Adding the novel MM-398 to standard treatment for metastatic pancreatic cancer patients who have already received gemcitabine improves survival, researchers said at the ESMO 16th World Congress on Gastrointestinal Cancer in Barcelona.
"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 .
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."
Notes to Editors
Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.
 Ko AH, Tempero MA, Shan Y-S, Su W-C, Lin Y-L, Dito E, Ong A, Wang Y-W, Yeh CG, Chen LT. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013; 109(4):920-925.
 Abstracts from the 16th ESMO World Congress on Gastrointestinal Cancer are published in Annals of Oncology, Volume 25 suppl 2 June 2014 (Ann Oncol 2014 Jun; 25(Suppl 2): 1-117) http://annonc.oxfordjournals.org/content/25/suppl_2.toc
 Abstract presentation: Wednesday, 25 June 2014, 17:00 hrs, Session II: Cancer of the pancreas and bile ducts
NAPOLI-1: Randomised Phase 3 Study of MM-398 (nal-IRI), with or without 5-Fluorouracil and Leucovorin, versus 5-Fluorouracil and Leucovorin, in Metastatic Pancreatic Cancer Progressed on or Following Gemcitabine-based Therapy
D. Von Hoff1, C.P. Li2, A. Wang-Gillam3, G. Bodoky4, A. Dean5, G. Jameson6, T. Macarulla7, K.H. Lee8, D. Cunningham9, J.F. Blanc10, R. Hubner11, C.F. Chiu12, G. Schwartsmann13, J. Siveke14, F. Braiteh15, V. Moyo16, B. Belanger16,N. Dhindsa16, E. Bayever16, L.T. Chen17
1Scottsdale Healthcare/TGen, Scottsdale, USA, 2Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, 3Washington University in St.Louis, St Louis, USA,4St László Teaching Hospital, Budapest, Hungary, 5St John of God Hospital SUBIACO, Subiaco, Australia, 6Scottsdale Health Care, Scottsdale, USA,7Vall d'Hebron University Hospital, Barcelona, Spain,8Seoul National University Hospital, Seoul, Korea, 9Royal Marsden Hospital, London, United Kingdom, 10Hopital Saint Andre, Bordeaux, France, 11The Christie NHS Foundation Trust, Manchester, United Kingdom, 12China Medical University Hospital, Taichung, Taiwan, 13Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil, 14Klinikum rechts der Isar der TU Muenchen, Munich, Germany, 15Comprehensive Cancer Centers of Nevada, Las Vegas, USA, 16Merrimack, Cambridge, USA, 17National Cheng Kung University Hospital, Tainan, Taiwan
MM-398 (nal-IRI) is a novel encapsulation of irinotecan in a long-circulating nanoliposome. MM-398 had clinical activity in a Phase 2 study of pts with metastatic pancreatic adenocarcinoma (mPAC) after prior gemcitabine-based therapy.
Pts with mPAC after prior gemcitabine-based therapy, were randomised 1:1:1 in an open-label study to receive: (A) MM-398 (120 mg/m2 IV over 90 min) q3w; (B) 5FU (2,000 mg/m2 over 24 h) plus racemic leucovorin (LV) (200 mg/m2 over 30 min) x 4w followed by 2w rest; or (C) combination of MM-398 (80 mg/m2 IVover 90 min) prior to 5FU (2,400 mg/m2 over 46 h) and racemic LV (400 mg/m2 over 30 min) q2w. The primary endpoint was OS in arms A and C, each vs. the control arm B.
A total of 417 patients were randomised, of which 398 received treatment. Baseline characteristics were balanced, 61% head of pancreas, and 68% liver metastases. OS, PFS, TTF, and ORR were significantly improved by MM-398 + 5FU/LV vs. 5FU/LV. Median OS was 6.1m (95% CI: 4.8-8.9) and 4.2m (3.3-5.3), respectively, HR = 0.67, p = 0.012; and median PFS 3.1m (2.7-4.2) and 1.5m (1.4-1.8), respectively, HR = 0.56, p < 0.001. MM-398 alone did not demonstrate a statistical improvement in efficacy. Major grade ≥3 AEs in the MM-398 + 5-FU/LV, MM-398 and 5-FU/LV arms were neutrophil count decreased (23.1%, 15.3%, 3%), fatigue (13.7%, 6.1%, 3.7%), diarrhoea (12.8%, 21.1%, 4.5%), and vomiting (11.1%, 13.6%, 3.0%), respectively; neutrophil count decreased was based on lab. values [by investigator report, "neutropenia", (14.5%, 5.4%, 0.7%) and "neutrophil count decreased" (10.3%, 8.2%,0.7%) respectively]. Additional AEs of interest were febrile neutropenia (1.7%, 4.1%, 0%) and sepsis (3.4%, 2.0%, 0.7%) in MM-398 + 5FU/LV, MM-398 and 5FU/LV respectively.