The approval was based on data from the phase 3 NAPOLI-1 trial, which demonstrated a 1.9-month improvement in overall survival (OS) with the addition of Onivyde to 5-FU and leucovorin.
The FDA has approved Onivyde (MM-398) in combination with 5-fluorouracil (5-FU) chemotherapy and leucovorin as a treatment for patients with metastatic pancreatic cancer following prior administration of a gemcitabine-based regimen.
The approval was based on data from the phase 3 NAPOLI-1 trial, which demonstrated a 1.9-month improvement in overall survival (OS) with the addition of Onivyde 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.
“Many FDA staff who review drug applications are clinicians as well, so it’s especially rewarding when we are able to expedite access to new treatments for patients with unmet needs,” Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “By using the Priority Review designation for the application for Onivyde, patients will have earlier access to a drug that helps extend survival.”
In the international trial, 417 patients with gemcitabine-refractory metastatic pancreatic cancer were randomized to Onivyde monotherapy, 5-FU with leucovorin (control), or Onivyde 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 2,000 mg/m2 with racemic leucovorin at 200 mg/m2 weekly for four weeks followed by two weeks of rest (149 patients). In the combination arm, intravenous Onivyde was administered at 80 mg/m2 prior to 5-FU at 2400 mg/m2 and racemic leucovorin at 400 mg/m2 every two weeks (117 patients). In the monotherapy group, Onivyde was administered at 120 mg/m2 every three weeks (151 patients).
Altogether, 61 percent of patients had cancer in the head of the pancreas and 68 percent had liver metastases. A majority of the patients (83 percent) were enrolled outside of the U.S. In the combination arm, the median age of patients was 63 years, 64 percent were Caucasian, and 29 percent were Asian.
The median progression-free survival was 3.1 months for the combination compared with 1.5 months with the control. At 12 weeks, 57 percent of patients treated with the combination were alive and progression-free compared with 26 percent with 5-FU and leucovorin alone.
The objective response rate by RECIST v1.1 criteria was 16 percent versus 1 percent, for the combination and control, respectively. For those with baseline CA19-9 levels of greater than 30 U/ml at baseline (84 percent in the combination arm), there was at least a 50 percent reduction in the marker for 36 percent of patients treated with the combination versus 12 percent in the control arm.
In a subanalysis that assessed patients who received at least 80 percent of the target dose in the first six weeks, there was an even greater OS benefit with Onivyde. In this per-protocol population, treatment with Onivyde plus 5-FU/leucovorin (66 patients) improved OS by 53 percent compared with 5-FU/ leucovorin alone (71 patients). The median OS was 8.9 versus 5.1 months for the combination and 5-FU/ leucovorin, respectively.
In patients receiving at least one dose of Onivyde, the most commonly reported grade ≥3 adverse events with the combination were neutrophil count decrease (20 percent), fatigue (14 percent), diarrhea (13 percent), vomiting (11 percent), nausea (8 percent), asthenia (8 percent), and abdominal pain (7 percent). In the per-protocol group, neutropenia and diarrhea were less common with the combination versus the full population, at 15 percent and 12 percent, respectively.
Onivyde 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. Moreover, in some cases, Onivyde alone was associated with more side effects than the drug in combination, suggesting that the drug should only be used in combination.
The rates of diarrhea were 12.8 percent versus 21.1 percent and the rates of vomiting were 11.1 percent versus 13.6 percent for the combination and single-agent Onivyde arms, respectively. Additionally, febrile neutropenia occurred in 1.7 percent of patients in the combination arm compared with 4.1 percent with Onivyde monotherapy and not at all with 5-FU/leucovorin alone.
Onivyde was approved along with a boxed warning regarding severe neutropenia and diarrhea. Additionally, given the differences in efficacy and adverse events, Onivyde is not approved for use as a single agent for the treatment of patients with metastatic pancreatic cancer.
Onivyde is a nanoliposomal encapsulation of irinotecan, allowing for the drug to stay in circulation for a longer duration compared with standard irinotecan. Additionally, this mechanism allows for higher drug uptake within tumor cells and conversion of irinotecan to its active form, SN38.
In the U.S., Onivyde is being developed by Merrimack Pharmaceuticals. In September 2014, Merrimack entered into an agreement with Baxalta, previously Baxter, to develop and commercialize the drug outside of the country. Additionally, in Taiwan, PharmaEngine controls commercialization rights for Onivyde.
Today, Onivyde was also approved in Taiwan in combination with 5-FU and leucovorin for patients with metastatic pancreatic cancer following gemcitabine-based therapy. This was the first regulatory approval granted to the medication and was also based on findings from the NAPOLI-1 trial.
At this time, Onivyde has been explored in a limited number of clinical trials. A phase 1 study is looking into the drug in combination with cyclophosphamide for pediatric patients with solid tumors. Additionally, a pilot study is exploring Onivyde biodistribution and the feasibility of ferumoxytol as a tumor-imaging agent. Early results from this pilot study have shown promise for this approach.
Chen L-T, Von Hoff DD, Li C-P, et al. Expanded analyses of napoli-1: Phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. J Clin Oncol. 2015;33 (suppl 3; abstr 234).