ROCKVILLE, Maryland—The Food and Drug Administration (FDA) has approved Amgen’s Kepivance (pal-ifermin) for use in decreasing the incidence and duration of severe oral mucositis in hematologic cancer patients undergoing high-dose chemotherapy, with or without radiation, followed by bone marrow transplantation. The drug’s labeling recommends its intravenous administration for 6 days, 3 days before and 3 days after myelotoxic therapy.
"Until now, severe painful oral mucositis has been considered an unmet medical need for which no effective therapies existed to reduce either its incidence or duration. The most we could do for our patients was to give them ice chips and narcotics to try and manage their pain," said Patrick Stiff, MD, professor of hematology/oncology and director of the Cardinal Bernardin Cancer Center, Loyola University Health System, Chicago, one of the lead investigators in the Kepivance pivotal trial. "We are excited to have a new option that will enable physicians to focus on helping to protect their patients with hematologic malignancies from this complication rather than solely managing its consequences."
11,000 Transplants a Year
About 11,000 adult US residents undergo bone marrow transplantation annually in the course of their treatment for hematologic cancer. According to Amgen, cancer patients rate oral mucositis as the most debilitating side effect of chemotherapy. FDA limited Kepivance’s approval to hematologic malignancies because its safety and efficacy have not been established in patients with nonhema-tologic malignancies. However, Roger M. Perlmutter, MD, PhD, Amgen’s executive vice president of research and development, said that the company is investigating Kepivance in other cancers.
Kepivance is a recombinant human keratinocyte growth factor that works at the cellular level to help reduce oral mucositis by protecting the epithelial cells that line the mouth and throat from chemotherapy and radiation damage, and by stimulating the growth and development of new epithelial cells to build up the mucosal barrier. The FDA approved its use in hematologic cancers on the basis of a pivotal phase III double-blind study submitted by Amgen (N Engl J Med 351:2590-2598, 2004), which also submitted a randomized, multicenter, placebo-controlled dose-schedule-ranging clinical study of 169 patients.
Pivotal Study
In the pivotal study, 212 patients received a high-dose cytotoxic regimen that consisted of fractionated total-body irradiation (1,200 cGy total dose), etoposide(Drug information on etoposide) (60 mg/kg), and cyclophosphamide(Drug information on cyclophosphamide) (100 mg/kg) followed by autologous hematopoietic stem-cell transplantation for the treatment of hematologic cancers. Study participants were randomized to either Kepivance 60 µg/kg/d or placebo. The trial’s primary endpoint was the number of days that patients’ experienced World Health Organization grade 3-4 oral mucositis.
The study showed that the Kepivance patients were significantly less likely to suffer serious (grade 3-4) oral mucositis than the placebo patients (63% vs 98%, P < .001). For grade 4 oral mucositis, the incidence was 20% in the Kepivance group vs 62% for placebo (P < .001). Among patients with grade 3-4 oral mucositis, the median duration was shorter with Kepivance (6 days vs 9 days for placebo, P < .001). For those with grade 4 mucositis, the median duration was 2 days for Kepivance vs 6 days for placebo (P = .004).
Compared with placebo, Kepivance patients reported significantly less soreness of the mouth and throat, used significantly less opioid analgesics, and were significantly less likely to need total parenteral nutrition.
FDA found that some data from the 169-patient back-up study supported the efficacy findings of the pivotal study. The supporting data came from a subset of patients who received the same dose and schedule of the drug as given in the 212-patient study.
Amgen submitted safety data from three randomized, placebo-controlled clinical studies that involved a total of 650 hematologic cancer patients, 409 treated with Kepivance and 241 given placebo. The data showed Kepivance to be safe and well-tolerated. Adverse events—mainly rash, pruritus, erythema, paresthesia, mouth/tongue disorders, and taste alterations—were mild to moderate and transient.
Grade 4 skin rash was reported in less than 1% of Kepivance patients. Nine Kepivance patients (3%) and five placebo patients (2%) experienced grade 3 rash. Five Kepivance patients and two who received placebo discontinued treatment because of their skin rash.
