ODAC Recommends Mylotarg Approval for AML Patients

BETHESDA, Md—In an unusual decision, the FDA’s 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 drug’s 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 committee’s unease over recommending a novel agent based on limited clinical findings and accepting the company’s novel interpretation of data that, it argued, represented a complete response in some patients.

The 11-2 vote favoring Mylotarg’s 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 AML cells.

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 months—rates it called comparable to those reported in the medical literature for off-label treatments of relapsed AML.

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 company’s 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, wasn’t as certain about the question of complete response. He asked whether CRp—a new designation for a group traditionally called partial responders—should 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 CR–CRp equivalence was sufficient for Ellin R. Berman, MD, associate professor, Hematologic Oncology Division, Memorial Sloan–Kettering 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 that—given the evidence currently available—many 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 aggressive chemotherapy.

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.