What question did this study set out to answer?

This research aims to evaluate the efficacy and biological effects of NIS793, a TGFβ antibody, in combination with chemotherapy in metastatic PDAC patients.

June 27, 2026Open Access

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

Key Points

This research aims to evaluate the efficacy and biological effects of NIS793, a TGFβ antibody, in combination with chemotherapy in metastatic PDAC patients.
Randomized, open-label, phase II study in treatment-naïve metastatic PDAC patients.
Primary endpoint was progression-free survival, with secondary endpoints including overall survival and biomarker analyses.
Biomarker assessments included tumor RNA sequencing, cfDNA profiling, and plasma proteomics.
NIS793 showed target engagement and inhibition of TGFβ signaling (HR for OS: 1.32; 95% CI: 0.84-2.07).
Clinical efficacy was not observed, with median PFS and OS comparable or numerically worse in NIS793 arm versus control.
Biomarker data indicated increased expression of neutrophil-related genes, suggesting tumor-promoting inflammation.

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).

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