First-line NALIRIFOX in patients with metastatic pancreatic ductal adenocarcinoma and pre-existing diabetes: NAPOLI 3 post hoc analysis.

4195 Background: Approximately 29% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) present with pre-existing diabetes. Diabetes increases the risk of peripheral neuropathy (PN), raising concerns that oxaliplatin-containing regimens may exacerbate PN risk. NALIRIFOX (liposomal irinotecan, oxaliplatin, leucovorin and 5-fluorouracil) is approved for first-line (1L) treatment of mPDAC based on significantly improved overall survival versus nab-paclitaxel plus gemcitabine (Gem+NabP) in the phase 3 NAPOLI 3 trial (hazard ratio 0.83; 95% confidence interval [CI] 0.70–0.99). The overall response rate (ORR) for NALIRIFOX was 41.8% (95% CI: 36.8–46.9%) and no unexpected safety concerns were identified. This post hoc exploratory analysis of NAPOLI 3 evaluates outcomes including PN development among patients with pre-existing diabetes. Methods: Patients randomized to 1L NALIRIFOX in NAPOLI 3 who had pre-existing diabetes were assessed, with subgroups according to whether or not they developed PN. The primary endpoint was ORR; patient characteristics and adverse event rates were also described. No hypotheses were tested owing to small sample sizes; results are descriptive. Results: Of 383 patients randomized to receive NALIRIFOX in NAPOLI 3, 96 (25%) had pre-existing diabetes, of whom 94 were included in the safety population. PN developed in 13/94 (14%) patients (Grade ≥3: 2/13 [15%]) with pre-existing diabetes, none of whom had evidence of PN at baseline. Among patients without diabetes, PN developed in 53/276 (19%; Grade ≥3: 10/53 [19%]). Patients with pre-existing diabetes who developed PN had a lower median age, lower proportion of males, higher metastatic burden, and higher frequency of tumors in the body of the pancreas than patients who did not develop PN (Table). Among patients with pre-existing diabetes, ORR for NALIRIFOX was 43.8% (42/96 [95% CI: 33.6–54.3%]); all responses were partial. ORR was 69.2% (9/13 [95% CI: 38.6–90.9%]) among patients with pre-existing diabetes who developed treatment-emergent PN and 40.7% (33/81[95% CI: 29.9–52.2%]) among those who did not (Table). Conclusions: In this exploratory analysis, PN incidence and clinical outcomes in patients with pre-existing diabetes were consistent with those without diabetes and with the overall NALIRIFOX population. In this small population, pre-existing diabetes did not appear to put patients at risk of developing treatment-emergent PN or to impact treatment outcomes. Clinical trial information: NCT04083235 . Patients with baseline diabetes who developed peripheral neuropathy(n = 13) Patients with baseline diabetes who did not develop peripheral neuropathy(n = 81) Baseline characteristics Age, median, years 63.0 66.0 Male, n (%) 6 (46.2) 52 (64.2) ≥ 3 metastatic sites, % 53.8 40.7 Tumor in body of pancreas, % 38.5 22.2 Efficacy ORR, % (95% CI) 69.2 (38.6–90.9) 40.7 (29.9–52.2)