Datopotamab Deruxtecan (Dato-DXd) and Pembrolizumab With or Without Platinum Chemotherapy in 1L Non-Small Cell Lung Cancer (TROPION-Lung07)

Inclusion Criteria:

1. Sign and date the Main Informed Consent Form (ICF), prior to the start of any study- specific qualification procedures.
2. Adults ≥18 at the time the Main ICF is signed.
3. Has tumor with PD-L1 TPS <50% as determined by PD-L1 IHC 22C3 pharmDx assay by central testing.
4. Has provided a formalin-fixed tumor tissue sample for the measurement of TROP2 protein expression and for the assessment of other exploratory biomarkers.
5. Has not been treated with systemic anticancer therapy for advanced or metastatic non-squamous NSCLC.
6. Has measurable disease based on local imaging assessment using RECIST v1.1.
7. 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).
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.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening.
5. Has an adequate treatment washout period before Cycle 1 Day 1.
6. Is willing and able to participate in the collection of patient-reported outcomes (PRO) data.

Exclusion Criteria:

1. Has received prior systemic treatment for advanced/metastatic NSCLC.
2. Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant (for NSCLC) 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.
5. 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.
6. Has spinal cord compression or clinically active untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.
7. 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.
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 within 28 days before randomization.
7. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses.
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
9. 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.
5. Has a history of severe hypersensitivity reactions to either the drugs or inactive ingredients of Dato-DXd, pembrolizumab, carboplatin, cisplatin or pemetrexed.
6. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
7. Has known human immunodeficiency virus (HIV) infection that is not well controlled.
8. Has active or uncontrolled hepatitis B or C infection.
9. Female who is pregnant or breastfeeding or intends to become pregnant.
10. Any other medical conditions, including cardiac disease or psychological disorders, and/or substance abuse.
11. 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.
12. Has active, known, or suspected autoimmune disease.
13. Has clinically significant corneal disease.
14. Has had an allogeneic tissue/solid organ transplantation.
15. 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.