On June 21, Pfizer and the US Food and Drug Administration announced the voluntary withdrawal of gemtuzumab ozogamicin (Mylotarg) from the market. The drug was initially approved for the treatment of patients with acute myeloid leukemia (AML) through the FDA’s accelerated approval program based on Phase II trials. A Phase III trial, however, failed to show clinical benefit and reported a higher death rate in the gemtuzumab arm. Leukemia experts say the rapid approval and subsequent withdrawal of gemtuzumab ozogamicin is an example of the FDA’s accelerated approval program working as it should. And while some clinicians express concern that they have lost a treatment option for AML patients, others think the withdrawal of gemtuzumab ozogamicin will have little or no impact on their patients or their practice.
The May 2000 approval was based on three Phase II trials involving 142 patients with relapsed AML. The single-agent therapy induced a complete response in 30% of the patients, including complete responses with incomplete platelet recovery. The initial indication was as a single agent in patients over the age of 60 with relapsed AML who were not considered candidates for cytotoxic therapy.
To confirm the value of gemtuzumab, the Southwest Oncology Group launched a Phase III trial in 2004 comparing chemotherapy plus gemtuzumab with chemotherapy alone in 627 previously untreated AML patients, age 18 to 60.
Interim analyses showed a complete response rate of 66% in the combination arm and 69% in the chemotherapy-alone arm, which ruled out the 12% improvement that researchers aimed for in the trial. (When complete responses with incomplete platelet recovery were included, the response rate rose to 74% in both arms.) Moreover, there was no difference in relapse-free survival, and the rate of fatal adverse events was significantly higher in the gemtuzumab group at 5.8% compared with 0.8% in the control arm.
“The toxicities were what one would typically expect for AML patients who undergo induction chemotherapy—infection and complications of neutropenia and so forth,” said the trial’s leader, Stephen Petersdorf, MD, Endowed Chair in Cancer Care and Associate Professor of Medical Oncology at the University of Washington.
What was odd, in his view, was that the rate of deaths in the experimental arm was similar to what has been seen in most other AML trials, while the rate in the control arm looked better than normal. He and his colleagues are still trying to figure out why that might have been the case, he said.
Impact on Care
The drug’s withdrawal is expected to affect only a minority of patients with AML, according to experts interviewed for this article.
“It is a drug that wasn’t used very often, and, over time, the circumstances in which it was used were fairly selective,” Dr. Petersdorf said. “If you had an older patient who was not in remission or was not a transplant candidate, it would be something to potentially give to them. A minority of patients responded, but it could give them some time in remission if they did respond.
“We don’t have a lot of drugs for AML, and this is now one less one.”
That view was echoed by Mikkael Sekeres, MD, MS, Director of the Leukemia Program and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee at the Cleveland Clinic Taussig Cancer Institute.
“I am of two minds about this decision. On the one hand, I give kudos to the FDA for pulling a drug from the market that doesn’t appear to have the type of efficacy we were hoping for in AML. On the other hand, it removes one of the weapons in my arsenal to combat this disease, and there are specific patients to whom I might have offered Mylotarg. But I don’t want to offer patients a drug that will result in a pyrrhic victory.”
Dr. Sekeres, a member of the FDA’s Oncologic Drugs Advisory Committee, is also OT’s Clinical Advisory Editor for Hematology/Oncology.
In contrast, both Richard Stone, MD, a medical oncologist at Dana-Farber Cancer Institute, and Brian Druker, MD, Director of the Knight Cancer Institute and Professor of Medicine at Oregon Health and Science University, say they rarely used gemtuzumab and thus its removal from the market will have little impact on their practice.
“It is not a drug I used very often for AML. I’ve never been overly impressed by it, and I’ve been concerned about its toxicity,” said Dr. Druker, who has turned his research focus from chronic myelogenous leukemia to AML in recent years.
The setting that is more of a concern, Dr. Stone said, is the care of patients with acute promyelocytic leukemia: “I haven’t used Mylotarg at all for AML in the recent past. However, it is occasionally useful for acute promyelocytic leukemia. So although it is a very small number of patients who might have benefited from Mylotarg in that situation, I think it is kind of too bad that they withdrew it without really thinking through all of the uses. It might have been important for a small number individuals.”
So what options remain for older patients with relapsed AML who are unwilling or unable to undergo another round of cytotoxic chemotherapy?
The best option is to look for a clinical trial, those interviewed by OT said.
“My treatment suggestion is to look for clinical trials. There are a number of clinical trials going on around the country looking for new drugs for this patient population. Some of them will be positive—like we saw with Mylotarg 10 or 15 years ago—and at least that is a first step,” Dr. Petersdorf said.
The other option is to use a hypomethylating agent, either azacitidine or decitabine, according to Dr. Sekeres and Dr. Druker. “Those agents are being studied in this setting and look promising, but with the usual caveat that these are Phase II studies” and thus could be over- or underestimating the benefit, Dr. Sekeres said.
‘Shows System Works’
All of the experts interviewed agree that the gemtuzumab ozogamicin story is an example of the FDA’s accelerated approval program working.
“If we are going to move into an era of more rapid drug approvals through the accelerated approval processes, then there have to be the follow-up studies,” Dr Druker said. “And those drugs that don’t work as well as initially thought or have unacceptable toxicity profiles, would get removed—that is the whole point behind the accelerated approval process. This is an example of things working as they should.”
Both Dr. Petersdorf and Dr. Sekeres concur with that view, but say the one glitch in the gemtuzumab experience, was the slow start to the confirmatory trial. “The confirmatory trial took 10 years to come to light,” Dr. Sekeres said. “That means that for 10 years, patients were exposed to a drug that added toxicity but didn’t improve overall survival. The system works, but where there probably should be more rigor is in truncating the time it takes a confirmatory study to shed light on whether a drug’s approval was appropriate or not.”
An interesting twist, Dr. Stone noted, is that while the overall results of the SWOG study are clear-cut, subgroup analyses and interim data from an ongoing trial in the United Kingdom suggest that AML patients with favorable cytogenetics may benefit from the addition of the drug to standard chemotherapy.
“I think the FDA was never that happy, in retrospect, that they approved this drug on Phase II data in a relatively select group of patients. I think they have been ruing that particular decision since then. Nonetheless, if the [UK Medical Research Council] trial is positive, I think one would have to re-open the issue, at least as a research question, as to whether one might to do another trial to break the tie. If the MRC trial is positive, then you have one positive and one negative. That is not usually enough to throw a drug out.”
Although the SWOG trial was not powered to support subgroup analyses, Dr. Petersdorf agrees that if both the mature SWOG data and the final MRC data trend toward benefit in patients with favorable cytogenetics, then the role of gemtuzumab in AML should be revisited.
In the meantime, however, Dr. Druker sees a side benefit to the withdrawal: Researchers will not have to use it as a control arm in clinical trials “It is pretty toxic and didn’t work that well, and we didn’t want to have to use it as a control arm. So there is probably a little bit of a sigh of relief in the clinical research community that we no longer have to have that debate.”