Building upon the modest activity noted in the phase 2 study, a randomized phase 3 study (NAPOLI-1) was launched with results recently presented at ESMO this summer.5

Four hundred and seventeen patients with gemcitabine-refractory metastatic pancreatic cancer were randomized 1:1:1 to receive MM-398 monotherapy, 5-FU/LV monotherapy, or the combination of MM-398 and 5-FU/LV. The study was initially developed as a two-arm study, but the third combination arm was added when emerging safety and pharmacokinetic data became available.

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In the monotherapy arms, MM-398 was given at 120 mg/m2 Q3 weeks and 5-FU was given at 2,000 mg/m2 Q2 weeks with LV. In the combination arm, MM-398 was administered at 80 mg/m2 Q2 weeks with 5-FU 2,400 mg/m2 and LV.

The primary endpoint was overall survival. MM-398 as a single agent was no better than 5-FU/LV. However, the combination arm demonstrated improved median OS of 6.1 months compared with 4.2 months for 5-FU/LV (hazard ratio [HR]=0.67, P=0.012).

The median PFS was also improved (3.1 months vs. 1.5 months, HR=0.56, P=0.0001). In patients in the combination arm, 16% had a partial response compared with 6% in the MM-398 arm and only 1% in the 5-FU arm. Most common grade 3/4 side effects of the combination included neutropenia (20%), fatigue (14%), diarrhea (13%), and vomiting (11%).

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So where does MM-398 stand in the potential treatment of advanced pancreatic cancer? The U.S. Food and Drug Administration recently granted MM-398 fast track designation for gemcitabine-refractory pancreatic cancer.

Assuming approval in gemcitabine-refractory pancreatic cancer, how will clinicians use it? For patients who have received prior gemcitabine and nab-paclitaxel as first-line therapy, the combination of MM-398 and 5-FU/LV will be a reasonable second-line therapy.

For those who have received FOLFIRINOX as initial therapy, it is unclear how much benefit will be derived from reusing 5-FU and a “different” irinotecan. Presentations to date have not clearly delineated what percent of patients received prior irinotecan, and how this group of patients performed. It may be more attractive to utilize gemcitabine and nab-paclitaxel as second-line therapy in this situation.

However, these clinical challenges are a good problem to have, as a new agent appears to be making its way to the clinic for metastatic pancreatic cancer.


  1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
  2. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703.
  3. Drummond DC, Noble CO, Guo Z, et al. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 2006;66(6):3271-3277.
  4. Ko AH, Tempero MA, Shan YS. 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.
  5. Von Hoff D, Li CP, Wang-Gillam A, et al. O-0003. NAPOLI-1: Randomized 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. Ann Oncol. 2014;25(suppl 2):ii105-ii106.