Inclusion Criteria:

          -  Advanced or metastatic NSCLC, histologically confirmed at diagnosis of NSCLC,
             documented negative test results for EGFR and ALK genomic alterations, and no known
             genomic alterations in ROS1, NTRK, BRAF, RET, MET, or other driver oncogenes with
             approved therapies (actionable genomic alterations).

          -  Documentation of radiological disease progression while on or after receiving the most
             recent treatment regimen, if any, for advanced or metastatic NSCLC.

          -  Must meet the following prior therapy requirements for advanced or metastatic NSCLC:

               -  Dose escalation (all cohorts): Has received ≤2 lines of prior anticancer therapy
                  for locally advanced or metastatic NSCLC.

               -  Dose expansion (cohorts with 4.0 mg/kg or 6.0 mg/kg Dato-DXd in combination with
                  200 mg fixed dose of pembrolizumab): Has not received PD-1/PD-L1, PD-L2, CTLA-4
                  directed immunotherapy and may or may not have been treated with systemic
                  chemotherapy for advanced or metastatic NSCLC.

               -  Dose expansion (cohorts with 4.0 mg/kg or 6.0 mg/kg Dato-DXd in combination with
                  200 mg fixed dose of pembrolizumab and 4 cycles of AUC 5 carboplatin or cisplatin
                  75 mg/m^2): Has not been treated with systemic anticancer therapy for advanced or
                  metastatic NSCLC.

          -  Willing and able to undergo a mandatory tumor biopsy.

          -  Archival tumor tissue from initial diagnosis, to the extent that archival tumor tissue
             is available, for measurement of TROP2 expression levels or other biomarkers.

          -  Has adequate bone marrow reserve and organ function at baseline within 7 days prior to
             Cycle 1 Day 1

        Exclusion Criteria:

          -  Experienced grade 3 or higher immune-related adverse events (AEs) with prior treatment
             of anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 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, OX 40, CD137).

          -  Received a live vaccine within 30 days prior to the first dose of study treatment.

          -  Active, known, or suspected autoimmune disease.

          -  Concomitant use of chronic systemic (IV or oral) corticosteroids or other
             immunosuppressive medications, except for managing AEs.

          -  Prior organ transplantation, including allogeneic tissue or solid organ
             transplantation.

          -  Has spinal cord compression or clinically active central nervous system metastases,
             defined as untreated and symptomatic, or requiring therapy with corticosteroids or
             anticonvulsants to control associated symptoms.

          -  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.

          -  Clinically severe pulmonary compromise resulting from intercurrent pulmonary
             illnesses.

          -  Has a history of malignancy, other than NSCLC, except (a) adequately resected
             non-melanoma skin cancer, (b) curatively treated in situ disease, or (c) other solid
             tumors curatively treated, with no evidence of disease for ≥3 years.