Early data reported late last year from the Phase II trials for the BCR-ABL tyrosine kinase inhibitor ponatinib (Iclusig) fielded much attention—so much, that the drug was approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) under the FDA's priority review program, which expedites the review process of promising new drugs (OT 1/25/13). But, after longer follow-up data revealed an increased frequency of arterial thrombotic events, the Food and Drug Administration moved to temporarily suspend marketing and commercial distribution of the drug.
The latest findings give sufficient reason to pause and review the drug's safety, said OT's Clinical Advisory Editor for Hematology/Oncology, Mikkael Sekeres, MD, MS, Director of the Cleveland Clinic Taussig Cancer Institute's Leukemia Program and Chair of the Hematology/Oncology Pharmacy and Therapeutics Committee, one of several leukemia experts interviewed for this article. “Patient safety always comes first. Whenever there is evidence of that magnitude, it's always right to make sure no additional people unsuspectingly are put in harm's way.” (He is also Chair of the FDA's Oncologic Drugs Advisory Committee—although that committee was not involved in the decisions for ponatinib.)
The FDA announced an investigation of an “increasing frequency of reports of serious and life-threatening blood clots and severe narrowing of blood vessels of patients taking the drug” on Oct. 11, and on Oct. 31 announced that sales and marketing of the drug were being suspended.
Jorge E. Cortes, MD, Deputy Department Chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center and the lead author of the drug's Phase II PACE trial, upon which the drug's approval was based, explained that with most tyrosine kinase inhibitors, most adverse events occur early in treatment—usually within the first three months—and that the risk then tends to go down.
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“The problem with this drug is that the rate of these events remains constant over time, which means that the incidence continues to increase significantly over time,” he said. “For the patients, they haven't had an adverse event in the first three months, they appear to still have the same chance in the next three months and the three months after that.”
The drug label did include information about the risks of blood clots in a Boxed Warning, as well as in the Warnings and Precautions section. Serious arterial blood clots had occurred in eight percent of patients in the first reports from the Phase II PACE trial, and blood clots in other veins occurred in three percent of patients receiving the drug in those trials. Those findings had been presented at the American Society of Hematology Annual Meeting last year (OT 2/25/13 issue).
The researchers had since submitted findings from the PACE trial for publication in the New England Journal of Medicine, which were published on Nov. 7 (2013;369:1783-1796). That paper noted that with an additional 13 months of exposure, in patients who continued in the trial, the cumulative incidence of serious arterial thrombotic events was 11.8 percent and the incidence of all arterial thrombotic events—serious or not—was 17.1 percent.
Cortes also noted that additional data based on even longer follow-up (than the PACE trial data) from the Phase I trial support the same trend of a constant rate of vascular events, which increased incidence overall.
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The most recent statements from the FDA citing the latest data reported that 24 percent of patients in the PACE Phase II trial and approximately 48 percent of patients in the Phase I clinical trial had experienced serious adverse vascular events, including fatal and life-threatening heart attack; stroke; loss of blood flow to the extremities resulting in tissue death; and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.
High blood pressure occurred in 67 percent of patients treated with the drug in clinical trials, and heart failure, including fatalities, occurred in eight percent of patients receiving the drug.
‘Shows that Accelerated Approval Pathway Works’
Sekeres said that “what has occurred with ponatinib—its receiving accelerated approval based on the signs of great activity and acceptable risk under the accelerated approval mechanism of the FDA, and the subsequent quick withdrawal when signs of higher than anticipated risk emerged—is a clear demonstration that the accelerated approval pathway works.”
He noted that the early Phase II clinical trial data submitted to the FDA on which the drug's approval was based showed very promising results with much lower rates for these types of adverse events. Among patients with chronic CML, 54 percent showed a major cytogenetic response. “This is a very heavily pre-treated population with very few options—for most, the only other option is bone marrow transplant,” Sekeres noted. “A cytogenetic response rate of 54 percent in this heavily pretreated population is really something.”
Also asked his opinion for this article, Michael J. Mauro, MD, Leader of the Myeloproliferative Diseases Program at Memorial Sloan-Kettering Cancer Center, who was an investigator on both the Phase I and Phase II trials (and an author on the NEJM paper reporting the Phase I data, 2012;367:2075-2088), agreed with the FDA's decision to initially approve the drug based on the evidence presented at the time: “There was clearly a very strong unmet need, so I don't believe they acted prematurely in approving it when they did.”
But, he added: “The FDA did the right thing in suspending the marketing and sales of the drug pending the review of the side effect data.”
For Some Patients, Benefits May Still Trump Risk
Despite the concerns over ponatinib's risk profile, there is also the concern that the suspension will limit patients' access for those who were responding and for whom the drug was working.
Brian Druker, MD, Director of the Oregon Health & Science University Knight Cancer Institute, said via email: “The FDA absolutely should review the data for Iclusig given the severity of side effects being reported and how frequent they appear to be. But, I do have concerns about suspending sales: There are a group of patients with the T315I mutation, for whom I and others believe that Iclusig is the best option available. We would very much have preferred the option to discuss available treatments and allow our patients to make an informed decision.
“My other concern is that it took over a week for there to be an agreed-upon mechanism for patients to obtain the drug through the IND process.”
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For patients responding to ponatinib at the time of its suspension, the FDA advised physicians to submit single-patient Investigational New Drug (IND) applications so that the patients could continue treatment (more information on how providers can obtain emergency access to the drug is available on the FDA's website: www.fda.gov/Drugs/DrugSafety/ucm373040.htm).
