FDA Accepts sNDA for Carfilzomib Label Update in Myeloma

Robert Orlowski, MD, PhD

Robert Orlowski, MD, PhD

The FDA has accepted a supplemental new drug application (sNDA) seeking to add overall survival (OS) data from the phase III ENDEAVOR trial to the label for carfilzomib (Kyprolis) for use in patients with relapsed or refractory multiple myeloma.

UPDATE 1/17/2018: FDA Approves Carfilzomib Label Update in Myeloma

Results from the primary ENDEAVOR OS analysis recently published in The Lancet Oncology showed that carfilzomib reduced the risk of death by 21% compared with bortezomib (Velcade) in patients with relapsed/refractory multiple myeloma.

Carfilzomib in combination with dexamethasone extended OS by 7.6 months compared with bortezomib and dexamethasone (47.6 vs 40 months; hazard ratio [HR], 0.791; 95% CI, 0.648-0.964; P = .010). Investigators wrote that the OS benefit was consistent for both patients who received previous bortezomib (HR, 0.75) and those who did not (HR, 0.84).

Carfilzomib is currently approved in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 to 3 lines of therapy. The treatment is also approved as a monotherapy for relapsed/refractory myeloma patients who have received 1 or more lines of therapy.

The Prescription Drug User Fee Act action date for the FDA’s decision on the label update is April 30, 2018.

“Effective proteasome inhibition is an essential approach to treating multiple myeloma. Patients in the ENDEAVOR study receiving Kyprolis and dexamethasone lived 7.6 months longer than those on Velcade and dexamethasone,” Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the manufacturer of carfilzomib, said in a statement. “These data, along with compelling overall survival results from the phase III ASPIRE trial, clearly demonstrate that Kyprolis-based regimens should be considered new standards of care for appropriate patients with relapsed multiple myeloma.”

In a separate press release today, Amgen reported 3-year follow-up data from ENDEAVOR, showing that carfilzomib plus dexamethasone reduced the risk of death by 24% versus bortezomib/dexamethasone, with a 9-month median OS benefit (47.8 vs 38.8 months; HR, 0.76; 95% CI, 0.63-0.92; P = .0017). There were no new safety concerns with the longer follow-up.

“For physicians making prescribing decisions, long-term follow-up helps to further support the safety and efficacy of a therapy and instills confidence in the treatment,” Robert Orlowski, MD, PhD, Florence Maude Thomas Cancer Research professor and chair, ad interim, Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, said in a statement. “The current 3-year follow-up analysis demonstrates that this proteasome inhibitor continues to demonstrate a prolonged overall survival benefit and consistent safety profile when combined with dexamethasone for relapsed multiple myeloma patients.”

From June 20, 2012, to June 30, 2014, 929 patients enrolled in ENDEAVOR, an open-label, randomized controlled study. Patients were randomly assigned to carfilzomib/dexamethasone (n = 464) or bortezomib/dexamethasone (n = 465) and treated at 198 medical centers in 27 countries in Europe, North America, South America, and the Asia-Pacific region.

Investigators administered carfilzomib at a starting dose of 20 mg/m2 on days 1 and 2 of cycle 1. If tolerated, the dose was escalated to 56 mg/m2 on day 8 of cycle 1. The 56 mg/m2 dose was then maintained on days 9, 15, and 16, and throughout subsequent cycles. Patients in the control arm received 1.3 mg/m2 of bortezomib. Most patients (75%) received bortezomib subcutaneously.

The median age of patients enrolled in the trial was 65 years, and 93% had an ECOG performance status of 0 or 1 (about 50% ECOG 0), and about 20% of the patients had high cytogenetic risk by fluorescence in situ hybridization.

In a posthoc landmark analysis measuring OS from time of progression, investigators found that median OS was 21.5 months in both groups (HR, 1.03; 95% CI, 0.822-1.297; P = 0.61).

Median duration of treatment was 48.0 weeks (median, 12 cycles) in the carfilzomib arm versus 27 weeks (median, 8 cycles) in the bortezomib group. Median relative dose intensity was 91% (IQR, 81-98) for carfilzomib and 85% (IQR, 70-96) for bortezomib.

Nearly all patients in both groups (99%) experienced any grade adverse events (AEs). The most common AEs (≥20%) in the carfilzomib arm were anemia, diarrhea, pyrexia, dyspnea, fatigue, hypertension, cough, insomnia, upper respiratory tract infection, peripheral edema, nausea, bronchitis, asthenia, back pain, thrombocytopenia, and headache.

Slightly more patients in the carfilzomib group experienced grade 3 or higher AEs (81% vs 71%). Frequent (≥5%) grade ≥3 AEs that occurred more often in the carfilzomib group included anemia (16% vs 10% in the bortezomib arm), hypertension (15% vs 3%), dyspnea (6% vs 2%), and decreased lymphocyte count (6% vs 2%). Rates of pneumonia (9%) and thrombocytopenia (9%) were equal in both groups.

Twenty-seven patients (6%) in the carfilzomib arm experienced grade ≥3 cardiac failure versus 9 patients (2%) in the bortezomib group. Six percent of patients assigned to carfilzomib and 3% of those assigned to bortezomib experienced grade ≥3 acute renal failure.

Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial [published online August 23, 2017]. Lancet Oncol. doi: 10.1016/ S1470-2045(17)30578-8.

Adverse events observed in this updated analysis were consistent with those previously reported for ENDEAVOR. Investigators noted that rates of grade ≥2 peripheral neuropathy were five-times higher in patients assigned to bortezomib (35% vs 7%).