Background: Single-agent chemotherapy, such as docetaxel, is the standard of care in patients with metastatic NSCLC who progressed on platinum-based therapy and checkpoint inhibitors. However, docetaxel is associated with poor survival (median overall survival [OS] of < 1 year); thus, novel agents are needed to further improve outcomes in this setting. 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 a single-arm expansion of the phase 1/2 IMMU-132-01 basket study of advanced epithelial cancers (NCT01631552), SG demonstrated an objective response rate (ORR) of 17% and median OS of 9.5 months, with a manageable safety profile in 54 patients with metastatic NSCLC who had multiple prior therapies (Heist RS, et al. J Clin Oncol. 2017). EVOKE-01 randomized phase 3 study was designed to further evaluate SG in patients with metastatic NSCLC. Methods: EVOKE-01 (NCT05089734) is an open-label, global, multicenter, randomized, phase 3 study comparing the efficacy and safety of SG vs docetaxel in patients with metastatic NSCLC. Key eligibility criteria include age ≥18 years, pathologically documented stage IV NSCLC at time of study entry, and progression after platinum-based chemotherapy and anti-PD(L)1 therapy given either in combination or sequentially. Patients with EGFR, ALK, or other known actionable genomic alterations must have also received treatment with ≥1 approved appropriate TKI. Other inclusion criteria are ECOG performance status 0-1 and adequate hematologic, hepatic, and renal function. Patients with prior treatment with topoisomerase inhibitors are excluded. Patients are randomized 1:1 to receive intravenous SG (10 mg/kg on day 1 and 8) or docetaxel (75 mg/m² on day 1) in 21-day cycles until progressive disease or unacceptable toxicity. Stratification is based on predominant histology (squamous vs nonsquamous), best response to prior immune therapy (PD/SD vs CR/PR), and prior therapy for actionable genomic alteration (yes vs no). The primary endpoint is OS. Key secondary endpoints include progression-free survival, ORR, duration of response, and disease control rate, as assessed by investigator RECIST v1.1, mean change from baseline in NSCLC-SAQ total score and shortness of breath, and safety. This study plans to enroll ̃520 patients globally and is open for recruitment. Clinical trial information: NCT05089734.