BETHESDA, MdIn an unusual decision, the FDAs Oncologic
Drugs Advisory Committee (ODAC) first voted against recommending
accelerated approval for Mylotarg (gemtuzumab ozogamicin,
Wyeth-Ayerst) for the treatment of patients with CD33-positive acute
myeloid leukemia (AML) in relapse. Then, after a sometimes intense
discussion, ODAC members urged the FDA to grant accelerated approval
for the drugs use in a limited subgroup of patients,
particularly those older than age 60.
The initial 7-to-4 vote (with 2 abstentions) against recommending
blanket accelerated approval for Mylotarg reflected the
committees unease over recommending a novel agent based on
limited clinical findings and accepting the companys novel
interpretation of data that, it argued, represented a complete
response in some patients.
The 11-2 vote favoring Mylotargs approval for a more restricted
usage indicated the belief of many ODAC members that the evidence
presented showed a benefit in selected AML patients.
If granted an accelerated approval, Wyeth-Ayerst would have to
conduct a phase IV postmarketing study to further demonstrate the
efficacy of the drug. Failure to do so could result in the FDA
revoking its marketing approval.
An estimated 9,700 new cases of AML will be diagnosed in the United
States in 2000 and about 7,100 AML patients will die. Among patients
who go into first remission, 60% to 80% relapse. A major goal of
treating first relapse now is to put patients into a second remission
so they can undergo stem cell transplant.
Mylotarg represents a new class of cancer treatment known as
antibody-targeted chemotherapy. It consists of a monoclonal antibody
that targets the CD33 antigen, which is found on the surface of most
The antibody is joined by a unique linker to an antitumor
antibiotic called calicheamicin. Wyeth-Ayerst researchers isolated
the antitumor drug from a type of clay found in Texas. When the
monoclonal antibody docks with the CD33 antigen, the antibiotic
enters the tumor cell and kills it.
There are no drugs approved for treating relapse in AML, although
physicians frequently prescribe cancer drugs off-label for patients
whose remission has failed. Wyeth-Ayerst contended that Mylotarg is
as effective as the off-label agents currently used and causes fewer
severe side effects.
The company presented data from one phase I and three phase II trials
to support its new drug application for Mylotarg. The phase II
studies were designated 201 (65 patients, 13 centers in the United
States and Canada); 202 (40 patients, 19 centers in eight European
countries); and 203 (37 patients, 21 centers in the United States and
five European nations).
Participants received two courses of Mylotarg, 14 days apart. The
dosage was 9 mg/m² given as a 2-hour outpatient infusion, and
patients underwent a bone marrow exam 28 days after their second
treatment. The median patient age was 61 years (range, 22 to 84
years), 59% were males, 94% were white, and the median duration of
their first remissions was 11.1 months.
The company claimed an overall remission rate of 30% (34% in those
younger than age 60 and 26% in those 60 and older) and an overall
median survival of 5.9 monthsrates it called comparable to
those reported in the medical literature for off-label treatments of
The median survival for the 42 responding patients had not been
reached at the time of latest data analysis but stood at 12.6 months,
said Mark Berger, MD, director of clinical research for Wyeth-Ayerst.
The overall response rate included two categories: complete response
(CR) for remissions that met the standard definition used in
leukemia, and morphologic response (CRp) in which the same criteria
as for complete response were met except that platelets did not rise
above 100,000/mL. Wyeth-Ayerst contended that CRp was equivalent to
CR in clinical benefit, with no differences in outcomes seen between
the two groups.
The FDA review of the data generally agreed with the companys
safety assessment of Mylotarg. It concluded the drug offered ease of
administration, Mylotarg patients spent fewer days in the hospital,
and some adverse events, including severe mucositis and infection,
seemed less severe in patients receiving the drug than in those
receiving conventional salvage regimens in literature reports. Liver
toxicity, including hepatic veno-occlusive disease, however, appeared
to be increased.
FDA reviewer Peter Bross, MD, wasnt as certain about the
question of complete response. He asked whether CRpa new
designation for a group traditionally called partial
respondersshould be considered CR. CRp was not a primary
endpoint, and patents were still required to achieve red cell
equivalence, he said. Excluding the CRp group left a complete
response rate of 17%, Dr. Bross added.
The evidence for CRCRp equivalence was sufficient for Ellin R.
Berman, MD, associate professor, Hematologic Oncology Division,
Memorial SloanKettering Cancer Center, and a voting consultant
to ODAC for the Mylotarg meeting. I think we have to keep an
open mind when we are dealing with a new agent like a monoclonal
antibody because it is not chemotherapy as we know it, she
said, touching on a theme voiced by several committee members.
As the ODAC discussion continued, a consensus emerged thatgiven
the evidence currently availablemany AML patients in relapse
would be better served by the use of aggressive chemotherapy
treatments than by Mylotarg. However, some members also expressed the
view that certain patients might have better outcomes if they had
access to the drug. In particular, panel members mentioned people
older than 60, who might be unwilling or unable to tolerate
As a result, the panel sought in its recommendation to limit the
indication for Mylotarg to whatever specific groups of AML patients
the FDA might decide were most likely to benefit from the drug.