MM-398 Demonstrates Survival Benefit in Phase III Pancreatic Cancer Trial

Andrea Wang-Gillam, MD, PhD

Second-line treatment with MM-398 (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin extended overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) compared with 5-FU and leucovorin alone for patients with metastatic pancreatic cancer, according to phase III results presented at the ESMO 16th World Congress on Gastrointestinal Cancer.

“The study showed that the combination resulted in superior overall survival compared to 5-FU and leucovorin, with an OS of 6.1 months,” study author Andrea Wang-Gillam, MD, PhD, an assistant professor of Medicine in the Division of Oncology in the Section of Medical Oncology at the Washington University School of Medicine and the Siteman Cancer Center, said in an interview withOncLive. “The combination arm also showed superior progression-free survival, overall response, and CA19-9 response.”

MM-398 is a nanoliposomal encapsulation of irinotecan, allowing for the drug to stay in circulation for a longer duration compared with standard irinotecan. Additionally, this mechanism allows for higher drug uptake within tumor cells and conversation of irinotecan to its active form, SN38.

“When they had done biopsy of the patients who had received MM-398 at the tumor site, they found five times higher active metabolite SN38,” Wang-Gillam noted. “This is a key feature that makes this delivery much more attractive than conventional irinotecan.”

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.

Prior studies demonstrated single-agent activity with MM-398, resulting in the three-arm NAPOLI-1 trial, which randomized patients 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.

“Initially the study was designed for patients to receive either MM-398 monotherapy or 5-FU/leucovorin,” Wang-Gillam noted. “The protocol was amended—adding a third arm combining MM-398 plus 5-FU/leucovorin—because at that time safety data were made available, and also based on PK data showing 2-week MM-398 resulted in a better PK profile.”

As monotherapy, intravenous MM-398 was administered at 120 mg/m²every 3 weeks. In the control, 5-FU was administered at 2000 mg/m²with racemic leucovorin at 200 mg/m²every 4 weeks followed by 2 weeks of rest. In the combination arm, MM-398 was administered at 80 mg/m²prior to 5-FU at 2400 mg/m²and racemic leucovorin at 400 mg/m²every 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 ORR was 16% versus 1% (P<.001) and CA19-9 levels were decreased by &ge;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.

&ldquo;MM-398, if approved, mainly would need to be used in combination with 5-FU/leucovorin based on the study, commonly in the second-line setting,&rdquo; Wang-Gillam said. &ldquo;In patients who received a gemcitabine-based regimen frontline, this would be a viable option for second line.&rdquo;

Based on findings from the phase III study, Merrimack Pharmaceuticals, the company developing MM-398, plans to submit a new drug application to the FDA for the combination by the end of 2014. However, the exact time frame for regulatory submission was not made clear.

Von Hoff D, Li CP, Wang-Gillam A, et al. 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. Presented at: the ESMO 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract O-0003.