First-in-Class Anti-Netrin-1 Antibody Shows Promise in Pancreatic Cancer Phase 1b Trial
核心洞察
NETRIS Pharma (搜索)'s NP137, a first-in-class anti-netrin-1 (搜索) monoclonal antibody, demonstrated significant clinical activity in a Phase 1b trial for locally advanced pancreatic cancer (搜索) when combined with standard chemotherapy.
The LAPNET-01 trial showed patients achieved a median progression-free survival of 10.85 months and overall survival of 16.43 months, with particularly strong results in patients with high neogenin (搜索) expression.
Patients with high tumor neogenin (搜索) expression achieved a median PFS of 15.65 months and a 40% conversion-to-surgery rate, representing a potential breakthrough for personalized pancreatic cancer (搜索) treatment.
NETRIS Pharma (搜索)'s experimental antibody NP137 has demonstrated promising clinical activity in patients with locally advanced pancreatic cancer (搜索), according to Phase 1b trial results published in Nature. The first-in-class anti-netrin-1 (搜索) monoclonal antibody showed the potential to overcome chemotherapy resistance, a major challenge in treating this aggressive cancer.
The LAPNET-01 trial enrolled 43 patients with locally advanced pancreatic ductal adenocarcinoma (搜索) (LAPC) across nine centers in France between March 2023 and June 2024. Patients received NP137 at 14 mg/kg every two weeks in combination with modified FOLFIRINOX (mFOLFIRINOX (搜索)) chemotherapy for up to 12 cycles.
Strong Survival Outcomes Across Patient Population
The trial achieved a median progression-free survival of 10.85 months and median overall survival of 16.43 months at a median follow-up of 13.1 months. Among 41 evaluable patients, 12 achieved confirmed partial responses for an overall response rate of 29%, with 88% of patients experiencing tumor shrinkage.
These outcomes compare favorably to benchmark data from the NEOPAN trial, which reported median PFS of approximately 9.7 months and median OS of approximately 15.7 months with FOLFIRINOX alone in LAPC patients.
Ten of 43 patients (23%) underwent post-therapy R0 resection, substantially higher than benchmark conversion rates from prospective LAPC trials. The NEOPAN and CONKO-007 trials reported R0 resection rates of 6% and 18% respectively, while PANOVA-3 reported 10.8% under gemcitabine/nab-paclitaxel.
Biomarker-Driven Efficacy in Neogenin-High Patients
The most striking results emerged in patients with high tumor neogenin (搜索) expression, a netrin-1 (搜索) receptor. This subset achieved a markedly superior median PFS of 15.65 months versus 10.22 months in the neogenin-low group (p=0.003). The neogenin-high group also demonstrated a 40% conversion-to-surgery rate and a 12-month overall survival rate of 100% at the time of data cut-off.
"The group of neogenin (搜索)-high patients, where we saw dramatically extended PFS and OS is unprecedented and opens a path for personalized and potentially more effective treatments of this group of pancreatic cancer (搜索) patients," said Gael Roth, MD, PhD, Professor in GI Oncology at Grenoble Alpes University Hospital (搜索) and LAPNET-01 lead investigator.
Neogenin (搜索) emerged as a candidate predictive biomarker for NP137 efficacy through pre-planned exploratory analyses of the netrin-1 (搜索) signaling pathway components.
Targeting Epithelial-to-Mesenchymal Transition
NP137 works by blocking netrin-1 (搜索), a protein ordinarily present only during embryonic development but abnormally activated during tumor progression. Scientists from the Cancer Research Centre of Lyon (搜索) discovered that netrin-1 activation partially drives epithelial-to-mesenchymal transition, a mechanism by which tumor cells resist treatment by quickly changing shape and behavior.
The antibody prevents netrin-1 (搜索) from interacting with its cellular receptor, thereby blocking the epithelial-to-mesenchymal transition of tumor cells and making tumors more sensitive to anticancer treatment.
"LAPNET-01 data strongly support the clinically meaningful potential of targeting the netrin-1 (搜索) / EMT axis to overcome the development of treatment resistance by PDAC, especially in neogenin (搜索)-high patients," said Patrick Mehlen, PhD, Chief Executive Officer of NETRIS Pharma (搜索).
Safety Profile and Next Steps
The safety profile was comparable to what is anticipated with the chemotherapy backbone alone. While 100% of patients experienced at least one adverse event, the grade 3 and above adverse event rate was 37%.
NETRIS plans to initiate a randomized, potentially registrational Phase 2 trial of NP137 in first-line metastatic PDAC, incorporating a neogenin (搜索) IHC assay to help validate this test as a potential companion diagnostic. The company is engaging with US and EU regulatory authorities to discuss the development pathway for NP137.
Addressing Critical Unmet Need
Pancreatic ductal adenocarcinoma (搜索) remains one of the most lethal malignancies, ranking as the fourth leading cause of cancer-related death globally with a five-year survival rate below 5%. LAPC represents roughly 30% of PDAC cases at diagnosis and occupies a particularly difficult clinical niche because tumors are predominantly unresectable yet lack distant metastases.
The current standard of care yields median PFS of 6-10 months and median OS of approximately 12-17 months in LAPC. The absence of a pharmacological EMT inhibitor in the approved oncology arsenal positions NP137 as a potential first-in-class agent addressing a resistance mechanism orthogonal to existing strategies like checkpoint inhibition and KRAS targeting.
Development of NP137 is also advancing in several other oncology indications including hepatocellular carcinoma (搜索) and head and neck squamous cell carcinoma (搜索).