Novel Form of Irinotecan Ups Survival in Pancreatic Cancer

Zosia Chustecka

June 26, 2014

A new version of a standard chemotherapy has shown an improvement in survival in metastatic pancreatic cancer in patients who had previously been treated with gemcitabine.

The investigational product, a novel encapsulation of irinotecan in a long-circulating nanoliposome (MM-398, Merrimack), was shown to extend overall survival, as well as progression-free survival, when it was added onto 5-fluorouracil (5-FU) and leucovorin as a second-line therapy.

The results come from a 417-patient phase 3 trial known as NAPOLI-1, presented this week at the European Society for Medical Oncology (ESMO) 16th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

The combination of MM-398 with 5-FU and leucovorin improved overall survival to 6.1 months compared with 4.2 months with the control group of 5-FU and leucovorin (P = .012; hazard ratio [HR], 0.67).

The addition of MM-398 also improved the progression-free survival to 3.1 months compared with 1.5 months in the control group (P = .0001; HR, 0.56).

NAPOLI-1 has demonstrated that MM-398 plus 5-FU/leucovorin is an effective second-line therapy in metastatic pancreatic cancer, commented ESMO spokesperson Roberto Labianca, MD, director of the Cancer Centre, Ospedale Giovanni XXIII in Bergamo, Italy, who was not involved in the trial.

"There is still a need for new treatments in metastatic pancreatic cancer and every attempt to increase the activity of chemotherapy is welcome," he said. "This trial has important clinical implications in a difficult setting, because we will be able to add the new drug to standard treatment and increase activity and efficacy."

"Future trials should evaluate this combination as first-line treatment and in locally advanced pancreatic cancer, " Dr. Labianca added.

Patients With Limited Options

"Patients with metastatic pancreatic cancer or pancreatic cancer in general have very limited options," said study author Andrea Wang-Gillam, assistant professor in the division of oncology at Washington University in St. Louis. "These patients just simply don't do well. This was a positive trial and will provide a new treatment option for patients with metastatic pancreatic cancer."

Dr. Wang-Gillam explained that the nanoliposomal delivery system used for irinotecan allows longer drug exposure in the circulation and more accumulation of the drug and its active metabolite, SN38, at the tumor site. The result is higher antitumor activity, she added.

The new product was shown to be more effective than conventional irinotecan alone in the preclinical setting, and an earlier phase 2 study had demonstrated the antitumor activity of MM-398 monotherapy as second-line treatment in patients with metastatic pancreatic cancer refractory to gemcitabine (Br J Cancer. 2013;109:920-925).

The current NAPOLI-1 trial was a global randomized phase 3 trial conducted at more than 100 sites, including Europe and the United States, and also Australia, Brazil, and Taiwan. A total of 417 patients were randomized, and 398 received treatment. Baseline characteristics were balanced between the treatment groups, and 61% of patients had cancer at the head of pancreas and 68% had liver metastases.

There were 3 treatment groups. Some patients received MM-398 alone (120 mg/m² intravenously [IV] over 90 min) every 3 weeks; others received standard treatment with 5-FU (2000 mg/m² over 24 h) plus racemic leucovorin (200 mg/m² over 30 min) for 4 weeks, followed a 2-week rest; and a third group received a combination of MM-398 (80 mg/m² IV over 90 min) prior to 5-FU (2400 mg/m² over 46 h) and racemic leucovorin (400 mg/m² over 30 min) every 2 weeks.

MM-398 alone did not provide any additional survival benefit over standard therapy. But adding the new product to standard therapy significantly improved survival, and also improved the overall response rate.

However, the addition of the new drug also increased adverse effects, as shown below. But Dr. Labianca commented that "the tolerability of MM-398 plus 5FU/leucovorin regimen was acceptable and the toxicity manageable."

Table. Adverse Effects in the 3 Treatment Groups

Adverse Effect MM-398 Alone MM-398, 5-FU, and Leucovorin 5-FU and Leucovorin
Diarrhea, % 21.1 12.8 4.5
Vomiting, % 13.6 11.1 3.0
Fatigue, % 6.1 13.7 3.7
Decreased neutrophil count, % 15.3 23.1 3.0
Febrile neutropenia 4.1 1.7 0.0
Sepsis 2.0 3.4 0.7


The study was funded by Merrimack, the manufacturer of MM-398.

European Society for Medical Oncology (ESMO) 16th World Congress on Gastrointestinal Cancer: Abstract O-0003. Presented June 25, 2014.


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