SigVie-003: Phase 3 trial of frontline sigvotatug vedotin plus pembrolizumab vs pembrolizumab alone in non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥50%.

Abstract

TPS8660 Background: Integrin beta-6 (IB6) is a tumor-associated membrane protein linked to poor outcomes in solid tumors, including NSCLC, where it is expressed in >90% of cases. Sigvotatug vedotin (SV), a novel, IB6-directed, vedotin-based, antibody-drug conjugate, has shown manageable safety and encouraging antitumor activity as monotherapy in advanced NSCLC in the phase 1 SGNB6A-001 study (Peters, ASCO 2024). Based on preclinical studies, SV may induce immunogenic cell death and enhance antitumor activity when used in conjunction with pembrolizumab, a PD-1 inhibitor. Therefore, SV plus pembrolizumab is also being evaluated in the SGNB6A-001 study. Initial results of the combination demonstrated promising antitumor activity with a manageable safety profile in advanced NSCLC (Sehgal, ASCO 2025). Based on these results, SV plus pembrolizumab is being investigated in the phase 3 SigVie-003 study. Methods: SigVie-003 (NCT06758401) is an open-label, randomized, controlled study evaluating the efficacy of SV plus pembrolizumab vs pembrolizumab monotherapy as first-line treatment in adults with locally advanced, unresectable, or metastatic NSCLC with high PD-L1 expression (tumor proportion score ≥50%). Patients (pts) with nonsquamous histology must have negative documentation for EGFR , ALK , and ROS1 mutations and no known actionable genomic alterations with approved first-line treatments per local standard of care. Pts must have an ECOG PS of 0 or 1 and have adequate organ function. Pts with stable, definitively treated, or inactive brain metastases <0.5 cm are eligible. Approximately 714 pts will be randomized at a 1:1 ratio to receive either SV 1.8 mg/kg AiBW (adjusted ideal body weight) intravenously on days 1, 15, and 29 plus pembrolizumab 400 mg intravenously on day 1 of a 42-day cycle (Q6W) or pembrolizumab 400 mg monotherapy Q6W. Randomization will be stratified by histology (nonsquamous vs squamous), ECOG PS (0 vs 1), region (East Asia vs rest of world), and presence or absence of brain metastases. Dual primary endpoints are overall survival and progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1. Secondary endpoints include PFS by investigator per RECIST 1.1, confirmed objective response rate and duration of response by both BICR and investigator per RECIST 1.1, safety, and pharmacokinetics and immunogenicity of SV when combined with pembrolizumab. Enrollment began Jul 23, 2025. A genAI tool (2/27/25; Pfizer; GPT-4o) developed the 1st draft; authors assume content responsibility. Frontline sigvotatug vedotin plus pembrolizumab vs pembrolizumab for non-small cell lung cancer with PD-L1 tumor proportion score ≥50%: phase III study design, Reck M, et al., Future Oncol , Dec 13, 2025, Taylor & Francis, reprinted by permission of the publisher Informa UK Limited trading as Taylor & Francis Ltd. Clinical trial information: NCT06758401 .