TROPION-Lung08: Targeted therapy alone, and in combination with a standard immunotherapy (Pembrolizumab), in people with advanced non-small cell lung cancer who have not received previous treatmentA Randomized, Open-label, Phase 3 Trial of Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone in Treatment-naive Subjects With Advanced or Metastatic PD-L1 High (TPS less than or equal to 50%) Non-small Cell Lung Cancer Without Actionable Genomic Alterations (TROPION-Lung08)

Exclusion

• 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.