Inclusion Criteria:

* Histologically confirmed at diagnosis of NSCLC that:

* Is advanced or metastatic.
* Participants with non-squamous histology must have documented negative test results for actionable EGFR and ALK genomic alterations. Participants with squamous histology are required to undergo testing for EGFR and ALK genomic alterations if they are nonsmokers or under the age of 40 years.
* Has either documented negative or unknown test results for actionable genomic alterations in ROS1, NTRK, BRAF, RET, MET, or other actionable oncogenic driver kinases.
* Participants with tumors that harbor KRAS mutations are eligible for this study.
* Participants with non-actionable genomic alterations in EGFR, ALK, ROS1, NTRK, BRAF, RET, MET, or other kinases are eligible for the study.
* 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.
* Is not a candidate for surgical resection or chemoradiation with curative intent.

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

* Malignancy treated with curative intent and with no known active disease for ≥3 years.
* 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.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/11/2024. Questions regarding updates should be directed to the study team contact.