PO.CL01.03 · 临床研究

LAPNET-01：一项评估NP137（一种上皮-间质转化抑制剂）联合mFOLFIRINOX一线治疗局部晚期胰腺导管腺癌的1b期研究的转化研究结果

LAPNET-01: Translational results of a Phase 1b evaluating NP137, an inhibitor of the epithelial-to-mesenchymal transition in combination with mFOLFIRINOX for the first-line treatment of locally advanced pancreatic ductal adenocarcinoma

编号 2445 展板 15 时间 4/20 09:00–12:00 区域 Section 40 主讲 Gaël Roth, M.D.

分会场 Biomarkers Predictive of Therapeutic Benefit 3

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作者与单位 Authors & Affiliations

Gaël Roth¹, Pascal Artru², Olivier Bouche³, Marc Manceau⁴, Nicolas Williet⁵, Julien Ghelfi⁶, Anthony Turpin⁷, Astrid Lièvre⁸, Jean Frederic Blanc⁹, Camille Evrard¹⁰, Jean Baptiste Bachet¹¹, Pauline Parent¹², Matthieu Roustit⁴, Hector Hernandez-Vargas¹³, Elise Georges¹⁴, Sébastien Hazard¹⁴, Benjamin Ducarouge¹⁴, Agnès Bernet¹⁵, Patrick Mehlen¹⁵

¹Department of Hepato-Gastroenterology and Digestive Oncology, CHU Grenoble Alpes, Grenoble, Grenoble, France,²Department of Hepato-Gastroenterology, Hôpital Jean-Mermoz, Lyon, France,³CHU Reims, Reims, France,⁴Inserm, HP2 - U1300, CHU Grenoble Alpes, Grenoble, France,⁵Department of Hepatogastroenterology and Gastrointestinal Oncology, CHU St Etienne, Grenoble, France,⁶Department of Radiology, CHU Grenoble Alpes, Grenoble, France,⁷Medical Oncology Department, Lille University Hospital, Lille, France,⁸Department of Gastroenterology, CHU Rennes, Rennes, France,⁹Department of Hepato-Gastroenterology and Digestive Oncology, CHU Bordeaux, Bordeaux, France,¹⁰Department of Medical Oncology, CHU Poitiers, Poitiers, France,¹¹Department of Gastroenterology, APHP - Pitié Salpetrière, Paris, France,¹²Medical Oncology Department, CHU Lille, Lille, France,¹³Genomics Consulting, Lyon, France,¹⁴NETRIS Pharma, Lyon, France,¹⁵Apoptosis, Cancer and Development Laboratory, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Lyon, France

摘要 Abstract

中文摘要

背景：胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，以侵袭性肿瘤播散和治疗耐药为特征，这些过程在很大程度上由上皮-间质转化（EMT）驱动。Netrin-1是EMT的关键调控因子。NP137是一种抗netrin-1抗体，已在临床前模型和一项1期单药治疗试验中显示出抑制EMT的作用。方法：LAPNET-01是一项单臂1b期临床研究，旨在评估NP137联合mFOLFIRINOX治疗局部晚期、不可切除的PDAC。对治疗前活检和手术标本进行激光捕获显微切割，以进行微量RNA测序。结果：本试验共纳入43例患者，接受mFOLFIRINOX加NP137治疗，每两周一次，最多12个周期（6个月）。NP137耐受性良好。中位PFS为10.9个月（95% CI，10.0-15.6），中位OS为16.4个月（95% CI，12.8-NR），在数据截止时有21例患者仍存活。联合治疗使23%的患者得以接受手术。对22例治疗前样本和6例手术样本成功进行了微量RNA测序，结果显示mFOLFIRINOX+NP137联合治疗主要下调的通路是EMT，从而为NP137的主要作用机制提供了临床验证。此外，生物信息学分析支持基线时高表达netrin-1受体neogenin（NEO1）的肿瘤具有延长的OS和PFS。在高NEO1亚组中，NP137治疗表现出优于低NEO1亚组的结局，包括更长的中位PFS（15.7对10.2个月，p<0.001）和更长的中位OS（未达到对16.5，p<0.024）。这些观察结果与实验数据一致，后者证明了neogenin在胰腺癌EMT及其进展中的作用。结论：NP137联合mFOLFIRINOX表现出良好的安全性、有前景的临床活性，以及由转化分析所支持的机制上独特的作用模式。这些结果支持在随机试验中进一步研究netrin-1阻断，并为NP137在胰腺癌中基于生物标志物的开发提供了理论依据。

查看英文原文 English abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by aggressive tumor dissemination and resistance to therapy; processes significantly driven by the epithelial-to-mesenchymal transition (EMT). Netrin-1 is a key regulator for EMT. NP137, an anti-netrin-1 antibody, has shown to inhibit EMT in preclinical models and in a phase 1 monotherapy trial. Methods: LAPNET-01 is a single arm phase Ib clinical study to assess the combination of NP137 with mFOLFIRINOX in locally advanced, unresectable PDAC. Laser capture microdissection was performed on pre-therapeutic biopsies and surgical specimens to allow microbulk RNA sequencing. Results: 43 patients were included in this trial and received mFOLFIRINOX plus NP137 once every two weeks for up to 12 cycles (6 months). NP137 was well tolerated. Median PFS was 10.9 months (95% CI, 10.0 - 15.6) and median OS was 16.4 months (95% CI, 12.8 - NR) with 21 patients still alive at time of the data cut-off. Surgery was made possible by the combination therapy in 23% of patients. Microbulk RNA sequencing was successfully performed on 22 pre-therapeutic and 6 surgery samples and revealed that the main pathway downregulated with the combination mFOLFIRINOX+NP137 is EMT, bringing a clinical validation of the main mechanism of action of NP137. Moreover, bioinformatic analyses supported an extended OS and PFS in tumors expressing high levels of the netrin-1 receptor neogenin (NEO1) at baseline. In the high-NEO1 subgroup, NP137 treatment demonstrated an improved outcomes compared to the low-NEO1 subgroup including longer median PFS (15.7 vs 10.2 months, p<0.001) and longer median OS (not reached vs 16.5, p<0.024). These observations are consistent with experimental data that demonstrated the implication of neogenin in pancreatic cancer EMT and its progression. Conclusion: NP137 in combination with mFOLFIRINOX demonstrates a favorable safety profile, promising clinical activity, and a mechanistically distinct mode of action supported by translational analyses. These results warrant further investigation of netrin-1 blockade in randomized trials and provide a rationale for biomarker-driven development of NP137 in pancreatic cancer.

利益披露 Disclosure

G. Roth, NETRIS Pharma ). P. Artru, None.. O. Bouche, None.. M. Manceau, None.. N. Williet, None.. J. Ghelfi, None.. A. Turpin, None.. A. Lièvre, None.. J. Blanc, None.. C. Evrard, None.. J. Bachet, None.. P. Parent, None.. M. Roustit, None. H. Hernandez-Vargas, NETRIS Pharma Independent Contractor. E. Georges, NETRIS Pharma Employment. S. Hazard, NETRIS Pharma Employment. B. Ducarouge, NETRIS Pharma Employment. A. Bernet, NETRIS Pharma Employment, Stock. P. Mehlen, NETRIS Pharma Employment, Stock.

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