Studies presented at the 2015 ASH Annual Meeting bolstered support for elotuzumab (Empliciti) given in combination with lenalidomide (Revlimid) for the treatment of multiple myeloma.
Elotuzumab is an immunostimulatory monoclonal antibody. It has a dual mechanism of action, directly activating natural killer cells and also working via antibody-dependent cell-mediated cytotoxicity (ADCC) to cause targeted myeloma cell death. Elotuzumab is approved for use in combination with lenalidomide/dexamethasone in patients with relapsed/refractory disease after one to three prior therapies.
ELOQUENT-2 Study
Paul Richardson, MD, of the Dana-Farber Cancer Institute, Boston, presented an update of the pivotal ELOQUENT-2 study of 646 relapsed patients, which led to the drug’s approval.1 The main analysis of ELOQUENT-2 was performed in November 2014, with results as of August presented at the 2015 ASCO Annual Meeting.
With extended follow-up, the study showed a 27% reduction in the risk of progression or death with elotuzumab/lenalidomide/dexamethasone compared with lenalidomide/dexamethasone alone (hazard ratio [HR] = 0.73; P = .0014). At this analysis, median progression-free survival was 19.4 months in the elotuzumab arm and 14.9 months in the control arm; 3-year progression-free survival was 26% vs 18%, translating into a relative improvement of 44% at 3 years, Dr. Richardson reported. In the previous 2-year analysis, progression-free survival rates were 41% and 27%, respectively.
Paul Richardson, MD
“The progression-free survival benefit with elotuzumab plus len/dex was maintained over time,” Dr. Richardson noted. “The combination was associated with 38% fewer patients starting a subsequent line of treatment during the follow-up period, and the progression-free survival benefit was observed across all subgroups.”
Moreover, the interim overall survival analysis demonstrated a strong trend in favor of the combination (HR = 0.77; P = .0257; threshold for significance, P = .014). Median overall survival was 43.7 months with elotuzumab/lenalidomide/dexamethasone and 39.6 months with lenalidomide/dexamethasone.
“The elotuzumab combination demonstrated a durable and clinically relevant improvement in progression-free survival and response rate,” Dr. Richardson noted. “Updated safety and tolerability data are consistent with previous findings, confirming that there is minimal incremental toxicity associated with the addition of elotuzumab to lenalidomide.”
Focusing on adverse events of special interest, he reported more toxicity of any grade for gastrointestinal side effects, respiratory disorders, renal and urinary disorders, peripheral neuropathy, hypertension, and deep vein thromboses. Infusion reactions of any grade were experienced by 10% of patients, with most being mild and occurring during the first treatment cycle only. There were no grade 4 or 5 reactions.
Elotuzumab Plus Bortezomib
An updated analysis of a study of elotuzumab plus bortezomib (Velcade)/dexamethasone was also presented at the ASH meeting.2
Antonio Palumbo, MD
“This is the first randomized controlled trial of elotuzumab in combination with a proteasome inhibitor,” according to Antonio Palumbo, MD, of the University of Torino in Italy. “This longer term follow-up demonstrates prolonged progression-free survival with elotuzumab plus bortezomib and a safety profile that is consistent over time, with minimal incremental toxicity, compared with bortezomib alone.”
The study included 152 patients with relapsed/refractory disease who had received at least one prior line of treatment. Patients were randomized to receive elotuzumab plus bortezomib and low-dose dexamethasone or bortezomib/dexamethasone alone.
“At the 2-year follow-up, elotuzumab in combination with bortezomib continues to show durable efficacy vs bortezomib alone,” Dr. Palumbo reported. The combination led to a 24% reduction in the risk of disease progression or death and a 25% reduction in the risk of death. When stratified by prognostic factors, the elotuzumab-treated patients had a 38% reduction in disease progression.
At 2 years, progression-free survival was 18% with the triplet and 11% with bortezomib/dexamethasone; median progression-free survival was 9.7 months vs 6.9 months (HR = 0.76; P = .0184), and 2-year overall survival was 73% and 68%, respectively. Median overall survival was not reached with the doublet but was 34.7 months in the control arm. Response rates were 66% with the doublet and 63% with bortezomib, with 36% and 27%, respectively, achieving at least a very good partial response.
“In the overall survival analysis, the trend is in favor of elotuzumab in combination with bortezomib,” Dr. Palumbo said.
He elaborated upon the mechanism of action of elotuzumab and explained that the study hoped to identify subsets of patients who may benefit most. In ADCC, the Fc portion of an IgG1 antibody binds to an FcγRIIIa (CD16) receptor expressed on natural killer cells. This gene has allelic variations that are associated with affinity for IgG1 antibodies. The high-affinity “VV” genotype results in enhanced ADCC and has been associated with improved clinical outcomes, he pointed out.
“As ADCC is a known mechanism of action of elotuzumab, we examined FcγRIIIa receptor polymorphisms for any association between genotype and clinical outcome,” he said. Indeed, the researchers observed a trend toward longer progression-free survival in patients receiving elotuzumab who were homozygous for the high-affinity (VV) FcγRIIIa V allele. This genetic subset had a median progression-free survival of 22.3 months—more than double that of other allelic subsets.
The safety profile of the combination was comparable to bortezomib/dexamethasone alone. Only one infusion reaction was observed (grade 1). ■
Disclosure: Dr. Richardson is on the adisory board of and has received research funding from Celgene and Bristol-Myers Squibb. Dr. Palumbo is a consultant for Amgen, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals, and Onyx Pharmaceuticals; and has received honoraria from Amgen, Array BioPharma, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals, Onyx Pharmaceuticals, and Sanofi Aventis.
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