Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.
The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.
"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."
Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.
"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."
The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.
Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."
Phase III Trials Underway
Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.
Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.
The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.
Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.