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.1
“Patients with metastatic pancreatic cancer or pancreatic cancer in general have very limited options,” said one 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.”
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, who noted that one of the biggest challenges in pancreatic cancer is drug delivery.
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
“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 said.
ESMO spokesperson Roberto Labianca, MD, Director of the Cancer Centre, Ospedale Giovanni XXIII in Bergamo, Italy, 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.” He 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.” ■
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