LAP-NET1: Phase 1b study investigating the association of NP137 with mFOLFIRINOX in locally advanced pancreatic ductal adenocarcinoma.

713 Background: Locally advanced Pancreatic Ductal Adenocarcinoma (LAP) accounts for 30–40% of Pancreatic Ductal Adenocarcinoma (PDAC), with median overall survival (OS) ~15 months. Chemotherapy constitutes the current standard of care; however, its optimization remains a considerable clinical challenge. Netrin-1, upregulated in ~60% of PDAC, promotes invasiveness and metastasis through epithelial–mesenchymal transition (EMT). NP137, a first-in-class anti–Netrin-1 monoclonal antibody, demonstrated EMT inhibition in phase I (Cassier et al., Nature 2023). The LAP-NET1 phase Ib study (NCT05546853) evaluates NP137 plus modified FOLFIRINOX (mFOLFIRINOX) in LAP. Methods: LAP-NET1 enrolled systemic-treatment–naïve LAP patients (NCCN criteria). A safety lead-in (3–12 pts, 3+3 design, NP137 14 vs 9 mg/kg) was followed by a 40-patient expansion. Treatment consisted of NP137 + mFOLFIRINOX every 2 weeks ×12 cycles. The primary endpoint was safety at 6 months (all-grade and grade 3/4 adverse events [AEs], CTCAE v5.0). Secondary endpoints included objective response rate (ORR, RECIST v1.1), 12-month progression-free survival (PFS) and OS, surgical conversion rate, CA19-9 response, quality of life (EORTC QLQ-C30), and exploratory transcriptomic analyses. Results: Forty-three patients were treated (51% male; median age 65). Median follow-up was 13.6 months. AE occurred in 93% of patients (30% grade 3/4). ORR and disease control rate were 34% and 95. Median PFS and OS were 11.2 and 16.8 months, with 6-/12-month rates of 88%/45% and 91%/66%, respectively. A >50% CA19-9 reduction from baseline was observed in 71%. Surgical resection was achieved in 9 (21%) patients. Conclusions: NP137 plus mFOLFIRINOX was well tolerated, without additional toxicity beyond chemotherapy, and demonstrated promising efficacy in LAP. These results support further evaluation in randomized trials. Correlative biomarker and transcriptomic analyses are ongoing and will be presented. Clinical trial information: NCT05546853 .