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

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.