Background: Current standard of care immunotherapy plus chemotherapy options for first-line extensive-stage small-cell lung cancer (ES-SCLC) are associated with modest improvements in median OS and PFS. In the KEYNOTE-604 study, first-line pembrolizumab plus etoposide/platinum (EP) significantly improved PFS (HR 0.75; 95% CI, 0.61‒0.91; P = 0.0023) compared with placebo plus EP in ES-SCLC; OS was also longer with pembrolizumab plus EP vs placebo plus EP but did not reach statistical significance (HR 0.80; 95% CI, 0.64‒0.98; P = 0.0164). Preclinical and clinical data suggest that blocking the interaction between the T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) and its ligands CD112 and CD155 with the anti-TIGIT humanized monoclonal antibody vibostolimab (MK-7684) yields promising antitumor activity when combined with pembrolizumab, with or without chemotherapy, including in patients with lung cancer. The current phase 3 study, KeyVibe-008 (NCT05224141), is comparing the efficacy and safety of first-line treatment with MK-7684A, a co-formulation of vibostolimab plus pembrolizumab, in combination with EP vs atezolizumab plus EP in patients with ES-SCLC. Methods: This multicenter, randomized, double-blind, phase 3 study is enrolling patients aged ≥18 years with histologically or cytologically confirmed, previously untreated ES-SCLC. Patients must have measurable disease per RECIST v1.1; ECOG PS of 0 or 1; no active CNS metastases/carcinomatous meningitis, autoimmune disease, neurologic paraneoplastic syndromes, pneumonitis, or interstitial lung disease; and must provide a pretreatment tumor sample. Patients are randomized 1:1 to receive up to 4 cycles of EP (cisplatin or carboplatin) in combination with MK-7684A (vibostolimab 200 mg + pembrolizumab 200 mg) Q3W or atezolizumab (1200 mg) Q3W, followed by MK-7684A or atezolizumab, respectively, until disease progression, unacceptable AEs, intercurrent illness, protocol violation, or investigator/patient decision. Randomization is stratified by ECOG PS (0 vs 1), LDH (≤ULN vs > ULN), liver metastases (yes vs no), and brain metastases (yes vs no). The primary endpoint is OS. Secondary endpoints include PFS, ORR, and duration of response per RECIST v1.1 by blinded independent central review; safety; and patient-reported outcomes (PROs). Tumor imaging occurs at baseline, every 6 weeks until 48 weeks, and every 9 weeks thereafter until disease progression, start of new anticancer treatment, withdrawal of consent, or death. PROs are assessed using validated instruments including the EORTC quality of life and EuroQol questionnaires. AEs are graded according to NCI CTCAE v5.0. Enrollment is ongoing worldwide. Clinical trial information: NCT05224141.