SAN FRANCISCO (FRONTLINE MEDICAL NEWS)A nanoliposomal formulation of irinotecan, MM-398, prolongs survival for patients with metastatic pancreatic cancer by nearly 2 months when combined with conventional chemotherapy drugs, according to an expanded analysis of the NAPOLI-1 trial. Results were reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

“This study’s intention-to-treat analysis demonstrated a statistically significant increase in overall survival with the MM-398 plus 5-FU/LV combination … over 5-FU/LV,” said Dr. Li-Tzong Chen of the National Institute of Cancer Research, Tainan, Taiwan. “The safety profile suggests the combination is associated with a manageable toxicity profile.”

In contrast, analyses did not show any significant survival advantage of monotherapy with MM-398 (also known as nal-IRI), which achieves extended circulation of irinotecan in the blood relative to the conventional formulation.

As a result of accumulated data, MM-398 in combination with 5-FU/LV has received fast-track status from the Food and Drug Administration.

“The survival was similar to previous reports of FOLFIRI in second-line pancreas cancer,” said invited discussant Dr. Laura W. Goff, assistant professor of medicine (hematology/oncology) at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn. “MM-398 appears to have activity in combination with 5-FU/LV in previously treated pancreas cancer.”

Session attendee Dr. Hanna Sanoff of the UNC Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., said, “I’d like to ask a little bit of a provocative question if I could. [Dr. Goff] showed us data that FOLFIRI actually looked pretty similar to nal-irinotecan and fluorouracil, so do you think that this warrants FDA approval in the absence of an appropriate comparator with the existing cheaper drug?”

“At the current time, no, I would not approve FDA approval,” Dr. Goff replied. “But I think it would be interesting to see where that would shake out. Obviously, we see this in pancreas cancer as well as in other regimens, there is not as much interest in investigating the standard already-approved therapies. I don’t know if MM-398 with 5FU is significantly different than FOLFIRI. But I don’t have a lot of clinical experience with it.”

In additional comments provided in an interview, Dr. Goff said, “I am always happy to have more options in pancreas cancer … Figuring out what to do with [MM-398] is going to be the hard part, but I think it will be exciting to see how it translates into other regimens, possibly even in combination with oxaliplatin; I think the company has that planned. And certainly seeing where this has a role, either in front line or in previously treated gemcitabine patients, is going to be important.”

“It will require bigger studies to sort out exactly how efficacious it is and where the best place to use it is going to be, but it’s exciting to have agents to explore,” she concluded.

The international randomized phase III trial, sponsored by Merrimack Pharmaceuticals, enrolled 417 patients with metastatic pancreatic cancer who had previously received gemcitabine-based therapy. They were randomized to receive the investigational agent MM-398 alone, 5-fluorouracil (5-FU) plus leucovorin (LV) alone, or the combination.

Intention-to-treat analysis showed that median overall survival was 4.2 months with 5-FU/LV alone but 6.1 months with MM-398 plus 5-FU/LV (hazard ratio, 0.57; P = .0009), Dr. Chen reported.

Findings were similar across subgroups and in the per-protocol population, defined as patients who received at least 80% of the dose intensity of the protocol-defined treatment during the first 6 weeks of treatment (8.9 vs. 5.1 months; hazard ratio, 0.47; P = .0018).

In addition, the MM-398 plus 5-FU/LV combination was associated with a better median progression-free survival (3.1 vs. 1.5 months, P = .0001), overall response rate (16% vs. 1%, P less than .001), and cancer antigen 19-9 (CA19-9) response rate (36% vs. 12%, P = .0009).

The combination did lead to higher rates of dose reductions and dose delays, but treatment discontinuations were generally similar at 11% with the combination and 8% with 5-FU/LV alone.

Patients in the combination group were more likely to experience various grade 3 or worse toxicities, such as fatigue (14% vs. 4%), diarrhea (13% vs. 5%), and a reduction in neutrophil count (20% vs. 2%).