Decreased appetite (DA) at baseline impacts prognosis in the NAPOLI-1 phase 3 study in metastatic pancreatic ductal adenocarcinoma (mPDAC) (2018)

Introduction: In NAPOLI-1 (NCT01494506), treatment with liposomal irinotecan + 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) significantly increased median overall survival (mOS) vs. 5-FU/LV (6.1 vs. 4.2 months; unstratified hazard ratio [HR]=0.67, 95% confidence interval [CI] 0.49–0.92; P = 0.012) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had progressed following gemcitabine-based therapy. We investigated the effect of metabolism and nutrition disorders (MNDs) on survival in NAPOLI-1 patients. Methods: This post-hoc analysis explored outcomes in patients with vs. without MNDs (based on MedDRA v14.1), including diabetes mellitus (DM), decreased appetite (DA; which included anorexia, poor appetite, lack of appetite, loss of appetite), hypercholesterolemia (HC), and dyslipidemia. Results: At baseline, 267/417 intent-to-treat (ITT) patients had any MND. Differences in baseline characteristics were observed in some MND subgroups vs. the ITT population: e.g. Karnofsky performance status (DA), gender and race (HC), albumin (DA, HC). Both mOS (3.6 vs. 5.3 months; HR = 1.65, 95% CI 1.25–2.18; P < 0.001) and median progression-free survival (mPFS) (1.6 vs. 2.6 months; HR = 1.42, 95% CI 1.09–1.85; P = 0.010) were significantly lower in patients with (n = 77) vs. those without DA (n = 340). A trend for lower OS was also noted in patients with HC but this did not reach statistical significance. mOS was 4.4 vs. 5.1 months in patients with (n = 47) vs. without HC (n = 370) (HR = 1.37, 95% CI 0.98–1.91; P = 0.063) while mPFS in these populations was 2.3 vs. 2.6 months, respectively (HR = 1.15, 95% CI 0.83–1.60; P = 0.390). No significant difference was observed in survival between patients with (n = 159) vs. without DM (n = 258) or those with (n = 87) vs. without dyslipidemia (n = 330). mOS was 5.6 vs. 4.8 months for patients with vs. without DM (HR = 0.88, 95% CI 0.70–1.11; P = 0.279) while mPFS was 2.8 vs. 2.3 months (HR = 0.86, 95% CI 0.69–1.08; P = 0.191). mOS was 4.7 vs. 5.1 months for patients with vs. without dyslipidemia (HR = 1.13, 95% CI 0.86–1.48; P = 0.375) while mPFS was 2.2 vs. 2.6 months (HR = 1.19, 95% CI 0.91–1.54; P = 0.196). For patients with vs. without any MND, mOS was 4.8 vs. 5.3 months (HR = 1.10, 95% CI 0.87–1.39; P = 0.412) while mPFS was 2.5 vs. 2.6 months (HR = 1.11, 95% CI 0.88–1.39; P = 0.358). In patients treated with nal-IRI+5-FU/LV, mOS (4.6–6.7 vs. 2.7–6.1 months; HR = 0.46–1.05) and mPFS (2.8–4.1 vs. 1.4–1.6 months; HR = 0.24–0.60) were generally improved vs. 5-FU/LV in all subgroups. Safety data, drug-related AEs and dose modifications/discontinuations were broadly similar to the overall NAPOLI-1 study arms. Conclusion: DA at baseline appears to have a prognostic impact on OS (P < 0.001) in mPDAC patients who progressed after gemcitabine-based therapy. The presence of HC may also impact OS. It is important to consider and appropriately manage patients with DA. Treatment with nal-IRI+5-FU/LV provides a benefit regardless of the presence/absence of MNDs. The effect of DM treatment should be explored further.