Survival Benefit With Onivyde Sustained in Updated Pancreatic Cancer Study Data

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This study of Onivyde, 5-FU and leucovorin for the treatment of patients with metastatic pancreatic cancer was presented at the 2016 Gastrointestinal Cancers Symposium.

The addition of Onivyde (liposomal irinotecan; nal-IRI; MM-398) to 5-fluorouracil (5-FU) and leucovorin reduced the risk of death by 25 percent for patients with metastatic pancreatic cancer following progression on a gemcitabine-based regimen. These updated data from the phase 3 NAPOLI-1 trial were presented at the 2016 Gastrointestinal (GI) Cancers Symposium, a meeting of hundreds of oncologists and other oncology professionals in San Francisco in mid-January.1

In the updated analysis that was conducted after 91 percent of events, median overall survival (OS) with Onivyde, 5-FU, and leucovorin was 6.2 months compared with 4.2 months for 5-FU and leucovorin alone. After 12 months, 26 percent of patients treated with the Onivyde combination remained alive compared with 16 percent 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, from the 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 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 2000 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 United States. In the combination arm, the median age of patients was 63 years, 64 percent were Caucasian and 29 percent were Asian.

In the primary analysis that was conducted after 83 percent events, median OS was 6.1 months with the Onivyde triplet compared with 4.2 months with 5-FU and leucovorin alone. The median progression-free survival was 3.1 months for the combination compared with 1.5 months with the control.The objective response rate was 7.7 percent versus 0.8 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 a reduction of at least 50 percent in the marker for 29 percent of patients treated with the Onivyde triplet combination versus 9 percent in the control arm.

Onivyde 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. Moreover, Onivyde 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 Onivyde, the most commonly reported AEs of at least grade 3 with the combination were neutropenia (20 percent), fatigue (14 percent), diarrhea (13 percent), vomiting (11 percent), nausea (8 percent), asthenia (8 percent), and abdominal pain (7 percent). 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 Onivyde combination versus single-agent, 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.

“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.2 In this analysis, median OS was similar between the Onivyde combination arm and the control for those with CA19-9 levels less than 120 (7.6 vs 7.2 months). As CA19-9 levels increased, the benefit with Onivyde became more dramatic. In those with levels of at least 12815 in the Onivyde combination arm (26 patients), median OS was 4.6 versus 1.9 months in the control arm (26 patients).

The FDA approved Onivyde 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, Onivyde is being developed by Merrimack Pharmaceuticals.

A phase 1 study is looking into Onivyde combination with cyclophosphamide for pediatric patients with solid tumors (NCT02013336). Additionally, a pilot study is exploring Onivyde biodistribution and the feasibility of ferumoxytol as a tumor-imaging agent (NCT01770353). Early results from this pilot study have shown promise for this approach.


  1. Wang-Gillam A, Li C-P, Bodoky G, et al. Updated overall survival analysis of NAPOLI-1: Phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. J Clin Oncol. 2016;34 (suppl 4S; abstr 417).
  2. Chen L-T, Siveke JT, Wang-Gillam A, et al. Effect of baseline carbohydrate antigen 19-9 (CA19-9) level on overall survival (OS) in NAPOLI-1 trial: A phase III study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. J Clin Oncol. 2016;34 (suppl 4S; abstr 425).