Date: 2016-10-11
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress
Company: Merrimack Pharmaceuticals (USA - MA)
Product: Onivyde™ (MM-398 - nanoliposomal irinotecan injection)
Action
mechanism: topoisomerase I inhibitor. MM-398 is a novel encapsulation of irinotecan in a long-circulating nanoliposomal formulation designed to increase drug deposition and prolong cytotoxic effects, with the goal of improving its anti-cancer properties. In May 2014, Merrimack announced that the Phase 3 trial, known as NAPOLI-1, studying MM-398 in combination with 5-fluorouracil (5-FU) and leucovorin achieved its primary and secondary endpoints for patients with metastatic pancreatic cancer who were previously treated with a gemcitabine-based therapy. In the study, the combination of MM-398 with 5-FU and leucovorin demonstrated a statistically significant improvement in overall survival, progression free survival and overall response rate compared to the control arm of 5-FU and leucovorin alone. Onyvide® in combination with 5-fluorouracil and leucovorin was approved by the FDA in October 2015 for the treatment of patients with metastatic adenocarcinoma of the pancreas whose disease progressed after gemcitabine-based therapy.
Disease: metastatic pancreatic cancer
Therapeutic area: Cancer - Oncology
Country: Argentina, Australia, Brazil, Canada, Czech Republic, France, Germany, Hungary, Italy, Korea, Republic of, South Africa, Spain, Taiwan, UK, USA
Trial
details: The study is an open label, randomized phase 3 study of MM-398 with or without 5-Fluorouracil (5-FU) and Leucovorin, versus 5-FU and leucovorin in metastatic pancreatic cancer patients who have progressed on prior gemcitabine based therapy. (NCT01494506)
Latest
news: * On October 11, 2016, Merrimack Pharmaceuticals announced final results from the pivotal Phase 3 NAPOLI-1 study validating the use of Onivyde® (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin, which represents a new standard of care for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) following treatment with gemcitabine-based therapy. The final NAPOLI -1 results were presented in a poster discussion session and a separate analysis of NAPOLI -1 safety-over-time data was presented in a poster session at the European Society for Medical Oncology 2016 Congress in Copenhagen . * On June 30, 2016, Merrimack Pharmaceuticals announced a newly presented analysis of the Phase 3 NAPOLI-1 data shows patients treated with Onivyde® (irinotecan liposome injection), also known as "nal-IRI," in combination with fluorouracil (5-FU) and leucovorin, maintain similar baseline quality of life at 12 weeks despite the addition of a second chemotherapeutic agent when compared to 5-FU and leucovorin alone. These findings were presented in an oral session by Dr. Richard Hubner , an investigator on the NAPOLI -1 trial and a Consultant Medical Oncologist at Christie NHS Foundation Trust , at the European Society for Medical Oncology (ESMO) 18th World Congress on Gastrointestinal Cancer in Barcelona, Spain. Previously reported Phase 3 NAPOLI-1 data demonstrate that the Onivyde® combination regimen significantly improves overall survival and progression-free survival when compared to 5-FU and leucovorin alone. * On January 19, 2016, Merrimack Pharmaceuticals announced that an updated overall survival analysis of the Phase 3 NAPOLI-1 study of Onivyde® (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin achieved a substantial improvement in 12-month overall survival in patients with post-gemcitabine metastatic pancreatic adenocarcinoma when compared to 5-FU and leucovorin alone. These updated data will be presented at the American Society of Clinical Oncology 2016 Gastrointestinal Cancers Symposium (ASCO GI), January 21-23, 2016, in San Francisco. * On November 23, 2015, Merrimack Pharmaceuticals and Baxalta announced that The Lancet has published the article "Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy ( NAPOLI -1): a global, randomized, open-label phase 3 trial" online in advance of its print issue. The NAPOLI -1 study results were the basis of the recent U.S. Food and Drug Administration (FDA) and Taiwan FDA approval of Onivyde™ (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. NAPOLI -1 was a randomized, open label Phase 3 study in patients with metastatic adenocarcinoma of the pancreas who received prior gemcitabine-based therapy, and was the largest Phase 3 study in this setting to date. Patients were enrolled at 76 sites in North America , South America , Europe , Asia and Oceania. The study evaluated Onivyde™, in combination with 5-FU and leucovorin administered every two weeks and as a monotherapy administered every three weeks. Each Onivyde™ containing arm was compared to a control arm of 5-FU and leucovorin. A total of 417 patients were randomized across the three arms. The primary endpoint of the study was overall survival. Key findings of the study as published in The Lancet include: The Onivyde™ combination regimen demonstrated a significant increase in median overall survival versus 5-FU and leucovorin alone: 6.1 months vs 4.2 months (p=0.012, unstratified hazard ratio for death (HR) =0.67, 95% CI: [0.49–0.92]). The monotherapy regimen in this study did not show improvement over the 5-FU and leucovorin arm: 4.9 vs 4.2 months (p=0.94, HR=0.99, 95% CI: [0.77–1.28]).
