Alfredo Carrato, MD
The European Commission (EC) has approved pegylated liposomal irinotecan (Onivyde) in combination with fluorouracil (5-FU) and leucovorin for patients with metastatic pancreatic adenocarcinoma following progression on a gemcitabine-based therapy.
The approval was based on findings from the phase III NAPOLI-1 trial, which demonstrated a 1.9-month improvement in overall survival (OS) with the addition of liposomal irinotecan to 5-FU and leucovorin. In the combination arm, the median OS was 6.1 months compared with 4.2 months with 5-FU and leucovorin alone (HR, 0.67; 95% CI, 0.49-0.92; P
The EC’s approval decision followed a positive recommendation from the Committee for Medicinal Products for Human Use. Pegylated liposomal irinotecan is now approved for use in this setting in the 28 countries of the European Union, as well as in Iceland, Liechtenstein and Norway.
"The burden of pancreatic cancer for patients, their families and healthcare providers is profound and the treatment options available, especially to those with metastatic disease, have not substantially evolved for decades," Alfredo Carrato, MD, professor of Medical Oncology at Alcala University and director of the Medical Oncology Department at Ramon y Cajal University Hospital in Madrid, Spain, said in a statement.
"With the approval of Onivyde, we have the first and only treatment approved for metastatic adenocarcinoma following gemcitabine-based therapy, and an option that may improve patient survival. This is an important advance for the field of oncology and the lives of those impacted by pancreatic cancer," added Carrato.
In the international trial, 417 patients with gemcitabine-refractory metastatic pancreatic cancer were randomized to liposomal irinotecan monotherapy, 5-FU with leucovorin (control), or liposomal irinotecan plus 5-FU and leucovorin. Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist could be administered in the combination arms.
In the control, 5-FU was administered at 2000 mg/m2
with racemic leucovorin at 200 mg/m2
weekly for 4 weeks followed by 2 weeks of rest (n = 149). In the combination arm, intravenous liposomal irinotecan was administered at 80 mg/m2 prior to 5-FU at 2400 mg/m2
and racemic leucovorin at 400 mg/m2
every 2 weeks (n = 117). In the monotherapy group, liposomal irinotecan was administered at 120 mg/m2
every 3 weeks (n = 151).
Altogether, 61% of patients had cancer in the head of the pancreas and 68% had liver metastases. A majority of the patients (83%) were enrolled outside of the United States. In the combination arm, the median age of patients was 63 years, 64% were Caucasian, and 29% were Asian.
The median progression-free survival was 3.1 months for the combination compared with 1.5 months with the control (HR, 0.56; 95% CI, 0.41-0.75; P
= .0001). At 12 weeks, 57% of patients treated with the combination were alive and progression-free compared with 26% with 5-FU and leucovorin alone.
The objective response rate by RECIST v1.1 criteria was 16% versus 1%, for the combination and control, respectively (P
<.001). For those with baseline CA19-9 levels of >30 U/ml at baseline (84% in the combination arm), there was a ≥50% reduction in the marker for 36% of patients treated with the combination versus 12% in the control arm (P
In patients receiving at least one dose of liposomal irinotecan, the most commonly reported grade ≥3 adverse events (AEs) with the combination were neutropenia (20%), fatigue (14%), diarrhea (13%), vomiting (11%), nausea (8%), asthenia (8%), and abdominal pain (7%).
Liposomal irinotecan monotherapy did not demonstrate superior efficacy compared with 5-FU and leucovorin. The median OS with monotherapy was 4.9 months versus 4.2 months with 5-FU and leucovorin (HR, 0.99; P
= .94). Moreover, liposomal irinotecan alone was associated with more AEs compared with the combination, suggesting that the drug should only be used in combination.
The rates of diarrhea were 12.8% for the combination versus 21.1% for the single-agent. The rates of vomiting were 11.1% versus 13.6% for the combination and single-agent arms, respectively. Additionally, febrile neutropenia occurred in 1.7% of patients in the combination arm compared with 4.1% with liposomal irinotecan monotherapy and not at all with 5-FU/leucovorin alone.
"As the only treatment for metastatic pancreatic cancer following gemcitabine-based therapy that may improve patient survival, Onivyde is the first innovation that offers the potential to improve outcomes for this challenging patient population," Philip J. Vickers, PhD, global head of research and development at Shire, the manufacturer of liposomal irinotecan in Europe, said in a statement. "The approval of Onivyde marks a significant step forward in Shire's focus to develop and commercialize treatments that represent the most promising science in oncology."
Liposomal irinotecan is a nanoliposomal encapsulation of irinotecan, allowing for the drug to stay in circulation for a longer duration compared with standard irinotecan. In the United States, the liposomal irinotecan combination was approved in October 2015 as a second-line therapy for patients with pancreatic cancer. Liposomal irinotecan is marketed by Merrimack Pharmaceuticals in the United States.
Wang-Gillam A, Li C-P, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.