Background: First-line treatment with immunotherapy has significantly improved survival in patients with adv/met NSCLC. Pembrolizumab (pembro) as monotherapy has shown superior efficacy compared with chemotherapy in treatment-naive patients with advanced NSCLC and PD-L1 expression ≥50%, but most patients will ultimately experience progression. Dato-DXd is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. In the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385; DS1062-A-J101), Dato-DXd 6 mg/kg monotherapy demonstrated an objective response rate (ORR) of 28% and a manageable safety profile in pretreated patients with NSCLC. In addition, preclinical studies showed that DXd ADCs combined with an anti–PD-1 antibody was more effective than monotherapy with either agent alone. The tolerability of Dato-DXd 6 mg/kg in combination with pembrolizumab was confirmed in the phase 1b TROPION-Lung02 trial (NCT04526691; DS1062-A-U102). Here we describe the phase 3 TROPION-Lung08 trial evaluating Dato-DXd combined with pembro in treatment-naive patients with adv/met NSCLC. Methods: TROPION-Lung08 (NCT05215340; DS1062-A-U304) is a global, randomized, open-label, phase 3 trial of Dato-DXd plus pembro vs pembro alone in treatment-naive patients with adv/met non-actionable oncogenic driven NSCLC with PD-L1 ≥50% (as determined by PD-L1 IHC 22C3 pharmDx assay). Approximately 740 patients will be randomized to receive pembro 200 mg plus Dato-DXd 6 mg/kg or pembro 200 mg alone every 21 days until discontinuation or 35 cycles of pembro. Randomization will be stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), histology (squamous vs nonsquamous), geographic region (East Asia vs rest of world), and smoking status (former/current vs never). Patients must have stage IIIB/IIIC NSCLC ineligible for curative treatment or stage IV disease. Patients must not have received prior systemic therapy; if patients received neoadjuvant/adjuvant systemic therapy without immune checkpoint inhibitors, it must have been given ≥6 months before the diagnosis of adv/met disease. The primary endpoints are progression-free survival (assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) and overall survival, with target hazard ratios of 0.65 and 0.75, respectively. Secondary endpoints include ORR, duration of response, time to response, disease control rate, safety, and antidrug antibody prevalence. Pharmacokinetic parameters, biomarkers, and patient-reported outcomes will also be explored. Clinical trial information: NCT05215340.