Abstract 7775: Pharmacodynamic biomarkers of TGFβR2xPD-1 bispecific antibody INCA33890 in patients with MSS metastatic colorectal cancer (mCRC)

Abstract INCA33890 is an TGFβR2xPD-1 bispecific antibody designed to antagonize TGFβR2/PD-1 signaling in immune cells co-expressing both targets. In the INCA 33890-101 study (NCT05836324) part 1A, 48 patients (pts) across 10 tumor types were evaluated with 7 dose levels (100, 300, 600, 900, 1200, 1500 mg Q2W and 900 mg Q4W). In part 1B, 94 pts with MSS mCRC were treated across 3 dose levels (300, 600, and 900 mg Q2W). During part 1B dose expansion, fresh or archival (≤3 years of first dose) baseline biopsies and on-treatment biopsies (Cycle 2, Day 15 C2D15 up to Cycle 2, Day 28) were required. We present pharmacodynamic biomarker analyses from pts in part 1A and part 1B with MSS mCRC. Peripheral blood from pts was analyzed by flow cytometry for receptor occupancy, anti-idiotype binding, and T-cell activation (Ki67 and HLA-DR). Cytokines (CXCL9, CXCL10, IFNγ) were measured in plasma using a 4-Plex ELLA or proinflammatory MSD assay. Intratumoral T-cell infiltration was measured at baseline and C2D15 using multiplex immunohistochemistry, which included CD8, Granzyme B, and FOXP3. Multiplex immunofluorescence staining for phosphorylated SMAD (pSMAD) and spatial transcriptomics using the Xenium immuno-oncology panel were also performed. Following INCA33890 treatment, PD-1 competitive binding decreased, demonstrating target engagement. Anti-idiotype binding of INCA33890 increased in both PD-1+ effector memory T cells and PD-1- naïve T cells, demonstrating dose-dependent engagement of TGFβR2 at the highest dose levels. At all doses, INCA33890 induced T-cell activation, evidenced by increased Ki67 and HLA-DR expression on peripheral T cells, and increased proinflammatory cytokines IFNy, CXCL9, and CXCL10. In pts with MSS mCRC, intra-tumoral CD8+ T-cell density was significantly increased in matched post-treatment tumor biopsies. pSMAD and T cell TGFβR2 response signatures were decreased in PD-1+ T cells in post-treatment biopsies of responding patients. In the INCA 33890-101 study, treatment with INCA33890 resulted in activation of peripheral CD4+ and CD8+ T cells, and increased T-cell infiltration within the tumor microenvironment. At the recommended doses for expansion, INCA33890 binding was specific for PD-1+ T cells, as evidenced by low anti-idiotype binding on naïve T cells, which do not express PD-1. Decreases in pSMAD and T-cell TGFβR2 response signature in intratumoral T cells demonstrated the inhibition of TGFβR2 by INCA33890. Citation Format: Michelle Kinder, Rui Hong, Chifei Sun, Yunlan Fang, Michael Smith, Cynthia Timmers, Chiara Greggio, Jordi Rodon Ahnert. Pharmacodynamic biomarkers of TGFβR2xPD-1 bispecific antibody INCA33890 in patients with MSS metastatic colorectal cancer (mCRC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7775.