The FDA has assigned a priority review designation to MM-398 (nal-IRI) in combination with 5-fluorouracil (5-FU) and leucovorin for patients with metastatic pancreatic cancer following treatment with a gemcitabine-based therapy, according to a statement from the drug's developers, Merrimack Pharmaceuticals and Baxter International.
The priority review was based on findings from the open-label phase III NAPOLI-1 trial, which demonstrated that the addition of MM-398 significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) compared with 5-FU and leucovorin alone. Under this review program, the FDA will make a decision on the application for nanoliposomal encapsulation of irinotecan by October 24, 2015.
"The rapid timeline associated with priority review designation brings Merrimack closer to our goal of making MM-398 available to patients with pancreatic cancer who have been previously treated with gemcitabine and are in significant need of treatment options," Robert Mulroy, president and CEO at Merrimack, said in a statement. "We look forward to working with the FDA as they review the application over the next several months."
In the NAPOLI-1 trial, 417 patients with gemcitabine-refractory metastatic pancreatic cancer were randomized to MM-398 monotherapy, 5-FU with leucovorin (control), or MM-398 plus 5-FU and leucovorin. Altogether, 61% of patients had cancer in the head of the pancreas and 68% had liver metastases. Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist could be administered in the combination arms.
Intravenous MM-398 was administered at 120 mg/m2
every 3 weeks in the single-agent arm. 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.
In the combination arm the median OS was 6.1 months compared with 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 ORR 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 commonly reported 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.
The new drug application for MM-398 was submitted on a rolling basis, as part of a fast track designation granted to the medication in November 2014. Additionally, both the FDA and European Medicines Agency (EMA) have granted the therapy an orphan drug designation. The EMA has accepted a marketing authorization application for MM-398, marking the beginning of this approval process.
In September 2014, Merrimack and Baxter entered into an agreement to develop and commercialize MM-398, with Merrimack retaining all rights to market the drug within the United States. In Taiwan, PharmaEngine controls commercialization rights for the drug.
"The acceptance of our marketing authorization application for review by the EMA is a positive indicator of the promise of this treatment to address a significant unmet need for patients with metastatic pancreatic cancer and the support for innovative new options," David Meek, head of Oncology at Baxalta, said in a statement. "We are actively advancing our plans to introduce nal-IRI following approval and look forward to extending the utility of the treatment to patients around the world."
Results from the NAPOLI-1 study have been presented at a number of major medical meetings, with initial data presented at the 2014 World GI Congress. In a subanalysis presented at the 2015 GI Cancers Symposium, the benefits of MM-398 were further defined.
In this per-protocol assessment, patients who received at least 80% of the target dose in the first 6 weeks and did not violate any inclusion or exclusion criteria experienced an even greater OS benefit with MM-398. In this population, treatment with MM-398 plus 5-FU/leucovorin (n = 66) improved OS by 53% compared with 5-FU/ leucovorin alone (n = 71). The median OS was 8.9 months with MM-398 compared with 5.1 months with 5-FU/ leucovorin (HR = 0.47; 95% CI, 0.29-0.77; P = .0018).
Outside of the NAPOLI-1 trial, MM-398 has been explored been explored in a limited number of clinical trials. A phase I study is looking into the drug in combination with cyclophosphamide for pediatric patients with solid tumors. Additionally, a pilot study is exploring MM-398 biodistribution and the feasibility of ferumoxytol as a tumor-imaging agent (NCT01770353). Early results from this pilot study have shown promise for this approach.
"We were encouraged by the results of the initial pilot phase of the study, particularly the data that suggest a relationship between high levels of ferumoxytol uptake and shrinkage of tumor lesions after MM-398 treatment," Jasgit Sachdev, MD, Virginia G Piper Cancer Center, said in a statement. "We are excited to continue to evaluate the activity of MM-398 and the predictive value of this imaging approach in additional patients with metastatic breast cancer."