Pfizer and the US Food and Drug Administration announced in June the removal of gemtuzumab ozogamicin (Mylotarg) from the US market. The withdrawal was based on negative results from a Southwest Oncology Group (SWOG) Phase III trial that compared chemotherapy to chemotherapy plus gemtuzumab in patients with acute myeloid leukemia (AML). Following the announcement, OT interviewed several leukemia experts to learn how the loss of the drug would affect their patients and practice. The consensus from that round of interviews, published in the August 10 issue, was that removal of the drug would affect “only” a minority of patients, and that this was an example of the accelerated approval program working as it should. Now, however, a second round of interviews demonstrate that not all leukemia experts are taking the change in stride, and that they don't think the community should either.
“I think the withdrawal of Mylotarg is going to have, potentially, an adverse effect on the outcome of many patients with leukemia, so one should deal with it with more concern,” said Hagop M. Kantarjian, MD, Professor and Chairman of the Department of Leukemia at the University of Texas MD Anderson Cancer Center.
“What is ironic is that we are in an era of individualized therapy. We talk about targeted treatments benefiting selected subsets of patients. And yet in leukemia, we withdraw a drug that is benefiting subsets of patients, because of the results in the average population.”
Gemtuzumab was initially approved in 2000 through the FDA's accelerated approval program based on Phase II trials. The SWOG trial was designed to confirm the efficacy and safety of gemtuzumab in AML patients. However, an interim analysis showed no improvement in the response rate with the addition of gemtuzumab. Also, there was a substantial increase in the risk of death in the combination arm, compared with the chemotherapy-alone arm. (Some investigators consider the difference in mortality a fluke, because the control arm had a much lower induction death rate than seen in other previous trials, while the gemtuzumab arm matched the rate seen in those other trials.)
Key: Effect on Subgroup with Favorable Cytogenetics
For Dr. Kantarjian though, the key finding from the SWOG trial is not the impact of the drug on the study population as a whole, but on the subgroup of patients with favorable cytogenetics. A posthoc subgroup analysis showed a trend for benefit in patients with favorable cytogenetics.
Moreover, a benefit for good-risk patients was also seen in a UK Medical Research Council Phase III trial led by Alan K. Burnett, MD, Professor of Haematology at the University of Wales College of Medicine in Cardiff, UK—expected to be published soon in the Journal of Clinical Oncology.
As in the SWOG trial, there was no advantage seen with the addition of gemtuzumab for the overall study population. However, a preplanned subgroup analysis showed a statistically significant improvement in overall survival in good-risk patients with the addition of gemtuzumab.
“From our point of view, it is quite difficult to do without gemtuzumab,” Dr. Burnett said. “At the moment—and for the last 15 months—we've had a trial using it, and Pfizer has agreed that we can finish it. So our problem won't arise for about another 18 months, by which time, I hope, perhaps Pfizer has either decided to go for another trial or some other company has taken it on.”
Farhad Ravandi-Kashani, MD, Associate Professor of Leukemia at MD Anderson, notes that targeting drugs toward molecularly defined patient subgroups is the way forward in cancer, and that therefore subgroup analyses should not be ignored.
“It is important not to discount subset analyses, at least when conducted in a formal way, like the MRC trial, and corroborated by a trend in another trial—the SWOG trial—and by Phase II studies,” he said. “The MRC study showed in predefined subset analyses, looking at cytogenetic risk groups, that there is a clear benefit for the addition of gemtuzumab in the favorable-risk subgroup, and a trend for benefit in the intermediate-risk group.”
Both Dr. Ravandi-Kashani and Dr. Burnett note that Phase II trials at their institutions suggest a benefit with the addition of gemtuzumab in other patient groups, such as those with acute promyelocytic leukemia or patients who are not fit enough for chemotherapy.
Showing some frustration with the situation, Dr. Ravandi-Kashani said, “Essentially you have a drug that has been developed and in use for 10 years, and clinicians have experience using it, so you are taking away a tool. The randomized controlled trial was in the first-line setting, and the initial approval was in the relapsed setting.
“I don't understand that completely—how you would withdraw a drug that was approved in the relapsed setting in the elderly based on a randomized-controlled trial in addition to chemotherapy in younger patients.”
MRC Data Not Included in FDA Submission
Although the academic researchers contend that the MRC data are essential in the evaluation of gemtuzumab, Pfizer did not include the data in their FDA submission. “We did not submit the MRC data. We just submitted the SWOG data,” said Mark Shapiro, MD, PhD, Senior Director and Hematology Team Leader in the US Medical Affairs Oncology Business Unit of Pfizer, Inc. in New York.
“It was the SWOG study that we previously agreed with the FDA would serve as the post-approval trial to confirm clinical benefit of Mylotarg, and indeed there were discussions with the FDA prior to that study starting where they agreed to utilize that study. The MRC study was not the post-approval study chosen.”
When asked whether the company might support future trials testing gemtuzumab in good-risk AML patients, based on the SWOG and MRC subset analyses, Dr. Shapiro said, “I don't think it would be appropriate for me to comment on that right now. We will need to see all the subset information that arise from the final analysis of the SWOG study.
“I think Professor Burnett's data are certainly intriguing, but it is a subset of patients in the study and not the whole study,” Dr. Shapiro said.
As for the appropriateness of designing a confirmatory trial in a different setting than the initial indication, he said it was common practice in oncology, and that this was the same disease, just a different mix of patients.
A Question of Economics?
Nearly all of the researchers interviewed for our two articles on this topic, both those who supported the withdrawal and those who opposed it, said they thought economics played into the company's decision to withdraw gemtuzumab without a fight.
“You didn't see a major fight from the drug company for the withdrawal of the drug, and what you have to watch is this: With this drug the sales every year are $20 million or less; the drug is going to lose its patent in two years, so nobody cares to defend this drug or make it available to the subsets of patients with leukemia who need it the most,” said Hagop Kantarjian, MD.
“This is what you are really seeing in cancer research. If there is a financial profit, there are big advocacy groups and big events around whether the drug is approved or not and whether it stays in the market or not. When there is no financial drive, such as with Mylotarg, everybody, including the drug company, is very happy to abandon it.”
When asked directly whether economics influenced the decision to withdraw gemtuzumab, Pfizer's Mark Shapiro, MD, PhD, said, “We had extensive discussions with the FDA, and because we were unable to confirm the benefit of the drug as required by the subpart H approval, the decision was made to withdraw. What I'd like you to be aware of is that Pfizer is committed to finding treatments for patients with a variety of cancers, including hematologic malignancies and we are still committed to that.”