Adding MM-398 (irinotecan liposome injection; nal-IRI; Onivyde) to 5-fluorouracil (5-FU) and leucovorin had no negative effect on quality of life (QOL) while significantly improving overall survival (OS) in patients with metastatic pancreatic cancer, according to an analysis of the phase III NAPOLI-1 trial presented at the 2016 World Congress on Gastrointestinal (GI) Cancer.
"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, PhD, 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 MM-398 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.2
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).
The addition of MM-398 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 (HR, 0.67; 95% CI, 0.49-0.92; P
QOL was among the NAPOLI-1 trial’s secondary endpoints. Hubner and colleagues assessed the impact of MM-398 on QOL and symptom burden in patients.
The QOL evaluation was done in 69% of patients in the intent to treat population receiving MM-398 plus fluorouracil/leucovorin and in 53% of patients receiving fluorouracil/leucovorin alone who also completed QOL assessments at baseline, every 6 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 >10% were categorized as Improved
, whereas patients who did not meet the improvement criteria and died or showed a score decrease >10% 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 MM-398 group, grade 3/4 adverse events occurred more frequently in the MM-398 versus control arm, including fatigue (27% vs 1%), diarrhea (13% vs 4%), and vomiting (11% vs 3%).
One potential limitation of the analysis was the small number of patients assessed, Hubner noted.
- Hubner R, Cubillo A, Blanc J-F, et al. 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. Presented at: 2016 World Congress on GI Cancer; June 28 - July 2, 2016; Barcelona, Spain. Abstract O-004.
- Wang-Gillam A, Li C-P, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545–557.
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