Abstract A131: Sigvotatug vedotin, an integrin-beta 6 directed antibody drug conjugate, demonstrates potent single-agent antitumor activity across NSCLC subtypes and the potential to combine with targeted therapies

Abstract Sigvotatug vedotin (SV) is an antibody-drug conjugate (ADC) directed to integrin-β6 (IB6), a member of the integrin family of adhesion proteins that is highly expressed in multiple solid tumors. SV delivers the clinically validated payload MMAE, which causes microtubule disruption, cell cycle arrest, and direct tumor cell apoptosis. SV is currently being evaluated in NSCLC as a monotherapy and NSCLC and HNSCC in combination with pembrolizumab. To better understand SV efficacy in these key indications, we profiled the internalization rate and in vitro activity of SV in a panel of NSCLC and HNSCC cell lines and PDX models. SV demonstrated anti-tumor activity in models with varying levels of IB6 expression and different histology subtypes, as well as in models with KRAS, EGFR, and ALK actionable genomic alterations. SV in combination with targeted therapies in NSCLC cell lines demonstrated combination benefit. In addition to direct anti-tumor activity on IB6-expressing cells, SV induced cell death in IB6-negative cancer cells in an admixed cell culture model of bystander activity. SV also induced tumor growth inhibition in PDX models with heterogenous IB6 expression. These results demonstrate broad efficacy of SV in nonclinical models of NSCLC with varying levels of IB6 expression, mutations, and histology subtypes. Additionally, SV may contribute to antitumor activity by depleting neighboring IB6-negative tumor cells via the bystander effect. These findings support the continued development of SV in NSCLC and provide scientific rationale to further explore SV efficacy in lung tumors with actionable genomic alterations. Citation Format: Gina M. LoMastro, Rebecca Mazahreh, Nic Garcia, Gillian Yang, Lauren Loh, Serena Wo, Lori Westendorf, Anita Kulukian, Sarah Anderson, Devra Olson, Kelly Hensley, Li-Ya Huang, Wenjing Yang, Betsy Gray, Robert P. Lyon, Vivian H. Trang, Joseph R. Dekker. Sigvotatug vedotin, an integrin-beta 6 directed antibody drug conjugate, demonstrates potent single-agent antitumor activity across NSCLC subtypes and the potential to combine with targeted therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A131.