Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.
In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.
The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.
The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.
Benefit Over Existing Therapies
Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.
The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.
The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.
"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).
The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.
The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.
The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."
Deaths, SAEs, and Discontinuations
There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.