Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial

Summary

Background

Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50–60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil.

Methods

We did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m²) and gemcitabine (1000 mg/m²) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m²) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m²) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m² on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the modified intention-to-treat (ITT) population, defined as all randomly assigned and assessable patients regardless of their eligibility and received treatments. This trial is registered at ClinicalTrials.gov, number NCT01964534. The trial has ended and we report the final analysis here.

Findings

Between Dec 12, 2013, and Oct 31, 2014, we randomly assigned 114 patients to treatment: 75 patients to the leucovorin and fluorouracil group and 39 to the gemcitabine group. One patient in the leucovorin and fluorouracil group did not have a 4-month assessment, and was thus excluded from the modified ITT analysis. Median follow-up was 13·1 months (95% CI 12·5–14·1). At 4 months, 40 (56%, 90% CI 45–66) of 72 patients in the leucovorin and fluorouracil group were alive and free from disease progression (21 [54%, 40–68] of 39 patients in the gemcitabine group were also alive and progression-free at 4 months). Grade 3–4 adverse events occurred in 33 (87%) of 38 patients in the gemcitabine group and in 56 (77%) of 73 patients in the leucovorin and fluorouracil group, with different toxicity profiles. The most common grade 3–4 adverse events in the leucovorin and fluorouracil group were neutropenia without fever (17 [23%]), fatigue (16 [22%]), paraesthesia (14 [19%]), diarrhoea (nine [12%]), and mucositis (seven [10%]); in the gemcitabine group they were neutropenia without fever (12 [32%]), thrombocytopenia (seven [18%]), fatigue (eight [21%]), anaemia (five [13%]), increased alanine aminotransferase and aspartate aminotransferase concentrations (five [13%] for both), and paraesthesia (four [11%]). Two participants died; one in the leucovorin and fluorouracil group from septic shock, and one in the gemcitabine group from diabetes compensation with acidosis; these deaths were deemed to be not related to treatment. Treatment-related serious adverse events occurred in 28 (38%) of 73 patients in the leucovorin and fluorouracil group and in 14 (37%) of 38 in the gemcitabine group.

Interpretation

Nab-paclitaxel plus simplified leucovorin and fluorouracil fulfilled the primary endpoint in that more than the required 50% of our study population were progression-free at 4 months, with a tolerable toxicity profile. This regimen thus deserves further assessment in a phase 3 trial.

Funding

GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) and Celgene through grants to GERCOR.

Introduction

The incidence of pancreatic adenocarcinoma is increasing in high-income countries and it is expected to become the second leading cause of cancer-related mortality in 2020.1, 2 The prognosis of this disease remains very poor with prevalence and incidence roughly equivalent; 5-year overall survival for patients diagnosed with the disease is less than 5%.³

Gemcitabine monotherapy was the standard treatment for patients with metastatic pancreatic adenocarcinoma for many years.⁴ Over the past decade, the results of several randomised phase 3 studies assessing combinations of cytotoxic agents or cytotoxic agents with targeted chemotherapy did not suggest these were superior compared with gemcitabine alone. The results from one phase 3 trial showed that gemcitabine plus erlotinib was associated with a significant but not clinically relevant benefit in overall survival.⁵ In 2011, the FOLFIRINOX regimen (fluorouracil, leucovorin, irinotecan, and oxaliplatin), and more recently the combination of nab-paclitaxel with gemcitabine, have been shown to be more effective than gemcitabine monotherapy in terms of the proportion of patients with an objective response, progression-free survival, and overall survival.6, 7 These regimens are now accepted as the standard first-line treatment options for metastatic pancreatic adenocarcinoma, but no published randomised trials have directly compared them. Moreover, a head-to-head comparison of trials assessing these two regimens is difficult, given differences in patient profiles and rates of second-line chemotherapy across participating countries.6, 7

Gemcitabine is a hydrophilic prodrug that requires the presence of specialised integral membrane nucleoside transporter proteins to efficiently permeate into tumour cells.⁸ Among these, the major mediator of gemcitabine uptake into human cells is the hENT1 protein. Intracellular gemcitabine must then be phosphorylated to its active diphosphate and triphosphate metabolites by subsequent kinases.9, 10 The first phosphorylation is achieved by deoxycytidine kinase in a rate-limiting step of its cellular anabolism. Findings from many retrospective studies in the adjuvant setting have suggested that the level of expression of hENT1 protein and deoxycytidine kinase could be predictive of gemcitabine's efficacy.11, 12, 13, 14 Moreover, these retrospective data suggested that gemcitabine might be inefficient in 50–60% of patients with pancreatic adenocarcinoma and thus not an optimum regimen for combination with nab-paclitaxel.11, 12, 13, 15

Fluorouracil as monotherapy or in combination with gemcitabine has shown some activity in the adjuvant setting of pancreatic adenocarcinoma and has become a key component of first-line and second-line regimens in metastatic disease.6, 16, 17, 18, 19 Nab-paclitaxel can be associated with a fluoropyrimidine with a tolerable toxicity profile.20, 21 The simplified leucovorin and fluorouracil regimen first developed by de Gramont and colleagues has shown a better toxicity profile than fluorouracil bolus.²² In comparison with capecitabine, the combination of leucovorin plus fluorouracil is associated with fewer occurrences of grade 3–4 diarrhoea and hand–foot syndrome, but more grade 3–4 neutropenia, which could however be controlled with the use of granulocyte colony-stimulating factor (G-CSF) when necessary.23, 24

The aim of the AFUGEM GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) randomised non-comparative phase 2 trial was to assess the tolerability and activity of a nab-paclitaxel plus simplified leucovorin and fluorouracil combination regimen in patients with untreated metastatic pancreatic adenocarcinoma.