October 22, 2015
On October 22, 2015, the U. S. Food and Drug Administration approved irinotecan liposome injection (ONIVYDE™, Merrimack Pharmaceuticals, Inc.), administered in combination with fluorouracil (5FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas whose disease has progressed following gemcitabine-based therapy. Irinotecan liposome is not approved for use as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.
The approval was based on the demonstration of improved overall survival (OS) in a multicenter, randomized, open-label, active-controlled, three-arm trial enrolling 417 patients with metastatic pancreatic adenocarcinoma with documented disease progression after gemcitabine-based therapy. Patients were randomly allocated (1:1:1) to receive irinotecan liposome in combination with 5FU and LV (n=117), irinotecan liposome (n=151), or 5FU and LV (n=149) until disease progression or unacceptable toxicity. Patients homozygous for the UGT1A1*28 allele initiated treatment with irinotecan liposome at a reduced dose in the two irinotecan liposome-containing arms. The primary study endpoint was OS, with comparisons of each of the two irinotecan liposome-containing arms with the 5FU/LV control arm; progression-free survival (PFS) and overall response rate (ORR) were secondary endpoints.
The trial showed a statistically significant improvement in OS [HR 0.68 (95% CI: 0.50, 0.93), p=0.014, log-rank test] for patients randomized to receive irinotecan liposome in combination with 5FU and LV compared to those randomized to receive 5FU/LV; the median OS was 6.1 and 4.2 months, respectively. PFS was also significantly longer in patients randomized to receive irinotecan liposome plus 5FU/ LV compared to those randomized to receive 5FU/LV [HR 0.55 (95% CI: 0.41, 0.75)], with median PFS of 3.1 and 1.5 months, respectively. The ORR was low in both arms (7.7% vs. 0.8%). There was no improvement in OS for patients randomized to receive irinotecan liposome alone compared to those randomized to receive 5FU/LV [hazard ratio=1.00, p =0.97].
Serious risks of irinotecan liposome injection include neutropenic fever or sepsis, severe diarrhea, and interstitial lung disease. Severe hypersensitivity reactions have occurred with irinotecan hydrochloride; irinotecan liposome injection is contraindicated in patients with severe allergic reactions to irinotecan liposome or irinotecan hydrochloride. The most common adverse drug reactions were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common severe (Grade 3-4) laboratory abnormalities were lymphopenia, and neutropenia. The most frequent adverse reactions resulting in discontinuation of irinotecan liposome were diarrhea, vomiting, and sepsis. The most frequent adverse reactions leading to dose reductions or delays were neutropenia, diarrhea, nausea/vomiting, anemia, fatigue, and thrombocytopenia.
The recommended dose and schedule of irinotecan liposome is 70 mg/m2 administered by intravenous infusion over 90 minutes, prior to leucovorin and fluorouracil, every two weeks. For patients homozygous for the UGT1A1*28 allele, the recommended starting dose of irinotecan liposome is 50 mg/m2 every two weeks.
Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207793lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).