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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).

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Journal
Clinical Cancer Research
Published
2026-06-25
DOI
https://doi.org/10.1158/1078-0432.ccr-26-0805
Primary Topic
Pancreatic and Hepatic Oncology Research
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article
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article

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

Li‐Yuan Bai, Viviana Cremasco, Cara Abecunas, Jennifer Mataraza et al.
Clinical Cancer Research
Pancreatic and Hepatic Oncology Research
article

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

Li‐Yuan Bai, Viviana Cremasco, Cara Abecunas, Jennifer Mataraza, Maria‐Athina Altzerinakou, Shiva Malek, Michèle Milella, Geraldine Bostel, Glenn Dranoff, Jie Yang, Heiko Maacke, Kirk Clark, Gerald W. Prager, Thomas Aparicio, Cheng Ean Chee, Zheng Zhou, Peter Grell, Claire Fabre, Bruno Bockorny, Shivan Sivakumar, Angelo L. Grauel, Marc R. Pelletier, Alice T. Shaw, Teresa Macarulla, David Tai, M Wong, Li Li, Mukta Joshi, Brigitte Schiessl, Xiaoping Zhu
article en

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).

Clinical Cancer Research
University of Verona (IT), Hebron University (PS), Novartis (Switzerland) (CH), Birmingham City University (GB), Beth Israel Deaconess Medical Center (US), China Medical University (TW), Westmead Hospital (AU), University College Birmingham (GB), University of Alabama at Birmingham (US), Novartis (China) (CN), Vall d'Hebron Institut de Recerca (ES), Masaryk Memorial Cancer Institute (CZ), Dana-Farber Cancer Institute (US), China Medical University Hospital (TW), Kaiser Permanente South San Francisco Medical Center (US), National Cancer Centre Singapore (SG), Hôpital Saint-Louis (FR), National University Hospital (SG), Medical University of Vienna (AT), University of Birmingham (GB)
Good health and well-being
Openalex Percentile: Top 8%
Pancreatic and Hepatic Oncology Research
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