Gemtuzumab Voluntarily Withdrawn From US Market

Roxanne Nelson

June 21, 2010

June 21, 2010 — Pfizer Inc has announced that it will be discontinuing commercial availability of gemtuzumab ozogamicin (Mylotarg; Wyeth) for the treatment of relapsed acute myeloid leukemia (AML), in the United States. It will also voluntarily withdraw the new drug application for gemtuzumab, effective October 15, 2010.

The action is at the request of the US Food and Drug Administration (FDA) after results from a recent clinical trial raised new concerns about the drug's safety profile and also failed to demonstrate clinical benefit to patients currently enrolled in trials.

"Mylotarg was granted an accelerated approval to allow patient access to what was believed to be a promising new treatment for a devastating form of cancer," said Richard Pazdur, MD, director, Office of Oncology Drug Products, part of FDA's Center for Drug Evaluation and Research, in a statement. "However, a confirmatory clinical trial and years of postmarketing experience with the product have not shown evidence of clinical benefit in patients with AML."

Gemtuzumab was approved on May 17, 2000, under the FDA's accelerated approval program, for the treatment of patients 60 years and older with recurrent AML, who were not considered candidates for other chemotherapy. The initial approval was based on the surrogate endpoint of response rate that was observed in 142 patients with AML across 3 clinical trials.

However, hepatotoxicity; specifically severe veno-occlusive disease; and hypersensitivity reactions including anaphylaxis, infusion reactions, and pulmonary events were observed after initial approval. This resulted in a black-box warning issued less than a year after its approval, as discussed in this article.

A confirmatory, post-approval clinical trial was begun in 2004, per FDA guidelines for accelerated approval. The randomized phase 3 comparative controlled trial (SWOG S0106) combined gemtuzumab with the chemotherapeutic agents daunorubicin and cytosine arabinoside vs chemotherapy alone in 627 patients younger than 61 years.

The trial was designed to determine whether adding gemtuzumab to standard chemotherapy demonstrated an improvement in survival time for patients with AML, but it was halted early when no benefit was observed. A greater number of deaths occurred in the cohort who received gemtuzumab vs those receiving chemotherapy alone. Among patients who were evaluable for early toxicity, the fatal induction toxicity rate was significantly higher in the combination therapy group vs the group receiving chemotherapy alone (16/283 = 5.7% vs 4/281 = 1.4%; P = .01).

"We are disappointed that the study did not confirm the clinical benefit of Mylotarg," said Mace Rothenberg, MD, senior vice president of clinical development and medical affairs for Pfizer Oncology Business Unit, in a release. "Our primary concern is for patients who suffer from AML, which remains a very serious and difficult-to-treat disease with limited treatment options. We advise patients to contact their physicians for further information."

Gemtuzumab No Longer Available

As a result of this action, gemtuzumab will no longer be commercially available to new patients. Patients who are currently receiving the drug may complete their therapy, after consulting with their physicians. Healthcare professionals should inform all patients receiving gemtuzumab of the potential adverse events associated with the agent, the FDA release notes.

All future use of gemtuzumab in the United States will require submission of an investigational new drug application to the FDA. Pfizer states that it is currently working the health authorities outside of the United States and will keep patients, regulatory authorities, investigators, and clinicians informed about FDA actions and appropriate next steps for gemtuzumab.

More information is available on the FDA's MedWatch Web site.

Any adverse events associated with gemtuzumab should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088; by fax 1-800-FDA-0178, online at https://www.accessdata.fda.go v/scripts/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.


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