ONCAlert | 2017 San Antonio Breast Cancer Symposium

Carfilzomib Shows Overall Survival Benefit Over Bortezomib in Myeloma

Jason Harris
Published Online:2:04 PM, Fri August 25, 2017

Sean E. Harper, MD
Carfilzomib (Kyprolis) reduced the risk of death by 21% compared with bortezomib (Velcade) in patients with relapsed/refractory multiple myeloma1, according to results from the phase III ENDEAVOR trial, now published in the Lancet Oncology.

The published results, previously reported at the 16th International Myeloma Workshop in New Delhi, showed that carfilzomib in combination with dexamethasone extended overall survival (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).

“In recent years, few clinical trials have demonstrated overall survival benefits in patients with relapsed or refractory multiple myeloma,” Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a press release. “In ENDEAVOR, the only head-to-head trial comparing proteasome inhibitors, Kyprolis showed a statistically significant overall survival benefit of 7.6 months over Velcade.”

Amgen manufactures the selective proteasome inhibitor carfilzomib. Harper said the company has already submitted these data to regulatory agencies in the United State and Europe to support a potential label update. 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.

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).

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%).

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.

Writing in an accompanying editorial, Niels WCJ van de Donk, MD, PhD, with the Department of Hematology, VU University Medical Center, said these results establish the carfilzomib/dexamethasone combination as the new standard of care in relapsed/refractory multiple myeloma.2 In the absence of head-to-head comparisons with triple-drug combinations, physicians should consider patient characteristics, tumor-related features, and type of response to previous treatments when making treatment decisions.

“Biomarkers that predict response, survival, and toxicity of these different regimens are urgently needed to guide treatment choices in individual patients,” wrote van de Donk. “Furthermore, the optimal sequence of available therapies is also an important question.”
 
 
References:
  1. 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.
  2. van de Donk NWCJ. Carfilzomib versus bortezomib: no longer an ENDEAVOR [published online August 23, 2017]. Lancet Oncol. doi: 10.1016/S1470-2045(17)30613-7.


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