Background: Most patients (pts) with advanced NSCLC do not harbor genomic alterations associated with approved first-line targeted therapies. The standard of care for these pts is a programmed death (ligand)-1 (PD-[L]1) inhibitor alone, if the tumor highly expresses PD-L1, or in combination with platinum doublet chemotherapy, independent of PD-L1 expression. However, most pts do not respond to these therapies or achieve only a transient response, highlighting an unmet need. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. In the phase 1/2 IMMU-132-01 basket study (NCT01631552), SG demonstrated an objective response rate (ORR) of 17% and median overall survival (OS) of 9.5 mo, with a manageable safety profile in 54 pts with metastatic NSCLC after multiple prior therapies (Heist RS, et al. J Clin Oncol. 2017). We hypothesize that combining SG with pembro or with pembro + platinum chemotherapy will improve outcomes for pts with advanced NSCLC. Methods: EVOKE-02 (NCT05186974) is an open-label, multicenter, multicohort, global phase 2 study evaluating SG plus pembro with or without carboplatin (carbo) or cisplatin (cis) in advanced NSCLC. Key eligibility criteria include age ≥18 y, stage IV NSCLC at enrollment, measurable disease by RECIST v1.1, ECOG performance status of 0 or 1, and adequate organ function. Pts must not have actionable genomic alterations and must not have received prior systemic therapy for metastatic NSCLC. Up to 164 pts will be enrolled. SG plus pembro will be assessed in squamous/nonsquamous NSCLC with Tumor Proportion Score (TPS) ≥50% (cohort A, ̃30 pts) and TPS < 50% (cohort B, ̃30 pts), and SG plus pembro with carbo/cis in nonsquamous (cohort C, ̃40 pts) and squamous (cohort D, ̃40 pts) NSCLC regardless of PD-L1 expression. Pts are randomly assigned if cohorts enrolling concurrently have overlapping eligibility. SG will be administered intravenously (IV) at 10 mg/kg on d 1 and 8 until disease progression or unacceptable toxicity, pembro 200 mg IV on d 1 for up to 35 cycles, carbo AUC 5 or cis 75 mg/m² on d 1 for up to 4 cycles in 21-d cycles. A safety run-in will be conducted for cohorts C and D (up to 24 pts each) to determine the optimal SG dose by dose de-escalation. Choice of platinum will be based on preliminary efficacy in safety run-in. The primary endpoints are ORR assessed by independent review per RECIST v1.1 and the incidence of dose-limiting toxicities per dose for the first 21 d of the safety run-in to determine the recommended phase 2 dose of SG in combination with pembro and a platinum. Key secondary endpoints include progression-free survival by independent review, OS, duration of response, disease control rate, and safety. This study is open for recruitment and is enrolling globally. Clinical trial information: NCT05186974.