Combining liposomal irinotecan (nal-IRI; MM-398; Onivyde) with 5-fluorouracil (5-FU) plus leucovorin dropped the risk of death in patients with metastatic pancreatic cancer by 25% following progression on a gemcitabine-based regimen, according to updated data from the phase III NAPOLI-1 trial.
Andrea Wang-Gillam, MD, PhD
Combining liposomal irinotecan (nal-IRI; MM-398; Onivyde) with 5-fluorouracil (5-FU) plus leucovorin dropped the risk of death in patients with metastatic pancreatic cancer by 25% following progression on a gemcitabine-based regimen, according to updated data from the phase III NAPOLI-1 trial being presented at the 2016 Gastrointestinal (GI) Cancers Symposium.1
In the updated analysis conducted after 91% of events, median overall survival (OS) with the treatment combinatiopn was 6.2 months compared with 4.2 months for 5-FU and leucovorin alone (unstratified HR, 0.75; P = .0417). After 1 year, 26% of patients treated with the liposomal irinotecan combination remained alive compared with 16% with 5-FU plus leucovorin alone. At approximately 20 months, survival was similar between the two groups.
"With a significant improvement in the 12-month overall survival rate and a well-defined safety and tolerability profile, the Onivyde combination regimen is well-positioned to become the standard of care in the post-gemcitabine setting," lead investigator Andrea Wang-Gillam, MD, PhD, Siteman Cancer Center and Washington University School of Medicine, St. Louis, said in a statement.
"This new therapy offers hope for extended life expectancy in a patient population with limited options."
In the international trial, 417 patients with gemcitabine-refractory metastatic pancreatic adenocarcinoma 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.
In the primary analysis that was conducted after 83% events, median OS was 6.1 months with the liposomal irinotecan triplet compared with 4.2 months with 5-FU and leucovorin alone (unstratified HR, 0.67;P= .012). 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).
The objective response rate was 7.7% versus 0.8%, for the combination and control, respectively. 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 29% of patients treated with the liposomal irinotecan triplet combination versus 9% in the control arm (P= .0006).
Liposomal irinotecan monotherapy did not demonstrate superior efficacy compared with 5-FU and leucovorin. In the updated analysis, median OS with monotherapy was 4.9 versus 4.2 months with 5-FU and leucovorin (HR, 1.08; P = .50). Moreover, liposomal irinotecan alone was associated with more adverse events (AEs) compared with the combination, suggesting that the drug should only be used in combination.
In patients receiving at least one dose of liposomal irinotecan, the most commonly reported grade ≥3 AEs with the combination were neutropenia (20%), fatigue (14%), diarrhea (13%), vomiting (11%), nausea (8%), asthenia (8%), and abdominal pain (7%). The rates of diarrhea were 12.8% versus 21.1% and the rates of vomiting were 11.1% versus 13.6% for the liposomal irinotecan combination versus single-agent, 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.
"Pancreatic cancer is a devastating disease with dismal survival," Wang-Gillam said. "These updated findings reinforce the overall survival benefit of Onivyde in treating patients with metastatic pancreatic adenocarcinoma who have progressed after gemcitabine-based therapy."
A biomarker analysis at the GI Cancers Symposium looked specifically at the impact of CA19-9 levels on efficacy.2In this analysis, median OS was similar between the liposomal irinotecan combination arm and the control for those with CA19-9 levels <120 (7.6 vs 7.2 months; HR, 1.12). As CA19-9 levels increased, the benefit with liposomal irinotecan became more dramatic. In those with levels ≥12815 in the liposomal irinotecan combination arm (n = 26), median OS was 4.6 versus 1.9 months in the control arm (n = 26; HR, 0.35; 95% CI, 0.19-0.64).
The FDA approved liposomal irinotecan for patients with pancreatic cancer following progression on a gemcitabine-based regimen in October 2015, based on the primary analysis of the NAPOLI-1 trial. In the United States, liposomal irinotecan is being developed by Merrimack Pharmaceuticals.
A phase I study is looking into liposomal irinotecanin combination with cyclophosphamide for pediatric patients with solid tumors (NCT02013336). Additionally, a pilot study is exploring liposomal irinotecan biodistribution and the feasibility of ferumoxytol as a tumor-imaging agent (NCT01770353). Early results from this pilot study have shown promise for this approach.