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) (Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone in the First-line Treatment of Subjects with Advanced or Metastatic NSCLC Without Actionable Genomic Alterations)

This study is designed to assess the efficacy and safety of datopotamab deruxtecan (Dato-DXd)
in combination with pembrolizumab versus pembrolizumab alone in participants with advanced or
metastatic non-small cell lung cancer (NSCLC).

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 NSCLC that meets all of the following criteria:

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
based on analysis of tumor tissue.

3. No known actionable genomic alterations 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.

- 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 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 msec 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.