1) indicating other targeted therapy, ECOG ≥2, or very limited life expectancy are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, these ADCs could shrink tumors or control disease in people whose cancer no longer responds to standard immunotherapy and chemotherapy.

How similar studies have performed: Other ADCs have produced tumor responses in subsets of lung cancer patients, so the approach has clinical precedent, though these specific agents remain under 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 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

Where this trial is running

Lexington, Kentucky and 32 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: Carcinoma, Non-Small-Cell Lung, Programmed Cell Death-1, Programmed Death-Ligand 1, Programmed Cell Death 1 Ligand 2

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.