The FDA advised immediate discontinuation for patients taking the drug who were not responding. And, the FDA also advised that health care professionals should not start treating new patients with ponatinib unless no other treatment options are available and all other therapies have failed.
Druker added that the FDA and Ariad, the drug's manufacturer, had since been “extremely responsive” to IND requests, although that process was labor intensive. “I do worry a bit about patients in the community whose physicians may be somewhat less experienced with this process,” he said.
An FDA spokesperson noted that in the time since the drug was withdrawn, as of Nov. 22, a total of 234 IND applications had been granted by the FDA. To streamline the process, the agency is allowing institutions to request multiple INDs during a single request. But, it is still up to individual physicians and care centers as to whether or not they will allow and go through the process to treat patients using an IND.
Making the Case for Ponatinib
Mauro emphasized that there are patients on ponatinib who continue to do well: “They really had clear indications for the drug and are responding. It is a lifesaving drug. Will people have the access, and will physicians be willing to do the work to maintain patients who are on ponatinib?
“There are today and will be in the future patients in whom the benefit is acceptable and who need access. We fear patients may face a greater risk of losing access to their therapy or being switched to less effective therapy—which could lead to relapse or progressive disease—that risk probably clearly outweighs whatever real or perceived vascular risk they might have.”
Mauro noted that the patients he would consider the drug an acceptable option for were those who had multi-drug resistant CML and resistant CML with the T315I mutation—ideally in whom the cardiovascular disease risk is known and can be monitored (or minimized with additional treatment). “The alternatives for these patients generally are palliative therapy—or transplant, which has its own associated morbidity and mortality associated with it that in many cases may be in the same range as or higher than the risks associated with ponatinib.”
Sekeres noted about the patients at Cleveland Clinic who will continue the drug: “These are patients in whom their disease has persisted despite other available therapies, and patients in whom their disease is too active for them to go to transplant—we are still using the drugs for these patients as a bridge to transplant.”
Cortes, who agreed that for some patients the potential benefits do likely outweigh the risks, pointed to two subsets of patients for whom the drug could still be considered:
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1. Patients with the T315I mutation (which the PACE trial data indicated were the patients with the highest rates of cytogenetic response); and
2. Patients who have already been treated with three other tyrosine kinase inhibitors and have had no response.
Cortes noted that most of the patients who developed the adverse events had risk factors, such as prior coronary artery disease, a history of smoking, and being obese—although there were also some patients who had no risk factors and still developed vascular events.
The next steps in determining for which population(s) the drug is appropriate and at what dose, he said, are to determine the mechanisms causing the adverse events. “We need to define how to make the drug as safe as possible—and the first decision is: do we allow this drug to continue or not.”
To Market Again or Not?
FDA statements noted that because neither the Phase I nor II trials included a control group, it is not possible to determine if the adverse events were due to the drug, but that the increasing rate and pattern of the events strongly suggested that many were drug-related. The agency said it has not yet identified a dose level or exposure duration that is safe.
“If the drug is not marketed again—that may not be the right decision, because in some patients the risk-benefit ratio is clearly still acceptable for ponatinib—and withdrawing the drug removes the important notion of patient choice,” Mauro said. “Patients should be able to decide what risk they're willing to manage as long as they are informed.”
The European Medical Authority (EMA) reviewed the same data as the FDA, but chose not to remove the drug's marketing authorization (see box). “The data appropriately led to a change in the warnings and the guidance recommended for physicians using ponatinib,” Mauro said. “I think one can't ignore a large governing body for the rest of the developed world and the U.S. feeling differently.”
Stephanie Yao of the FDA Office of Media Affairs said the agency will continue to work with Ariad to further understand the risk—and identify potential patient populations in which the benefit may outweigh the risks. Ponatinib could either be withdrawn, or it could be returned to market, depending on the FDA's subsequent determinations, she said, although she could not give an estimated timeline of when the additional review would be completed.
Differing Interpretations from Abroad
The European Medical Authority (EMA) has not suspended or withdrawn the marketing authorization for ponatinib. A November 8 statement from the EMA's Pharmacovigilance Risk Assessment Committee advised the manufacturer that the drug's label should include strengthened warnings on cardiovascular risk and guidance on optimizing patients' cardiovascular therapy before starting treatment. And, a November 22 statement made the following recommendations for physicians to minimize patients' risk of blood clots:
* The drug should not be used in patients who have had a heart attack or stroke, unless the potential benefits outweigh the risks;
* Cardiovascular risks of all patients should be assessed and measures should be taken to reduce risks before starting and during treatment;
* Hypertension should be controlled during treatment and providers should consider interrupting treatment if it is not controlled; and
* Patients should be monitored for evidence of vascular occlusion or thromboembolism, and treatment should be interrupted immediately if it occurs.
The EMA said their review of the data had found the rate of serious occlusive vascular events to be 22 percent for the Phase I trial and 13.8 percent for the Phase II trial, as of September 2013—both of which were much lower than what the FDA had reported.
Michael J. Mauro, MD, Leader of the Myeloproliferative Diseases Program at Memorial Sloan-Kettering Cancer Center who was an investigator on the drug's Phase I and II trials, said that the different interpretation and calculation of rates of toxicity as reported by the manufacturer versus the FDA was concerning, given that everyone was looking at the same raw data. This is an example of the need for common parameters for calculating such risks, he said. “One can render different opinions on their impact and their weight, but there shouldn't be different ways of interpreting the risks or different ways of categorizing them. That's a lesson this experience has taught us.”
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