Frontline sigvotatug vedotin plus pembrolizumab vs pembrolizumab for non-small cell lung cancer with PD-L1 tumor proportion score ≥50% - Phase III study design

Sep 23, 2026

Integrin beta-6 (IB6) is a tumor-associated membrane protein expressed at low levels in healthy tissues but elevated in many cancers, including non-small cell lung cancer (NSCLC), where it correlates with poor outcomes. In phase I, IB6-directed sigvotatug vedotin (SV) showed manageable safety and encouraging efficacy as monotherapy and with pembrolizumab in advanced solid tumors. The phase III Sigvie-003 study evaluates SV plus pembrolizumab versus pembrolizumab alone as first-line treatment in adult locally advanced, unresectable, or metastatic NSCLC with PD-L1 tumor proportion score ≥50%. The open-label randomized design targets progression-free survival by blinded independent central review and overall survival as dual primary endpoints.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Introduction

Background

Non-small cell lung cancer

Plain language summary

FUTURE ONCOLOGY 2025, VOL. 21, NO. 30, 3891–3901 [https://doi.org/10.1080/14796694.2025.2596228](https://doi.org/10.1080/14796694.2025.2596228) CLINICAL TRIAL PROTOCOL Frontline sigvotatug vedotin plus pembrolizumab vs pembrolizumab for non-small cell lung cancer with PD-L1 tumor proportion score ≥50%: phase III study design Martin Reck a, Shun Lub, Kenneth J. O’Byrnec, Carlos Barrios d, Dmitri Pavlove, Fabian Tay fand Marcelo V. Negrao g aAirway Research Center North, Center for Lung Research, LungenClinic, Grosshansdorf, Germany; bShanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai School of Medicine, Shanghai Jiao Tong University, Shanghai, China; cPrincess Alexandra Hospital, Translational Research Institute and Queensland University of Technology, Brisbane, QLD, Australia; dCentro de Pesquisa em Oncologia, Hospital São Lucas, Porto Alegre, Brazil; eOncology Research & Development, Pfizer, San Diego, CA, USA; fOncology Research & Development, Pfizer, Zurich, Switzerland; gDepartment of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA ABSTRACT Integrin beta-6 (IB6) is a tumor-associated membrane protein involved in many cellular processes, including wound healing and tissue remodeling. While IB6 expression is constitutively low in healthy tissues, high IB6 expression in numerous cancers, including non-small cell lung cancer (NSCLC), is associated with poor outcomes. In a phase I study, the novel IB6-directed vedotin-based antibodydrug conjugate sigvotatug vedotin (SV) showed manageable safety and encouraging efficacy asa monotherapy and in combination with pembrolizumab in patients with advanced solid tumors, including NSCLC. Based on those results, the phase III Sigvie-003 study is evaluating SV plus pembrolizumab compared with pembrolizumab monotherapy as first-line treatment in adult patients with locally advanced, unresectable, or metastatic NSCLC with high programmed cell death ligand 1 expression (tumor proportion score ≥50%) . Here, we describe the design of the Sigvie-003 study, which is an open-label, randomized, controlled phase III study. Approximately 714 patients will be randomized 1:1 . The dual primary endpoints are progression-free survival as assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; secondary endpoints include additional efficacy, safety and tolerability, pharmacokinetics, and immunogenicity endpoints. Clinical trial registration: NCT06758401 ([https://clinicaltrials.gov/study/NCT06758401](https://clinicaltrials.gov/study/NCT06758401)). PLAIN LANGUAGE SUMMARY Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Integrin beta-6 (IB6) is a protein found in small amounts on the surface of healthy cells and in larger amounts on some types of cancer cells, including NSCLC. Sigvotatug vedotin (SV) is a medicine that works by binding to IB6 and delivering a toxic substance to kill cells. Pembrolizumab is a medicine that targets and blocks a protein on the surface of immune system cells, which may help the immune system kill cancer cells. Sigvie-003 is a clinical trial investigating SV combined with pembrolizumab in participants with NSCLC that has spread beyond the lungs (advanced or metastatic disease) and has not been treated since spreading beyond the lungs. The trial is evaluating if the combination of SV and pembrolizumab increases the length of time a participant is alive after the start of treatment (overall survival) or alive without their cancer getting worse (progression-free survival) compared with pembrolizumab alone. Participants are also monitored for side effects and to see if their cancer has shrunk or disappeared. We describe the design of Sigvie-003 . ARTICLE HISTORY Received 5 November 2025 Accepted 24 November 2025 KEYWORDS Non-small cell lung cancer; sigvotatug vedoti

FAQs

What is the main purpose of the Sigvie-003 phase III trial?

To compare SV plus pembrolizumab with pembrolizumab alone as first-line treatment for adults with locally advanced, unresectable, or metastatic NSCLC with PD-L1 tumor proportion score ≥50%.

What are the dual primary endpoints in the study?

Progression-free survival assessed by blinded independent central review using RECIST v1.1, and overall survival.

How does Sigvotatug vedotin work in the trial?

SV binds to integrin beta-6 (IB6) and delivers a toxic substance to kill cancer cells.

Sep 23, 2026

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