The FDA has granted MM-398 (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin a Fast Track designation as a second-line treatment for patients with metastatic pancreatic cancer, based on data from the phase III NAPOLI-1 study that were presented at the 2014 World Congress on Gastrointestinal Cancer in June 2014.
In the NAPOLI-1 trial, treatment with MM-398 plus 5-fluorouracil (5-FU) and leucovorin extended overall survival (OS) by 37% and progression-free survival (PFS) by 44%, when compared with 5-FU and leucovorin alone for patients with metastatic pancreatic cancer following progression on a gemcitabine-based regimen.
The new Fast Track designation is meant to expedite the development and review of MM-398, which is a nanoliposomal encapsulation of irinotecan. As part of the FDA’s expedited review program, Merrimack Pharmaceuticals can submit information for a New Drug Application for MM-398 to the FDA in sections. The company announced that it plans to initiate the submission process in 2014, with a targeted completion date set for the beginning of 2015.
"It is crucial to develop new therapies for patients with pancreatic cancer, particularly for those patients who have previously received gemcitabine-based therapy where there is currently no consensus on the standard of care," Eliel Bayever, MD, vice president at Merrimack and the medical director for MM-398, said in a statement. "We will continue to work diligently on our NDA submission in an effort to bring MM-398 to patients who are facing this aggressive disease as quickly as possible."
The phase III open-label NAPOLI-1 trial enrolled 417 patients with gemcitabine-refractory metastatic pancreatic cancer. Altogether, 61% of patients had cancer in the head of the pancreas and 68% had liver metastases. Patients were randomized in a 1:1:1 ratio to MM-398 monotherapy, 5-FU with leucovorin (control), or MM-398 plus 5-FU and leucovorin. Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist could be administered in arms A and C.
As monotherapy, intravenous MM-398 was administered at 120 mg/m2
every 3 weeks. In the control, 5-FU was administered at 2000 mg/m2
with racemic leucovorin at 200 mg/m2
every 4 weeks followed by 2 weeks of rest. In the combination arm, MM-398 was administered at 80 mg/m2
prior to 5-FU at 2400 mg/m2
and racemic leucovorin at 400 mg/m2
every 2 weeks.
Patients in the combination arm had a median OS of 6.1 months versus 4.2 months with 5-FU and leucovorin alone (HR = 0.67; 95% CI, 0.49-0.92; P
= .012). The median PFS was 3.1 months for the combination compared with 1.5 months with the control (HR = 0.56; 95% CI, 0.41-0.75; P
= .0001). The overall response rate was 16% versus 1% (P
<.001) and CA19-9 levels were decreased by ≥50% in 36% versus 12% of patients in the combination and control arms, respectively.
MM-398 monotherapy did not demonstrate superior efficacy compared with 5-FU and leucovorin. Moreover, in some cases, MM-398 alone was associated with more side effects than the drug in combination. The rates of diarrhea were 12.8% versus 21.1% and the rates of vomiting were 11.1% versus 13.6% for the combination and single-agent MM-398 arms, respectively. Additionally, febrile neutropenia occurred in 1.7% of patients in the combination arm compared with 4.1% with MM-398 monotherapy and not at all with 5-FU/leucovorin alone.
The most frequent grade 3/4 adverse events with MM-398 plus 5-FU/leucovorin were neutrophil count decrease (23.1%), fatigue (13.7%), diarrhea (12.8%), and vomiting (11.1%). Investigator assessed neutropenia occurred in 14.5% of patients receiving the MM-398 combination, whereas neutrophil count decrease was reported in the lab reports for 10.3% of patients.