TROPION-Lung07: This study is designed to assess how safe and effective targeted therapy (called Dato-DXd) is when given in combination with immunotherapy, compared to immunotherapy in combination with chemotherapy, in people with non-small cell lung cancerA Randomized Phase 3 Study of Datopotamab Deruxtecan (Dato-DXd) and Pembrolizumab With or Without Platinum Chemotherapy in Subjects With No Prior Therapy for Advanced or Metastatic PD-L1 TPS <50% Non-squamous Non-small Cell Lung Cancer Without Actionable Genomic Alterations

Exclusion

• Has received prior systemic treatment for advanced/metastatic NSCLC.

• Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant (for NSCLC) setting:

  • Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I.
  • TROP2-targeted therapy.
  • 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).
  • Any other immune checkpoint inhibitors.
• Has received a live vaccine or live-attenuated vaccine 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.
• Has spinal cord compression or clinically active untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.

• Uncontrolled or significant cardiovascular disease, including:

  • Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >470 msec regardless of sex.
  • Myocardial infarction within 6 months prior to randomization.
  • Uncontrolled angina pectoris within 6 months prior to randomization.
  • LVEF <50% by ECHO or MUGA scan within 28 days before randomization.
  • New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening.
  • Uncontrolled hypertension within 28 days before randomization.
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.

• History of another primary malignancy (beyond NSCLC) except for:

  • 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.
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  • Adequately treated carcinoma in situ without evidence of disease.
  • Participants with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤T2cN0M0 without biochemical recurrence or progression.
• Has a history of severe hypersensitivity reactions to either the drugs or inactive ingredients of Dato-DXd, pembrolizumab, carboplatin, cisplatin or pemetrexed.
• Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
• Has known human immunodeficiency virus (HIV) infection that is not well controlled.
• Has active or uncontrolled hepatitis B or C infection.
• Female who is pregnant or breastfeeding or intends to become pregnant.
• Any other medical conditions, including cardiac disease or psychological disorders, and/or substance abuse.
• Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Has active, known, or suspected autoimmune disease.
• Has clinically significant corneal disease.
• Has had an allogeneic tissue/solid organ transplantation.
• Has received prior radiotherapy ≤4 weeks of start of study intervention or more than 30 Gy to the lung within 6 months of Cycle 1 Day 1.