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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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Most Read Articles
Prof. Corinne Faivre-Finn, 30 Nov 2020
Consolidation therapy with the PD-L1 inhibitor durvalumab (Imfinzi®, AstraZeneca) following chemoradiation therapy (CRT) has become the standard of care in patients with unresectable stage III non-small-cell lung cancer (NSCLC), based on primary results of the PACIFIC study. The 4-year update of the study, presented recently at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020), demonstrated durable and sustained survival benefits that were consistent with those reported in the primary analyses.
Dr. Roy Herbst, Dr. David Spigel, 09 Jul 2020
The third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) osimertinib is a standard of care in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC). Results of the ADAURA study, presented at the American Society of Clinical Oncology 2020 Virtual Scientific Programme (ASCO 2020), support earlier use of osimertinib in the adjuvant setting, with superior disease-free survival (DFS) in patients who underwent complete resection of stage IB/II/IIIA EGFR-positive NSCLC. 
Prof. Mark Shackleton, 01 Apr 2020
In recent years, the focus on immuno-oncology has generated a wealth of compelling evidence supporting the use of immune checkpoint inhibitors – in particular those targeting the programmed death-ligand 1 (PD-L1) or PD-1 pathway. At the 8th Oncology Summit organized by the Hong Kong Society of Clinical Oncology, Professor Mark Shackleton of Alfred Health and Monash University, Australia, discussed recent advances in immunotherapy for the management of metastatic Merkel cell carcinoma (MCC) with a focus on the role of the PD-L1 inhibitor avelumab.  
Dr. Keith Wong, 30 Nov 2020
The B-cell lymphoma-2 (BCL-2) inhibitor, venetoclax, has demonstrated promising efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). However, the associated risk of tumour lysis syndrome (TLS) in certain patients necessitates prophylactic measures and close monitoring. In an interview with MIMS Oncology, Dr Keith Wong from the haematology department of a public hospital in Hong Kong discussed important treatment considerations for patients with CLL, and highlighted prophylactic and supportive measures established at his hospital to mitigate the risk of TLS complications associated with venetoclax-based therapy.