ROCKVILLE, MarylandThe 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.
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 (60 mg/kg), and 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
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
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 eventsmainly rash,
pruritus, erythema, paresthesia, mouth/tongue disorders, and taste
alterationswere 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.