World GI 2014 Press Release: International Phase III Trial Shows Survival Benefit of MM-398 Added to Standard Treatment in Post-Gemcitabine Metastatic Pancreatic Cancer

Barcelona/Lugano - 25 June 2014

“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, USA. “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 (nal-IRI) is a nanoliposomal irinotecan: this delivery system allows longer drug exposure in the circulation and more accumulation of the drug and its active metabolite SN38 at the tumour site,” Wang-Gillam said. “MM-398 therefore generates higher anti-tumour activity and is more effective than conventional irinotecan alone in the preclinical setting.”

The phase II study had demonstrated the anti-tumour activity of MM-398 monotherapy as second-line treatment in patients with metastatic pancreatic cancer refractory to gemcitabine [1].

The current NAPOLI-1 trial was a global randomised phase III trial at more than 100 sites. There were 3 treatment arms: MM-398, standard treatment with 5-fluorouracil (5FU)/leucovorin, and MM-398 plus 5FU/leucovorin. The trial included 417 patients who had progressed or received prior gemcitabine-based therapy. The primary endpoint was overall survival.

Overall survival was significantly improved with the combination therapy of MM-398 plus 5FU/leucovorin compared to 5FU/leucovorin alone. Median overall survival was 6.1 months in the MM-398 plus 5FU/leucovorin group compared to 4.2 months in the group receiving standard treatment with 5FU/leucovorin alone (hazard ratio [HR]=0.67, p=0.012). Progression-free survival also improved significantly, from 1.5 months with the standard therapy to 3.1 months in patients receiving MM-398 plus 5FU/leucovorin (HR=0.56, p<0.001). MM-398 alone did not provide any additional survival benefit over standard therapy.

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

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

Wang-Gillam concluded: “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.”

Commenting on the data, ESMO spokesperson Roberto Labianca, Director of the Cancer Centre, Ospedale Giovanni XXIII in Bergamo, Italy, who was not involved in the trial, said: “There is still a need for new treatments in metastatic pancreatic cancer and every attempt to increase the activity of chemotherapy is welcome. NAPOLI-1 evaluated a new formulation of irinotecan (nal-IRI). With the new drug added to 5FU and leucovorin, patients had improved overall survival, overall response rate, progression-free survival and time-to-treatment failure; tolerability of the nal-IRI plus 5FU/leucovorin regimen was acceptable and toxicity manageable. 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.”

Labianca concluded: “NAPOLI-1 demonstrated that nal-IRI plus 5FU/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.”