Onivyde FDA Approved to Treat Metastatic Pancreatic Cancer

The FDA has approved MM-398, branded as Onivyde (irinotecan liposome injection) in combination with 5-fluorouracil (5-FU) chemotherapy and leucovorin for patients with metastatic pancreatic cancer. The treatment follows prior administration of a gemcitabine-based regimen.


The FDA has approved MM-398, branded as Onivyde (irinotecan liposome injection), in combination with 5-fluorouracil (5-FU) chemotherapy and leucovorin for patients with metastatic pancreatic cancer. The treatment follows prior administration of a gemcitabine-based regimen.

The approval was based on data from the phase III NAPOLI-1 trial, which demonstrated a 1.9-month improvement in overall survival (OS) with the addition of MM-398 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, 0.57; 95% CI, 0.41-0.80; P = .0009).

“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, MD, 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 MM-398 monotherapy, 5-FU with leucovorin (control), or MM-398 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 MM-398 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, MM-398 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 a subanalysis that assessed patients who received at least 80% of the target dose in the first 6 weeks, there was an even greater OS benefit with MM-398. In this per-protocol population, treatment with MM-398 plus 5-FU/leucovorin (n = 66) improved OS by 53% compared with 5-FU/ leucovorin alone (n = 71). The median OS was 8.9 versus 5.1 months for the combination and 5-FU/ leucovorin, respectively (HR, 0.47; 95% CI, 0.29-0.77; P = .0018).

In patients receiving at least one dose of MM-398, the most commonly reported grade ≥3 adverse events with the combination were neutrophil count decrease (20%), fatigue (14%), diarrhea (13%), vomiting (11%), nausea (8%), asthenia (8%), and abdominal pain (7%). In the per-protocol group, neutropenia and diarrhea were less common with the combination versus the full population, at 15% and 12%, respectively.

MM-398 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, 0.93; P = .5545). Moreover, in some cases, MM-398 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% versus 21.1% and the rates of vomiting were 11.1% versus 13.6% for the combination and single-agent MM-398 arms, respectively. Additionally, febrile neutropenia occurred in 1.7% of patients in the combination arm compared with 4.1% with MM-398 monotherapy and not at all with 5-FU/leucovorin alone.

MM-398 was approved along with a boxed warning regarding severe neutropenia and diarrhea. Additionally, given the differences in efficacy and adverse events, MM-398 is not approved for use as a single agent for the treatment of patients with metastatic pancreatic cancer.

MM-398 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 United States, MM-398 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 MM-398.

Today, MM-398 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, MM-398 has been explored in a limited number of clinical trials. A phase I study is looking into the drug in combination with cyclophosphamide for pediatric patients with solid tumors (NCT02013336). Additionally, a pilot study is exploring MM-398 biodistribution and the feasibility of ferumoxytol as a tumor-imaging agent (NCT01770353). 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).