Biomarker analysis from patients with metastatic PDAC treated with TGFβ antibody, NIS793, plus abraxane+gemcitabine vs. abraxane+gemcitabine alone in a phase II, open label, randomized study.

Authors

Marc Pelletier, Jie Yang, Mukta Joshi, Angelo Grauel, Cara Abecunas, Maria Athina Altzerinakou, Zheng Zhou, Xiaoping Zhu, Kirk Clark, Li Li, Li-Yuan Bai, Michele Milella, Teresa Macarulla Mercade, Wai Meng David Tai, Bruno Bockorny, Peter Grell, Shivan Sivakumar, Mark Ka Wong, Cheng Ean Chee, Thomas Aparicio, Gerald Prager, Geraldine Bostel, Brigitte Schiessl, Heiko Maacke, Glenn Dranoff, Alice Shaw, Claire Fabre, Jennifer Mataraza, Shiva Malek, Viviana Cremasco

Published in

Clinical cancer research : an official journal of the American Association for Cancer Research. Jun 25, 2026. Epub Jun 25, 2026.

Abstract

Transforming Growth Factor Beta (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human monoclonal antibody targeting TGFβ, demonstrated anti-fibrotic and immunomodulatory activity in preclinical models and early-phase trials.
We conducted a randomized, open-label, phase II study in treatment-naïve metastatic PDAC patients to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cfDNA profiling, and plasma proteomics.
NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of CAF markers (ACTA2, FAP) and collagen-related signatures. Despite proof-of-mechanism, clinical efficacy was not observed: median PFS and OS were comparable or numerically worse in NIS793 arm versus control (HR for OS in NIS793+ABRA/GEM vs ABRA/GEM: 1.32; 95% CI: 0.84-2.07). Safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes post-treatment, suggesting potential induction of tumor-promoting inflammation.
NIS793 effectively inhibited TGFβ signaling and led to stroma remodeling but failed to improve outcomes in metastatic PDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition(NCT04390763).

PMID:
42347868
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.