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Biomarker Analysis from Patients with Metastatic PDAC Treated with TGFβ Antibody NIS793 plus Abraxane + Gemcitabine versus Abraxane + Gemcitabine Alone in a Phase II, Open-Label, Randomized Study.

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
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Abstract

PURPOSE: Transforming growth factor β (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in the 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 mAb targeting TGFβ, demonstrated antifibrotic and immunomodulatory activity in preclinical models and early-phase trials. PATIENTS AND METHODS: We conducted a randomized, open-label, phase II study in treatment-naïve patients with metastatic PDAC (mPDAC) to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel (or Abraxane)/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. The 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, cell-free DNA 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 cancer-associated fibroblast 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 the NIS793 arm versus control (HR for OS in NIS793 + ABRA/GEM vs. ABRA/GEM: 1.32; 95% confidence interval, 0.84-2.07). The safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes after treatment, suggesting potential induction of tumor-promoting inflammation. CONCLUSIONS: NIS793 effectively inhibited TGFβ signaling and led to stromal remodeling but failed to improve outcomes in mPDAC. 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.

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HumansGemcitabineAntineoplastic Combined Chemotherapy ProtocolsDeoxycytidineFemaleTransforming Growth Factor betaCarcinoma, Pancreatic DuctalBiomarkers, TumorMalePancreatic NeoplasmsAgedMiddle AgedAlbumin-Bound PaclitaxelAntibodies, Monoclonal, HumanizedAdultAntibodies, MonoclonalJournal ArticleClinical Trial, Phase IIRandomized Controlled Trial

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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. 2026-09-15. Biomarker Analysis from Patients with Metastatic PDAC Treated with TGFβ Antibody NIS793 plus Abraxane + Gemcitabine versus Abraxane + Gemcitabine Alone in a Phase II, Open-Label, Randomized Study.. https://doi.org/10.1158/1078-0432.ccr-26-0805

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Adult subjectAged subjectAntibodies, Monoclonal, Humanized subjectAntineoplastic Combined Chemotherapy Protocols subjectBiomarkers, Tumor subjectClinical Trial, Phase II subjectFemale subjectHumans subjectJournal Article subjectMale subjectMiddle Aged subjectRandomized controlled trials study

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