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The Committee for Medicinal Products for Human Use has recommended the approval of pegylated liposomal irinotecan (Onivyde) in combination with fluorouracil and leucovorin for patients with metastatic pancreatic adenocarcinoma following progression on a gemcitabine-based therapy.
Philip J. Vickers, PhD
The Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of 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 positive opinion 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 = .012).
The positive opinion was sent to the European Commission for a final regulatory decision, which is expected within 67 days. Baxalta submitted the application for liposomal irinotecan, which is now owned by Shire. In the United States, the agent is marketed by Merrimack Pharmaceuticals.
"This regulatory milestone is an important step for patients with metastatic pancreatic adenocarcinoma who have progressed after gemcitabine-based therapy," Philip J. Vickers, PhD, head of R&D, Shire, said in a statement. "There has been little improvement in prognosis for patients in this setting for over 20 years, and given this high unmet need we look forward to receiving the final approval decision from the European Commission."
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 = .0009).
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.
"We are grateful to all of the patients, families and investigators who contributed to the development of Onivyde, and to our partner Shire, together with whom we are committed to advancing the availability of this important therapy to patients facing this devastating disease with few treatment options," Robert Mulroy, president and CEO of Merrimack, said in a statement.
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.
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.