Background: Immunotherapies targetingprogrammed cell death-1 (PD-1) and its ligand PD-L1 have transformed 1L mNSCLC. However, in a subset of patients (pts) with PD-L1-low or PD-L1-negative disease (i.e. PD-L1 TC expression <50% or <1%, respectively), anti-PD-(L)1 therapies, with or without CT, are associated with shorter overall survival (OS) than in pts with PD-L1-high disease. Dual inhibition of PD-1 and CTLA-4 is often undertaken in PD-L1-low, and especially PD-L1-negative, mNSCLC to address the poorer prognosis in these pts. Although combination therapy using lower doses of CTLA-4 inhibitors has shown benefit in this setting, toxicity at higher doses has limited the clinical utility of this approach. Volrustomig (MEDI5752) is a monovalent, PD-1/CTLA-4 bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1, with increased CTLA-4 blockade on PD-1+ activated T cells compared to PD-1– resting peripheral T cells. This mode of action may facilitate enhanced CTLA-4 inhibition at tolerable doses beyond those achievable with current PD-1/CTLA-4 combinations. Data from the first-in-human phase 1/2 study (NCT03530397) showed encouraging antitumor activity and acceptable tolerability with 1L volrustomig plus carboplatin/pemetrexed (CP) in NSCLC, particularly in pts with PD-L1 TC <1%. The phase 3, two-arm, parallel-group, randomized, multicenter, open-label eVOLVE-Lung02 study (NCT05984277) is designed to evaluate the efficacy of 1L volrustomig plus CT versus pembrolizumab plus CT in mNSCLC pts with PD-L1 TC <50%. Methods: Eligibility criteria include age ≥18 years; ECOG performance status 0 or 1; histologically or cytologically documented squamous (sq) or non-squamous (non-sq) stage IV NSCLC with PD-L1 TC expression <50%; wild-type EGFR, ALK, or ROS1; and no prior systemic therapy for mNSCLC. Approximately 900 pts will be randomized 1:1 to receive histology-specific CT (sq, paclitaxel plus carboplatin; non-sq, CP with pemetrexed maintenance at investigator discretion) in combination with either volrustomig or pembrolizumab (200 mg) every 3 weeks (Q3W) for 4 cycles; after this volrustomig or pembrolizumab will be administered Q3W until completion of 24 months of treatment or disease progression, or other discontinuation criteria are met. Randomization will be stratified according to histology (sq vs non-sq), PD-L1 (<1% vs 1–49%), smoking (never vs former/current), and region (Asia vs rest of world). Primary endpoints are progression-free survival (PFS) per RECIST v1.1 and OS in the PD-L1 TC <1% population. Secondary endpoints include PFS and OS in all randomized pts (PD-L1 TC <50%), overall response rate, duration of response, PFS2, safety and tolerability, patient-reported outcomes, pharmacokinetics, and immunogenicity. Enrollment is ongoing. Clinical trial information: NCT05984277.