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Combining Dato-DXd with Pembrolizumab for Advanced Lung Cancer Treatment

A Randomized, Open-label, Phase 3 Trial of Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone in Treatment-naïve Subjects With Advanced or Metastatic PD-L1 High (TPS ≥50%) Non-small Cell Lung Cancer Without Actionable Genomic Alterations (TROPION-Lung08)

PHASE3 · Daiichi Sankyo · NCT05215340

This study is testing if combining a new lung cancer drug with an existing treatment can help people with advanced lung cancer live longer and feel better compared to using the existing treatment alone.

Quick facts

PhasePHASE3
Study typeInterventional
Enrollment740 (estimated)
Ages18 Years and up
SexAll
SponsorDaiichi Sankyo (industry)
Drugs / interventionspembrolizumab, radiation, prednisone, datopotamab
Locations243 sites (Chandler, Arizona and 242 other locations)
Trial IDNCT05215340 on ClinicalTrials.gov

What this trial studies

This study evaluates the effectiveness and safety of datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab compared to pembrolizumab alone in patients with advanced or metastatic non-small cell lung cancer (NSCLC) that does not have actionable genomic alterations. Participants will be randomized to receive either the combination treatment or pembrolizumab alone, focusing on those with high PD-L1 expression. The study aims to measure progression-free survival and overall survival as primary outcomes. It includes a structured approach with distinct periods for tissue screening, treatment, and follow-up.

Who should consider this trial

Good fit: Ideal candidates are adults with advanced or metastatic non-squamous NSCLC who have high PD-L1 expression and have not received prior systemic therapy.

Not a fit: Patients with squamous histology or those who have previously received systemic therapy for advanced NSCLC may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a more effective first-line therapy option for patients with advanced NSCLC.

How similar studies have performed: Other studies have shown promising results with similar immunotherapy combinations, indicating potential for success in this approach.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

Participants eligible for inclusion in the study must meet all inclusion criteria within 28 days of randomization into the study.

* Sign and date the Tissue Screening and Main Informed Consent Forms, prior to the start of any study-specific qualification procedures.
* Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time of informed consent.
* Histologically documented non-squamous NSCLC that meets all of the following criteria (Note: Subjects with squamous histology were eligible prior to Protocol Version 5.0. After Protocol Version 5.0, subjects with squamous histology are not eligible. Subjects with mixed histology, including those with a squamous component, remain eligible the study even after Protocol Version 5.0):

  1. Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition). Participants with early-stage NSCLC who have relapsed should be restaged during screening to ensure their eligibility for the study.
  2. Documented negative test results for epidermal growth factor receptor (EGFR), lymphoma kinase (ALK), and proto-oncogene1 (ROS1) actionable genomic alterations (AGAs) based on analysis of tumor tissue. If test results for EGFR, ALK, and ROS1 are not available, subjects are required to undergo testing performed locally for these genomic alterations.
  3. No known AGAs in neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF), rearranged during transfection (RET), mesenchymal-epithelial transition factor (MET), or other actionable driver kinases with locally approved therapies. (Testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to randomization). Subjects whose tumors harbor KRAS mutations are eligible for the study.
* Has provided a formalin-fixed tumor tissue sample for the measurement of trophoblast cell surface protein 2 (TROP2) protein expression and for the assessment of other exploratory biomarkers.
* Tumor has high programmed death receptor-1 (PD-L1) expression (TPS ≥50%) as determined by PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay by central testing (minimum of 6 slides).
* Has an adequate treatment washout period before Cycle 1 Day 1.
* Measurable disease based on local imaging assessment using RECIST Version 1.1.
* Has left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before randomization.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening.
* Has a life expectancy of at least 3 months.
* Adequate bone marrow function within 7 days before randomization.

Exclusion Criteria:

* Has received prior systemic treatment for advanced or metastatic NSCLC.
* Has received prior treatment for NSCLC with any of the following, including in the adjuvant/neoadjuvant setting:

  1. Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I.
  2. TROP2-targeted therapy.
  3. Any anti-programmed death receptor-1 (PD-1), anti-PD-L1, or anti-PD-ligand 2 (L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).
  4. Any other immune checkpoint inhibitors. Participants who received adjuvant or neoadjuvant therapy OTHER than those listed above, are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced/metastatic disease.
* Has spinal cord compression or active and untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases and who are asymptomatic may participate provided they are radiologically stable.
* Has received prior radiotherapy \< 4 weeks of start of study intervention or more than 30 Gy (unit of ionizing radiation dose in the International System of Units) to the lung within 6 months of Cycle 1 Day 1.
* History of another primary malignancy (beyond NSCLC) except for:

  1. Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study treatment and of low potential risk for recurrence.
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  3. Adequately treated carcinoma in situ without evidence of disease.
  4. Participants with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤T2cN0M0 without biochemical recurrence or progression and who in the opinion of the Investigator are not deemed to require active intervention.
* Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
* Clinically severe pulmonary compromise, as judged by the investigator, resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder, or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement or prior complete pneumonectomy.
* Uncontrolled or significant cardiovascular disease, including:

  1. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval \>470 ms regardless of sex (based on the average of the 12-lead electrocardiogram determination at screening).
  2. Myocardial infarction within 6 months prior to randomization.
  3. Uncontrolled angina pectoris within 6 months prior to randomization.
  4. LVEF \<50% by ECHO or MUGA scan within 28 days before randomization.
  5. New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening.
  6. Uncontrolled hypertension (resting systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg) within 28 days before randomization.

Participants with a history of Class 2 to 4 CHF prior to screening, must have returned to Class 1 CHF and have LVEF ≥50% (by either an ECHO or MUGA scan within 28 days before randomization) in order to be eligible.

* Clinically significant corneal disease.
* Has received a live vaccine or live-attenuated vaccine (messenger ribonucleic acid and replication-incompetent adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study drug. For any participant receiving an approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine, please follow the vaccine label and/or local guidance.
* Active, known, or suspected autoimmune disease (has an active autoimmune disease that has required systemic treatment in the past 2 years).
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosage \>10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy ≤7 days prior to the first dose of study drug.
* Has known human immunodeficiency virus (HIV) infection that is not well controlled.
* Has an active hepatitis or uncontrolled hepatitis B or active hepatitis C infection.
* Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
* Had an allogeneic tissue/solid organ transplant.
* Has a history of severe hypersensitivity reactions to either the drug or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or pembrolizumab.

Where this trial is running

Chandler, Arizona and 242 other locations

+193 more sites — see ClinicalTrials.gov for the full list.

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: Metastatic Non Small Cell Lung Cancer, Advanced Non Small Cell Lung Cancer, Datopotamab Deruxtecan, Pembrolizumab

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.