Perioperative NALIRIFOX in Patients with Resectable Pancreatic Ductal Adenocarcinoma: An Updated Analysis of Survival and Response Biomarkers from the Phase II nITRO Trial.

Introduction. Less than half of pancreatic ductal adenocarcinoma (PDAC) patients are alive after 5 years, even when diagnosed at an early stage. NALIRIFOX is a three-drug combination that has recently been shown to improve overall survival (OS) in advanced PDAC. The phase II, single-arm nITRO trial evaluated the activity of NALIRIFOX as perioperative treatment in patients with resectable PDAC (<180° contact with the wall of major veins). The study met its primary endpoint, achieving an R0 resection rate of 65.3%. Here, we report updated survival outcomes and translational analyses aimed at identifying potential biomarkers. Methods. Plasma concentrations of 25 cytokines were measured using a multiplex xMAP/Luminex platform on baseline blood samples. Whole-exome sequencing was performed on germline DNA to evaluate genes potentially involved in PDAC pathogenesis. Variants of uncertain significance (VUS) were assessed using in silico tools. Plasma cytokine levels and germline pathogenic mutations were correlated with treatment response and survival outcomes. Results. With a median follow-up of 50.2 months, the median OS in the intention-to-treat population was 32.3 months (95%CI 26.6-38.0). Among resected patients, median disease-free survival (DFS) and OS were 19.4 and 47.9 months, respectively. TNF-α, a potent activator of the TAK1/NF-κB chemoresistance pathway, was the circulating factor most strongly associated with response, probability of resection, and DFS. More than one-fourth of profiled patients carried germline likely pathogenic (gLPV) or pathogenic (gPV) variants in at least one of the DNA damage-repair (DDR) or cancer-predisposition genes analyzed. This subgroup showed clinically meaningful improvements in both DFS and OS. Approximately half of the VUS were reclassified as potentially damaging based on in silico analyses. Patients with both gDDR deficiency and low TNF-α levels achieved the longest OS. Conclusions. Updated survival outcomes confirmed previous results of the nITRO trial. Biomarker analyses identified a subgroup of patients most likely to benefit from this treatment approach.