A global, multicenter, randomized, open-label, active-controlled Phase 3 study

• Approximately 740 eligible subjects will be randomized in a 1:1 ratio as indicated below:
  Arm 1: 200 mg pembrolizumab, followed by Dato-DXd (6.0 mg/kg), each administered on Day 1 of every 21-day cycle
  Arm 2: 200 mg pembrolizumab, administered on Day 1 of every 21-day cycle
  Randomization will be stratified by Eastern Cooperative Oncology Group performance status (ECOG PS) (0 vs 1), histology (squamous vs non-squamous), geographical region (East Asia vs rest of world [ROW]) and smoking status former/current vs never).
  No crossover between the 2 study treatment arms is permitted

PFS and OS

• Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemo radiation, or Stage IV NSCLC disease at the time of randomization
• Documented negative test results for EGFR, ALK, and ROS1 actionable genomic alterations 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.
• No known actionable genomic alterations in NTRK, BRAF, RET, MET, or other actionable driver kinases with locally approved therapies. (Testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to enrollment). Subjects with squamous NSCLC are only required to undergo EGFR, ALK, and ROS1 testing if they have no history of tobacco smoking or were diagnosed with NSCLC at <40 years of age.
• Subjects whose tumors harbor KRAS mutations are eligible for the study.
• Tumor has high PD-L1 expression (TPS ≥50%) as determined by PD-L1 IHC 22C3 pharmDx assay by central testing (minimum of 6 slides).
• Has provided a formalin-fixed tumor tissue sample (minimum of 10 [preferably 15] × 4-micron sections or block equivalent) for the measurement of TROP2 protein expression and for the assessment of other exploratory biomarkers. - Has left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO)or multigated acquisition scan (MUGA) within 28 days before randomization.
• ECOG PS of 0 or 1 at screening

• Has received prior systemic treatment for advanced/metastatic NSCLC
• Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant setting:
• Any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I
• TROP2-targeted therapy
• Any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137)
• Any other ICIs
• Subjects 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 or metastatic disease
• Has spinal cord compression or active and untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 2 weeks by repeat imaging (note: repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 7 days before the first dose of study drug.
  • A computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the brain at baseline (MRI preferred) is required for all subjects
• Has received prior radiotherapy ≤4 weeks of start of study intervention or more than 30Gy to the lung within 6 months of Cycle 1 Day 1
• 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 and who in the opinion of the Investigator are not deemed to require active intervention
• 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 and who in the opinion of the Investigator are not deemed to require active intervention.
• Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) within 28 days before randomization.
• Significant corneal disease.
• Had an allogeneic tissue/solid organ transplant