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Krypolis (Carfilzomib) Superior to Velcade (Bortezomib) in Head-to-Head Trial
The late-stage ENDEAVOR trial evaluating Kyprolis (carfilzomib, Onyx Pharmaceuticals/Amgen) for injection in combination with low-dose dexamethasone compared with Velcade (bortezomib, Millennium Pharmaceuticals) and low-dose dexamethasone has met its primary endpoint of progression-free survival (PFS).
Patients with relapsed multiple myeloma treated with carfilzomib lived twice as long without their disease worsening, demonstrating statistically and clinically significant superiority over bortezomib (median PFS: 18.7 months vs. 9.4 months, respectively; hazard ratio: 0.53).
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.
Treatment discontinuation because of adverse events and on-study deaths were comparable between the two treatment arms. However, the rates of cardiac and renal failure were higher in the carfilzomib arm than in the bortezomib arm. There was also an increase in the incidence of hypertension and dyspnea in the carfilzomib arm compared with the bortezomib arm.
The ENDEAVOR (RandomizEd, OpeN-Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial evaluated carfilzomib in combination with low-dose dexamethasone compared with bortezomib in combination with low-dose dexamethasone in 929 patients with multiple myeloma whose disease had relapsed after at least one, but not more than three, prior therapeutic regimens. PFS, the trial’s primary endpoint, was defined as the time from treatment initiation to disease progression or death.
Patients received carfilzomib as a 30-minute infusion along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was administered at 20 mg/m2 on days 1 and 2, followed by escalation to 56 mg/m2 on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m2 in cycle 1 were kept at that 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 low-dose dexamethasone (20 mg) were administered bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.
Multiple myeloma is the second most common hematologic cancer and results from an abnormality of plasma cells, usually in the bone marrow. In the U.S., approximately 83,000 people have multiple myeloma. More than 22,000 new cases were diagnosed and more than 10,000 people died in 2013.
In July 2012, the FDA granted accelerated approval to Kyprolis (carfilzomib) for the treatment of patients with multiple myeloma who had received at least two prior therapies, including bortezomib and an immunomodulatory agent, and had demonstrated disease progression on or within 60 days of completion of the last therapy. FDA approval was based on the response rate. A clinical benefit, such as an improvement in survival or symptoms, has not been verified.
Carfilzomib is administered intravenously over 2 to 10 minutes on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17 to 28) at a recommended cycle-1 dosage of 20 mg/m2/day. If this dosage is tolerated, carfilzomib is then administered in an increased cycle-2 and subsequent-cycle dosage of 27 mg/m2/day.
Source: Amgen; March 1, 2015.