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Expanded Indication Sought for Carfilzomib (Kyprolis) in Relapsed Multiple Myeloma
A supplemental New Drug Application (sNDA) has been submitted to the FDA for carfilzomib (Kyprolis, Amgen) to seek an expanded indication for the treatment of patients with relapsed multiple myeloma (RMM) who have received at least one prior therapy. Carfilzomib is currently approved in the U.S. for the treatment of patients with RMM as monotherapy.
The sNDA is based on data from the global ENDEAVOR trial, the first of two head-to-head phase III studies of carfilzomib versus bortezomib (Velcade, Millennium Pharmaceuticals). RMM patients treated with carfilzomib and dexamethasone lived twice as long without their disease worsening, demonstrating statistically and clinically significant superiority over bortezomib and dexamethasone (median progression-free survival [PFS]: 18.7 months versus 9.4 months, respectively; hazard ratio = 0.53; P < 0.0001).
The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary objectives of a higher overall response rate and a lower rate of neuropathy events. Overall survival data continue to be monitored.
Treatment discontinuation due to adverse events and on-study deaths was comparable between the two treatment arms. The rates of cardiac and renal failure were higher in the carfilzomib arm than in the bortezomib arm. There were also higher rates of hypertension and dyspnea with carfilzomib.
The ENDEAVOR (RandomizEd, OpeN Label, Phase III Study of Carfilzomib Plus DExamethAsone Vs. Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial involved 929 patients whose multiple myeloma had relapsed after at least one, but not more than three, prior therapeutic regimens. The study’s primary endpoint was PFS, defined as the time from treatment initiation to disease progression or death.
Patients received carfilzomib as a 30-minute infusion along with dexamethasone (20 mg). Carfilzomib was initiated at a starting dose of 20 mg/m2 in cycle 1 on days 1 and 2. If tolerated, the dose was escalated to a target dose of 56 mg/m2 on day 8 of cycle 1. The patients were kept at 56 mg/m2 on days 9, 15, and 16 on a 28-day cycle. Patients who tolerated 56 mg/m2 in cycle 1 were kept at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle. Patients who received bortezomib (1.3 mg/m2) with dexamethasone (20 mg) were administered bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of the drug. More than 75% of the patients in the control arm received bortezomib subcutaneously. The study was conducted at 235 sites worldwide.
Carfilzomib is also being evaluated in the CLARION trial, a head-to-head phase III, multicenter, open-label, randomized study in transplant-ineligible patients with newly diagnosed multiple myeloma. The study is evaluating the safety and efficacy of carfilzomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone.
Carfilzomib is currently indicated as a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy. The FDA approval was based on the response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
Multiple myeloma is the second most common hematologic cancer. In the U.S., approximately 96,000 people have, or are in remission from, multiple myeloma. In 2014, the estimated number of new cases of the disease was more than 24,000, and the estimated number of deaths was 11,090.
Source: Amgen; July 23, 2015.