Unfortunately, the FOCUS study did not meet its primary endpoint of prolonging overall survival in this heavily pretreated group of patients.
—Heinz Ludwig, MD
Carfilzomib (Kyprolis), as a single agent, failed to improve survival in relapsed and refractory myeloma patients, as compared with a corticosteroid and optional cyclophosphamide, in the phase III FOCUS trial, presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.1
“Unfortunately, the FOCUS study did not meet its primary endpoint of prolonging overall survival in this heavily pretreated group of patients,” said Heinz Ludwig, MD, of Wilhelminen Cancer Research Institute in Vienna.
Patients treated with carfilzomib had a median overall survival (the primary endpoint) of 10.2 months, compared to 10 months in the placebo arm (hazard ratio [HR] = 0.975, P = .42). Carfilzomib was, however, superior in terms of objective responses, clinical benefit, and disease control.
Dr. Ludwig and his colleagues believe the comparable outcomes are largely due to the better-than-expected survival in the placebo arm. “The trial was designed with the assumption that the control group would have a median overall survival of 6 months, based on historical reports,” he said. “The control arm performed better than expected.”
He also said that contemporary regimens should include a corticosteroid, which was not done in the 2008-designed FOCUS trial. “Drugs in myeloma are not used as single agents. If dexamethasone had been introduced, the results may have been much better,” he predicted.
The randomized phase III FOCUS trial aimed to show an overall survival benefit in end-stage patients. Investigators allocated 315 patients with relapsed and refractory myeloma to single-agent carfilzomib (20 mg/m2 on days 1 and 2, followed by 27 mg/m2 on days 8, 9 , 15, and 16 of cycle 1, followed by 27 mg/m2 on days 1, 2, 8, 9, 15, and 16 for cycles 2–9, and on days 1, 2, 15, and 16 for cycles 10+) or low-dose corticosteroids, with or without oral cyclophosphamide (50 mg/ d)—95% received cyclophosphamide. Patients had received at least three prior regimens, and almost 30% were treated with more than six.
In addition to the similar overall survival, median progression-free survival was also similar: 3.7 months in the carfilzomib group and 3.3 months in the control arm (HR = 1.091, P = .25). Significant benefits were observed with carfilzomib, however, in objective response rate (19.1% vs 11.4%, P = .03), clinical benefit rate (31.2% vs 20.9%, P = .02), and disease control rate (75.8% vs 67.7%, P = .05).
There was a tendency for the carfilzomib group to have prolonged time to the next antimyeloma therapy (7.1 vs 5.7 months) and to be less likely to be censored because of this (7.6% vs 20.3%), he added. Time to treatment failure (progression-free survival events and nonprotocol therapy) was 3.4 and 2.2 months, respectively.
Safety of Carfilzomib
The safety profile of single-agent carfilzomib was consistent with previous studies in heavily pretreated patients, except for renal impairment events.
Grade ≥ 3 treatment-emergent adverse events occurred in 75.2% of the carfilzomib arm and 71.2% of the control arm, which were serious in 58.6% and 51.0% and led to discontinuation of a study drug in 14.6% vs 20.3%. Cardiac toxicity was not increased with carfilzomib, and peripheral neuropathy rates were low, approximately 4% per arm.
More grade ≥ 3 acute renal failure events, however, were observed with carfilzomib (17.2% vs 5.2%), but in both arms, they occurred more often in patients with lower baseline creatinine clearance. Also, more patients with renal impairment or acute renal failure had light chain proteinuria or urine protein eletrophoresis positivity.
Dr. Ludwig said the results of this study are not in line with “exciting” emerging data. “Carfilzomib-based combinations are promising,” he noted.
Citing recent studies, he said that in treatment-naive patients, carfilzomib plus lenalidomide (Revlimid) and low-dose dexamethasone led to a 100% response rate, 3-year overall survival of 100%, and 3-year progression-free survival of 79.6%.2 In relapsed/refractory patients, increasing the dose of carfilzomib (from 20 mg/m2 to 56 mg/ m2) plus low-dose dexamethasone was associated with a 55% response rate in relapsed patients.3 In the phase III ASPIRE study, carfilzomib/lenalidomide/low-dose dexamethasone yielded an 8.7-month improvement in progression-free survival, vs lenalidomide/low-dose dexamethasone.4
Faith Davies, MD, of the University of Arkansas for Medical Sciences, Little Rock, noted in her discussion that carfilzomib is “an effective treatment with a good safety profile.” The FOCUS study indicates the “difficulties in developing a drug in the relapsed/refractory myeloma space,” she suggested.
She noted there is no standard control arm for studies, and in this case, the 10-month median survival in the sixth line of treatment “seems very good.” She reiterated Dr. Ludwig’s point: Single agents are not used in this population. ■
Disclosure: Drs. Ludwig and Davies reported no potential conflicts of interest.
1. Ludwig H, Masszi T, Pertucci MT, et al: Carfilzomib vs low-dose corticosteroids and optional cyclophosphamide in patients with relapsed and refractory multiple myeloma: A phase 3 study (FOCUS). ESMO 2014 Congress. Abstract LBA28. Presented September 29, 2014.
2. Dytfeld D, Jasielec J, Griffith KA, et al: Carfilzomib, lenalidomide, and low-dose dexamethasone in elderly patients with newly diagnosed multiple myeloma. Haematologica 99:e162-e164, 2014.
3. Papadopoulos KP, Siegel DS, Vesole DH, et al: Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. September 15, 2014 (early release online).
4. Amgen: Amgen announces phase 3 ASPIRE trial of Kyprolis® in patients with relapsed multiple myeloma met primary endpoint. Press release. August 4, 2014. Available at wwwext.amgen.com.
Accessed October 23, 2014.