The extended data cutoff occurred at final database lock in November 2015 after 382 OS events that had occurred in the intention-to-treat (ITT) population. In this extended analysis of NAPOLI -1, the previously described overall survival advantage was maintained for ONIVYDE in combination with 5-FU and leucovorin versus 5-FU and leucovorin alone: 6.2 months versus 4.2 months (p=0.039, hazard ratio (HR) =0.75, 95% CI: [.057 - .99]). Findings also showed that one in four patients treated with the ONIVYDE combination regimen survived one year or more, a significant milestone. This was represented by a 26% probability of survival at one year for patients receiving ONIVYDE in combination with 5-FU and leucovorin versus 16% for patients who received 5-FU and leucovorin alone. Furthermore, disease control was achieved in twice as many patients treated with ONIVYDE in combination with 5-FU and leucovorin (52%) compared to 5-FU and leucovorin alone (24%). The demonstrated improvements in overall survival for the ONIVYDE combination regimen were achieved with little or no impact on quality of life over 12 weeks despite the addition of a second chemotherapeutic agent to 5-FU and leucovorin, a therapy recognized as a well-managed treatment for metastatic pancreatic cancer.
Results from a separate analysis of the NAPOLI -1 data evaluating the incidence and prevalence of gastrointestinal toxicities and neutropenia during the course of treatment with ONIVYDE plus 5-FU and leucovorin showed that the majority of these adverse events occurred early in treatment with decreased incidence and severity thereafter. Dose reductions or dose delays were commonly used to manage these adverse events and may account for the decreased incidence and/or severity that was observed.
The primary Phase 3 NAPOLI-1 data were the basis of the FDA and Taiwan FDA approvals of the Onivyde® (irinotecan liposome injection) combination regimen in October 2015 . They were also the basis of the European Union's Committee for Medicinal Products for Human Use (CHMP) positive opinion issued in July 2016 . The Onivyde® combination is designated as a category 1 treatment option in the 2016 National Comprehensive Cancer Network (NCCN) guidelines for pancreatic adenocarcinoma in the United States as well as a category 2B status in the 2015 European Society for Medical Oncology (ESMO) clinical practice guidelines in the European Union .
Methodology and Results: Effects of nal-IRI (MM-398) ± 5-fluorouracil on quality of life (QoL) in NAPOLI -1: A phase 3 study in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy (Abstract O-004)
Quality of life was assessed using the European Organization for Research and Treatment of Cancer quality of life core questionnaire, which includes functional scales (physical, role, cognitive, emotional and social), symptom scales (appetite loss, constipation, diarrhea, dyspnea, fatigue, insomnia, nausea and vomiting and pain), and a global health and quality of life scale.
