LIPOSOMAL IRINOTECAN FOR PANCREATIC CANCER

SAN FRANCISCO — An expanded analysis of the phase 3 NAPOLI-1 trial supports the benefit of adding MM-398 (irinotecan liposome injection) to 5-fluorouracil (5-FU) plus leucovorin (LV) in patients with metastatic pancreatic cancer previously treated with gemcitabine. The new data were presented here at the 2015 Gastrointestinal Cancers Symposium.

Median overall survival was better with MM-398 plus 5-FU/LV than with 5-FU/LV alone (8.9 vs 5.1 months; hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.29 - 0.77; P = .0018).

The updated analysis evaluated MM-398 in the per protocol population, which involved patients who received at least 80% of the target dose in the first 6 weeks.

These findings confirm previous results from the primary intent to treat (ITT) analysis, said study author Li-Tzong Chen, MD, PhD, from the National Institute of Cancer Research in Tainan City, Taiwan. "The data are continuing to mature and these analyses reinforce our conclusions about the potential for MM-398 in patients with metastatic pancreatic cancer who have previously received gemcitabine," he said.

MM-398, currently under development by Merrimack, is an investigational nanotherapeutic that consists of 80,000 molecules of the chemotherapeutic irinotecan stably encapsulated in a 100 mm liposome sphere.

The level of SN-38, the active metabolite of MM-398, was 9.6 ng/g in the tumor and was 1.7 ng/mL in blood at 72 hours.

In a phase 2 trial, median survival was 5.2 months for patients with refractory metastatic pancreatic cancer treated with MM-398 (Br J Cancer. 2013;109:920-925).

Consistent Benefit Seen

In the NAPOLI-1 study, an international multicenter trial conducted at more than 100 sites, 417 patients with metastatic pancreatic cancer previously treated with gemcitabine were randomized to one of three treatments. The primary end point was overall survival.

One-third of the patients received single-agent MM-398 120 mg/m² every 3 weeks; one-third received 5-FU 2000 mg/m² over 24 hours and racemic LV 200 mg/m² over 30 minutes for 4 weeks followed by 2 weeks off (the control group); and one-third received MM-398 80 mg/m² every 3 weeks followed by 5-FU 2400 mg/m² over 46 hours and racemic LV 400 mg/m² over 30 minutes.

Primary results from NAPOLI-1 were presented last year at the European Society for Medical Oncology meeting. At that time, researchers reported that overall survival was better with the combination of MM-398 plus 5-FU/LV than with 5-FU/LV alone (6.1 vs 4.2 months; HR, 0.67; P = .012).

In the per protocol analysis, overall survival was significantly longer with the combination therapy, Dr Chen reported. "It also significantly improved overall survival in the non-per protocol population, compared with the control arm" (4.4 vs 2.8 months; HR, 0.56; 95% CI, 0.33 - 0.97; P = .0365).

"We looked to see if there were any demographic characteristics that were more likely to be included in the per protocol population, but they were similar and there were no real differences in the population," Dr Chen said.

Significant differences were also observed between the combination of MM-398 plus 5-FU/LV and 5-FU/LV alone for overall progression-free survival (3.1 vs 1.5 months; log-rank test P = .0001), median progression-free survival at 12 weeks (57% vs 26%), overall response rate (16% vs 1%; Fisher's exact test P = .001), and CA19-9 response (36% vs 12%; Fisher's exact test P = .0009).

No benefit was observed with single-agent MM-398; however, in the ITT analysis, median overall survival was better with single-agent MM-398 than with 5-FU/LV (4.9 vs 4.2 months; P = .5545).

A sensitivity analysis favored the combination therapy over 5FU/LV alone across prognostic subgroups, tumor characteristics, and previous treatments, Dr Chen explained.

The safety profile for the combination was manageable and consistent with previously reported safety results, the researchers report. The most frequent adverse events were neutropenia (20% in the combination group vs 2% in the control group), fatigue (14% vs 4%), and gastrointestinal effects such as diarrhea (13% vs 5%) and vomiting (11% vs 3%).

In a discussion of the study, Laura Goff, MD, assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee, noted that MM-398 resulted in an increase in overall survival, and that a partial response rate of 16% in a second-line population is "provocative."

"MM-398 appears to have activity in combination with 5-FU/leucovorin in previously treated pancreas cancer, and it has received fast-track status from the FDA," Dr Goff said.

The study was funded by Merrimack Pharmaceuticals Inc. 

2015 Gastrointestinal Cancers Symposium (GICS): Abstract 234. Presented January 16, 2015.