Phase 3 trial launches for novel antibody targeting integrin beta-6 in advanced lung cancer

Integrins, a large family of transmembrane receptors, are emerging as potential biomarkers. Integrins facilitate bidirectional communication between the extracellular matrix, which regulates cell functions, and the cytoskeleton, which is a network of protein fibers. This pathway plays a crucial role in gene expression.

Specifically, integrin beta-6 (IB6) is a protein that is overexpressed in some types of cancer cells, including non-small cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. About 87% of lung cancer cases are NSCLC, which may not cause symptoms and is often diagnosed after it has metastasized, according to the American Cancer Society.

High levels of IB6 are often found in NSCLC, making it a good target for treatment. A preclinical study found that in lung cancer, IB6 was correlated with interleukin-8 levels and promoted cancer cell growth through a specific signaling pathway, IL-8 MAPK/ERK signaling.

A phase 3 trial has recently begun recruiting patients with advanced or metastatic NSCLC to study the safety and efficacy of a novel monoclonal antibody that targets IB6. Pfizer’s sigvotatug vedotin is a humanized monoclonal antibody that binds specifically to IB6, and it has the ability to induce immunogenic cell death. Sigvotatug vedotin is being studied in combination with Merck’s Keytruda (pembrolizumab) compared with Keytruda alone in the open-label Sigvie-003 trial. The rationale for the trial design was recently published in Future Oncology.

Researchers in the Future Oncology paper indicated that sigvotatug vedotin’s ability to induce immunogenic cell death may enhance antitumor activity. Previous research with other vedotin-based antibody drug conjugates has found that when combined with immunotherapies, safety is manageable.

Initial results from a phase 1 trial specifically with sigvotatug vedotin and Keytruda as a first-line treatment for patients with advanced NSCLC were presented at the 2025 American Society of Clinical Oncology annual meeting. Results showed objective response rates between 50% and 61.5% in patients with PD-L1 tumor proportion score (TPS) less than 1% and greater than 1%. PD-L1 TPS is used to predict response to immunotherapy and is defined as the ratio of PD-L1-positive tumor cells and PD-L1-negative cells. Any-grade and grade ≥3 treatment-related adverse events were reported in 80% and 37% of patients.

The phase 3 Sigvie-003 trial will enroll 714 patients who are not candidates for surgery and who do not have EGFR, ALK or ROS1 mutations. Patients will also be selected based on PD-L1 TPS that is greater than or equal to 50%. The PD-L1 TPS score that is greater than or equal to 50% is a key cutoff for identifying those who would likely benefit from immunotherapy.

The primary endpoints are overall survival and progression-free survival by blinded independent review committee (BICR). The secondary endpoints are: progression-free survival by investigator, objective response rate by BICR and by investigator, safety and tolerability, pharmacokinetics and immunogenicity.

Treatment will be administered until completion of the maximum number of cycles (applicable to pembrolizumab), disease progression, unacceptable toxicity, withdrawal of consent, end of study, or discontinuation for any other reason.