Patients completed the European Organization for Research and Treatment of Cancer quality of life core questionnaire at treatment start, every 6 weeks and 30 days post-follow-up visit. A total of 154 patients (Onivyde® in combination with 5-FU and leucovorin, n=71; 5-FU and leucovorin, n=83) comprised the population for this analysis. Sixty-nine percent (49/71) of patients in the Onivyde® combination regimen group and 53% (44/83) in the 5-FU and leucovorin group had evaluable data at 12 weeks. No substantial differences are identified in the percentage of patients exhibiting improved, stable or worsening quality of life in the global health status, functional scale or symptom scale scores between the two study arms. The analysis demonstrates that in the NAPOLI -1 study, evaluable patients treated with the Onivyde® combination regimen were able to maintain quality of life over 12 weeks and there were no significant differences versus the 5-FU and leucovorin-treated patients in quality of life response despite the addition of a second chemotherapeutic agent.
Analysis of the updated data supports the robustness of the overall survival benefit of the Onivyde® combination therapy observed in the primary analysis of the NAPOLI -1 trial. Updated findings showed one in four patients treated with Onivyde® survived a milestone of one year or more: 12-month overall survival estimates of 26% (95% CI, 18-35%) for Onivyde® in combination with 5-FU and leucovorin, a 63% improvement when compared to 16% (95% CI, 10-24%) for 5-FU and leucovorin alone. No new safety or tolerability concerns were note in the updated analysis.
In this analysis of updated data from the NAPOLI -1 study, the previously described overall survival and progression free survival benefits were maintained for the Onivyde® in combination with 5-FU and leucovorin arm compared with 5-FU and leucovorin alone. This data analysis presents updated estimates of overall survival based on 378 events and includes data from all patients randomized across the three arms of the study. Twelve-month survival estimates for Onivyde® in combination with 5-FU and leucovorin were 26% (95% CI, 18-35%) compared to 16% (95% CI, 10-24%) for 5-FU and leucovorin alone. Six-month survival estimates were 53% (95% CI, 44-62%) for the Onivyde® combination regimen versus 38% (95% CI, 29-47%) for 5-FU and leucovorin. No new safety or tolerability concerns were noted in the updated data analysis. The most common grade 3+ adverse events occurring at a ? 2% incidence in the ONIVYDE-containing arms were neutropenia, diarrhea, vomiting, and fatigue.
In another updated analysis of NAPOLI -1 data, patients with a recorded baseline CA19-9 measurement were divided into quartiles to evaluate the treatment effect pattern of CA19-9 levels with Onivyde® in combination with 5-FU and leucovorin or 5-FU and leucovorin alone. A total of 213 patients treated with the Onivyde® combination regimen or 5-FU and leucovorin alone had a baseline CA19-9 measurement and were included in this analysis. Results show the observed overall survival and progression free survival benefits for the Onivyde® combination regimen compared to 5-FU and leucovorin alone were greatest among patients with the highest baseline CA19-9 levels. These results suggest that baseline CA19-9 levels are associated with the treatment effect observed for the Onivyde® combination regimen in metastatic pancreatic cancer patients.
Onivyde™ in combination with 5-FU and leucovorin achieved a longer progression-free survival compared with the 5-FU and leucovorin arm (3.1 months versus 1.5 months; unstratified HR=0.56 [95% CI, 0.41–0.75]).
Unconfirmed objective response rate was higher in the Onivyde™ in combination with 5-FU and leucovorin arm than in the 5-FU and leucovorin arm: 16% (19/117) versus 1% (1/119) (difference 15.4 percentage points, 95% CI, 8.5-22.3; p<0.0001).
The most common grade 3 or 4 adverse events that occurred more frequently in the Onivyde™ in combination with 5-FU and leucovorin arm ( > 2% incidence versus 5-FU and leucovorin) were neutropenia, diarrhea, vomiting, and fatigue.
Baxalta Incorporated is responsible for the development and commercialization of Onivyde™ outside of the United States and Taiwan under the exclusive licensing agreement with Merrimack. In May 2015 , the European Medicines Agency accepted for review Baxalta's marketing authorization application for Onivyde™ based on the same clinical results.
