Adding Novel Agent to Standard Therapy Improves Survival in Patients With Pancreatic Cancer After Prior Gemcitabine-Based Therapy


Key Points

  • MM-398 plus fluorouracil/leucovorin significantly improved overall survival and progression-free survival in patients with metastatic pancreatic cancer who had progressed or received prior gemcitabine-based therapy.
  • The combination regimen provides a new second-line treatment option for patients with metastatic pancreatic cancer.

The addition of the novel agent MM-398 to standard treatment improved overall survival in patients with metastatic pancreatic cancer who have already received gemcitabine, according to a phase III trial reported at the ESMO 16th World Congress on Gastrointestinal Cancer in Barcelona (Abstract O-0003).

“Patients with metastatic pancreatic cancer or pancreatic cancer in general have very limited options,” said study author Andrea Wang-Gillam, MD, PhD, 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.”

One of the biggest challenges in pancreatic cancer is drug delivery. MM-398 is a novel encapsulation of irinotecan in a nanoliposome, a delivery system that allows longer drug exposure in circulation and more accumulation of the drug and its active metabolite at the tumor site. “MM-398 therefore generates higher antitumor activity and is more effective than conventional irinotecan alone in the preclinical setting,” Dr. Wang-Gillam said.

A phase II study had previously demonstrated the antitumor activity of MM-398 monotherapy as second-line treatment in patients with metastatic pancreatic cancer refractory to gemcitabine.

NAPOLI-1 Trial

The current NAPOLI-1 trial was a global randomized phase III trial at more than 100 sites. Patients were randomly assigned to receive either MM-398 alone, standard treatment with fluorouracil (5-FU)/leucovorin, or MM-398 plus 5-FU/leucovorin. The trial included 417 patients who had progressed or received prior gemcitabine-based therapy, and the primary endpoint was overall survival.

Overall survival was significantly improved with the combination therapy of MM-398 plus 5-FU/leucovorin compared to 5-FU/leucovorin alone. Median overall survival was 6.1 months in the MM-398 plus 5-FU/leucovorin group compared to 4.2 months in the group receiving standard treatment with 5-FU/leucovorin alone (hazard ratio [HR] = 0.67, P = .012).

Progression-free survival also improved significantly, from 1.5 months with the standard therapy to 3.1 months in patients receiving MM-398 plus 5-FU/leucovorin (HR = .56, P < .001). MM-398 alone did not provide any additional survival benefit over standard therapy.

“The results are very exciting because the trial met its primary endpoint and found a highly statistically significant benefit of MM-398 plus 5-FU/leucovorin on overall survival and progression-free survival compared to 5-FU/leucovorin alone. We also found a significant benefit of the combination therapy on overall response rate and biochemical response,” said Dr. Wang-Gillam.

Combination therapy led to more gastrointestinal side effects than standard treatment alone. Diarrhea occurred in 12.8%, 21.1%, and 4.5% of the MM-398 plus 5-FU/leucovorin, MM-398 alone, and 5-FU/leucovorin alone groups, respectively. Vomiting occurred in 11.1%, 13.6% and 3.0%, respectively, and fatigue in 13.7%, 6.1% and 3.7%, respectively.

New Option for Pancreatic Cancer

“Our results are indicative of a successful effort in developing new drugs toward pancreatic cancer. We now have another viable option in this devastating disease,” Dr. Wang-Gillam concluded.

Commenting on the data, ESMO spokesperson Roberto Labianca, Director of the Cancer Centre, Ospedale Giovanni XXIII in Bergamo, Italy, said, “There is still a need for new treatments in metastatic pancreatic cancer, and every attempt to increase the activity of chemotherapy is welcome.... 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.”

Dr. Labianca concluded, “NAPOLI-1 demonstrated that [MM-398] plus 5-FU/leucovorin was an effective second-line therapy in metastatic pancreatic cancer. Future trials should evaluate this combination as first-line treatment and in locally advanced pancreatic cancer.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.