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.

In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy.

在胰腺导管腺癌 (PDAC) 中，TGFβ驱动的间质化促进了化疗耐药和免疫抑制，限制了治疗效果。

NIS793, a fully human mAb targeting TGFβ, demonstrated antifibrotic and immunomodulatory activity in preclinical models and early-phase trials.

NIS793，一种针对TGFβ的全人源单克隆抗体，在临床前模型和早期试验中显示出了抗纤维化和免疫调节活性。

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.

我们进行了一项随机、开放标签、II期研究，评估在治疗未接受的转移性PDAC (mPDAC) 患者中，NIS793 ± spartalizumab (抗PD-1) 联合白蛋白结合型紫杉醇 (或Abraxane)/吉西他滨 (ABRA/GEM) 与ABRA/GEM单独使用的效果。

The primary endpoint was progression-free survival(PFS); secondary endpoints included overall survival(OS), safety, pharmacokinetics, and biomarker analyses.

主要终点是无进展生存期 (PFS)；次要终点包括总生存期 (OS)、安全性、药代动力学和生物标志物分析。

Exploratory assessments included paired tumor RNA sequencing, cell-free DNA profiling, and plasma proteomics.

探索性评估包括配对肿瘤RNA测序、循环游离DNA分析和血浆蛋白质组学。

Results

NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses.

NIS793显示了靶点结合和TGFβ信号通路的抑制，通过转录组和蛋白质组分析得到证实。

Stromal remodeling was evident, with significant downregulation of cancer-associated fibroblast markers (Acta2, Fap) and collagen-related signatures.

间质重塑明显，癌症相关成纤维细胞标志物（Acta2, Fap）和胶原蛋白相关标志物显著下调。

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).

尽管有机制证明，但未观察到临床疗效：NIS793组与对照组的中位无进展生存期（PFS）和总生存期（OS）相当或在数值上更差（NIS793 + ABRA/GEM与ABRA/GEM相比的OS风险比：1.32；95%置信区间，0.84-2.07）。

The safety profile was manageable, with no unexpected toxicities.

安全性可控，没有出现意外的毒性反应。

Biomarker data revealed increased expression of neutrophil-related genes after treatment, suggesting potential induction of tumor-promoting inflammation.

生物标志物数据显示治疗后中性粒细胞相关基因表达增加，表明可能诱导了促进肿瘤的炎症。

Conclusions

NIS793 effectively inhibited TGFβ signaling and led to stromal remodeling but failed to improve outcomes in mPDAC.

NIS793有效地抑制了TGFβ信号传导并导致基质重塑，但在mPDAC中未能改善结果。

These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC.

这些发现突显了TGFβ生物学的复杂性，并对将其阻断与化疗联合用于PDAC治疗提出警告。

Future strategies should consider context-dependent effects of TGFβ inhibition.

未来的策略应考虑TGFβ抑制的上下文依赖效应。