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Phase I/II: NALIRIFOX tolerable for treatment-naïve patients with locally advanced or metastatic PDAC

Natalia Reoutova
16 Sep 2020

Liposomal irinotecan in combination with 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (OX) (NALIRIFOX regimen) is tolerable and possesses antitumour activity in previously untreated patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC), according to long-term follow-up results of a phase I/II trial presented at WCGC 2020.

“Gemcitabine plus albumin-bound paclitaxel particles [nab-paclitaxel] and FOLFORINOX [irinotecan + 5-FU + LV + OX] are the established first-line treatment options for metastatic PDAC,” said first author, Dr Zev Wainberg of University of California Los Angeles, Los Angeles, California, US. “However, the non-liposomal irinotecan component of FOLFIRINOX has a complex and rapid metabolism, a short half-life and dose-limiting toxicity, such as gastrointestinal adverse events [AEs].” [Clin Pharmacokinet 2018;57:1229-1254; Camptosar US prescribing information, January 2020]

On the other hand, in a preclinical setting, the active metabolite of liposomal irinotecan persists in tumours for longer than non-liposomal irinotecan. [Cancer Res 2014;74:7003-7013] “At the same time, preclinical data suggest that prolonged exposure may be more important than high concentrations to mediate beneficial cytotoxic activity,” added Wainberg.

The study was conducted in two parts: the safety run-in dose-exploration phase determined the optimal doses of liposomal irinotecan (50 mg/m2 [free base], 5-FU (2,400 mg/m2), LV (400 mg/m2) and OX (60 mg/m2), which were given to all patients (n=32) in the dose-expansion phase. The primary objective of the dose-expansion phase was to assess safety and tolerability, while median progression-free survival (PFS) and median overall survival (OS) served as secondary endpoints. [Wainberg Z et al, WCGC 2020, abstract LBA-1]

The majority (87.5 percent) of patients in the pooled population of the dose-exploration and dose-expansion cohorts had metastatic disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 1 (56.3 percent). None of the patients discontinued treatment due to treatment-emergent AEs (TEAEs), while a quarter required dose adjustments.

Serious TEAEs, the most common of which were febrile neutropenia and nausea, occurred in 31.3 percent of patients, while TEAEs led to the death of three patients (9.4 percent). Grade 3 TEAEs were reported by 68.8 percent of patients, with grade 3 neutropenia, febrile neutropenia and hypokalaemia being experienced by 31.3 percent, 12.5 percent of 12.5 percent of patients, respectively. “Granulocytic colony-stimulating factors were not administered prophylactically, nor mandated, but left up to the discretion of individual treatment centres,” noted Wainberg.

The Kaplan-Meier estimates of median PFS and median OS from this safety population were 9.2 months (95 percent confidence interval [CI], 7.69 to 11.96) and 12.6 months (95 percent CI, 8.74 to 18.69), respectively. One patient had a complete response, 10 patients (31.3 percent) achieved partial response and 15 patients (46.9 percent) had stable disease. The overall response rate was 34.4 percent, while disease control rate at 16 weeks was 71.9 percent, and median duration of response was 9.4 months.

“These findings suggest that NALIRIFOX is tolerable for treatment-naïve patients with locally advanced or metastatic PDAC. No new safety signals were identified. Observed antitumour activity can be described as promising and therefore warrants further investigation,” concluded Wainberg. “Efficacy of NALIRIFOX is the primary objective of the ongoing phase III NAPOLI-3 study in patients with previously untreated metastatic PDAC.”

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