Addition of Onivyde to Standard Care Improves Survival, Does Not Worsen Quality of Life in Pancreatic Cancer

The addition of Onivyde (MM-398) to 5-fluorouracil (5-FU) and leucovorin significantly improved overall survival (OS) while having no negative impact on quality of life (QOL) for patients with metastatic pancreatic cancer, according to an analysis of the phase 3 NAPOLI-1 trial presented at the 2016 World Congress on Gastrointestinal (GI) Cancer, a gathering of oncology professionals from around the world in Barcelona, Spain.

"This quality of life analysis of the NAPOLI-1 data underscores the significant clinical benefit the Onivyde regimen provides to a patient population with few treatment options,” Richard Hubner, an investigator on the NAPOLI-1 trial and Consultant Medical Oncologist at Christie NHS Foundation Trust, said in a statement.

“Fluorouracil and leucovorin is recognized as a well-tolerated therapy for metastatic pancreatic cancer patients. The addition of Onivyde, a second chemotherapeutic agent, to this treatment regimen demonstrated significant improvement in median overall survival, progression-free survival, and overall response rate with little or no impact on baseline quality of life at 12 weeks, as shown in this analysis. This further supports the growing recognition that the Onivyde combination regimen is a clinically beneficial treatment option for metastatic pancreatic cancer patients who have progressed on gemcitabine-based therapy."

In October 2015, the FDA approved Onivyde in combination with 5-FU and leucovorin as a treatment for patients with metastatic pancreatic cancer following prior administration of a gemcitabine-based regimen, based on results from the NAPOLI-1 trial.

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 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).

The addition of Onivyde to 5-FU and leucovorin improved OS by 1.9 months. In the combination arm, the median OS was 6.1 months compared with 4.2 months with 5-FU and leucovorin alone.

QOL was among the NAPOLI-1 trial’s secondary endpoints. Hubner and colleagues assessed the impact of Onivyde on QOL and symptom burden in patients.

The QOL evaluation was done in 69 percent of patients in the intent to treat population receiving Onivyde plus fluorouracil/leucovorin and in 53 percent of patients receiving fluorouracil/leucovorin alone who also completed QOL assessments at baseline, every six weeks during treatment, and at 30 days after study completion.

Patients in both treatment groups demonstrated an observed median change from baseline in Global Health Status (GHS) score of 0 after 12 weeks on study. The observed median change included assessments on subscale scores regarding financial difficulties, physical, emotional, cognitive and social functioning, plus symptom subscores on pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, nausea and vomiting.

“Global health status and functional scale scores were not significantly different between treatment arms at baseline and showed no appreciable change over 12 weeks,” Hubner said when presenting the data at the World GI Congress.

Baseline median GHS scores were similar in both treatment groups and ranged from 0 to 33 points. Changed scores greater than 10 percent were categorized as Improved, whereas patients who did not meet the improvement criteria and died or showed a score decrease greater than 10 percent were categorized as Worsened. Those patients meeting neither improved nor worsened criteria were deemed Stable.

Pairwise treatment group comparison was done using the Cochran-Mantel-Haenszel test. A difference of 0 was observed in the subscale scores for global health status, and emotional, cognitive, social and role functioning. A change of -6.7 points in the physical functioning scale was below the 10-point threshold and determined as “no change.”

No substantial differences were seen in symptom scale scores between the treatment arms for nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea. Fatigue subscores increased from baseline at week 12 by 11 points, which corresponded to a “moderate” increase.

Although a manageable safety profile was demonstrated in the Onivyde group, grade 3/4 adverse events occurred more frequently in the Onivyde versus control arm, including fatigue (27 percent vs 1 percent), diarrhea (13 percent vs 4 percent) and vomiting (11 percent vs 3 percent).

One potential limitation of the analysis was the small number of patients assessed, Hubner noted.