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Biomarker Analysis from Patients with Metastatic PDAC Treated with TGFβ Antibody NIS793 plus Abraxane + Gemcitabine
Marc Pelletier1, Jie Yang1, Mukta Joshi1
1Novartis BioMedical Research, Cambridge, Massachusetts.
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.
Insights
Transforming Growth Factor Beta (TGFβ) inhibition via NIS793 did not improve outcomes for pancreatic cancer patients. The drug engaged the target and remodeled stroma but failed to enhance progression-free or overall survival.
Area of Science:
- Oncology
- Immunology
- Translational Research
Background:
- Transforming Growth Factor Beta (TGFβ) has a dual role in cancer, suppressing tumors early but promoting progression and immune evasion later.
- In pancreatic ductal adenocarcinoma (PDAC), TGFβ drives desmoplasia, leading to chemoresistance and immunosuppression.
- NIS793 is a monoclonal antibody targeting TGFβ with demonstrated anti-fibrotic and immunomodulatory effects in preclinical studies.
Purpose of the Study:
- To evaluate the efficacy and safety of NIS793 combined with standard chemotherapy and immunotherapy in treatment-naïve metastatic PDAC.
- To assess the impact of NIS793 on progression-free survival (PFS) and overall survival (OS) in PDAC patients.
- To explore the drug's mechanism of action through biomarker analyses, including RNA sequencing, cfDNA profiling, and proteomics.
Main Methods:
- A randomized, open-label, phase II study was conducted in metastatic PDAC patients.
- Patients received NIS793 plus spartalizumab (anti-PD-1) and nab-paclitaxel/gemcitabine (ABRA/GEM) or ABRA/GEM alone.
- Primary endpoint was PFS; secondary endpoints included OS, safety, and biomarker analyses.
Main Results:
- NIS793 achieved target engagement and suppressed TGFβ signaling, evidenced by transcriptomic and proteomic changes.
- Stromal remodeling occurred, with decreased expression of cancer-associated fibroblast (CAF) markers and collagen signatures.
- No significant improvement in PFS or OS was observed; median survival was comparable or worse in the NIS793 arm. Increased neutrophil gene expression suggested potential pro-tumor inflammation.
Conclusions:
- NIS793 effectively inhibited TGFβ signaling and remodeled the tumor stroma but did not improve clinical outcomes in metastatic PDAC.
- These findings suggest caution against TGFβ blockade in combination with chemotherapy for PDAC due to potential context-dependent effects.
- Future research should consider the complex, context-dependent roles of TGFβ in cancer progression and treatment response.
