On June 2, 2015 Bristol-Myers Squibb reported that results from an interim analysis of its Phase III, randomized, open-label ELOQUENT-2 trial were published in the June 2 online edition of the New England Journal of Medicine (Press release, Bristol-Myers Squibb, JUN 2, 2015, View Source [SID:1234505207]). The trial (n=646) evaluated elotuzumab, an investigational immunostimulatory antibody, in combination with lenalidomide and dexamethasone (ELd) versus lenalidomide and dexamethasone alone (Ld) for the treatment of relapsed or refractory multiple myeloma. The study met its co-primary endpoints demonstrating superior progression-free survival (PFS) and overall response rate (ORR).
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The ELd arm demonstrated a 30% reduction in the risk of disease progression or death compared to the Ld arm (HR 0.70, 95% CI, [0.57, 0.85]; p = 0.0004). The PFS rates in the ELd arm versus the Ld arm were 68% versus 57% at 1 year and 41% versus 27% at 2 years, respectively. A significant ORR also was observed with 79% (74% to 83%) in the ELd arm compared to 66% (60% to 71%) in the Ld arm (odds ratio, 1.9; 1.4 to 2.8; p=0.0002). The safety profile was consistent with previously-reported studies and there were minimal incremental adverse events (AEs) with the addition of elotuzumab to lenalidomide and dexamethasone.
"Despite advances in treatment, multiple myeloma remains a largely incurable disease," said lead author Sagar Lonial, M.D., chief medical officer of the Winship Cancer Institute of Emory University School of Medicine. "These ELOQUENT-2 data are significant because they show that adding elotuzumab to the standard treatment yielded an impressive reduction in the risk of disease progression, which was maintained over time, demonstrating the benefit of an immune-based approach in multiple myeloma."
Results from the ELOQUENT-2 trial will be presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago during an Oral Abstract Session on Tuesday, June 2 from 9:45 – 9:57 a.m. CDT [Abstract # 8508].
Also presented in a poster session at ASCO (Free ASCO Whitepaper) on Sunday, May 31 were results from the Phase II study that evaluated elotuzumab in combination with bortezomib and dexamethasone (EBd, n=77) versus bortezomib and dexamethasone (Bd, n=75) alone in patients with relapsed or refractory multiple myeloma [Abstract #8573]. Consistent with data from ELOQUENT-2, results from the Phase II study demonstrated a 28% reduction in the risk for disease progression or death in the EBd arm compared to Bd alone (HR 0.72, 70% CI, 0.59, 0.88). One-year PFS rates were 39% (95% CI 28%, 50%) for EBd versus 33% (95% CI 22%, 44%) for Bd. One-year survival rates were 85% (95% CI 75%, 92%) in the EBd arm versus 74% (95% CI 62%, 83%) in the Bd arm. Grade 3-4 AEs were reported in 68% of patients in the EBd group and 60% in the Bd group, including infections (19% vs. 15%), thrombocytopenia (9% vs. 17%), and peripheral neuropathy (8% vs. 9%).
"These trials, which evaluated elotuzumab in combination with either an IMiD or a proteasome inhibitor, demonstrated that elotuzumab, an immunostimulatory antibody, has the potential to be a new modality for the treatment of multiple myeloma," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "Bristol-Myers Squibb continues to make great progress toward delivering on our commitment to expand the role of immunotherapy into hematologic malignancies, such as multiple myeloma. We look forward to continued follow-up of the ELOQUENT-2 trial as we know improvement in long-term outcomes, including survival, is critical for patients."
About ELOQUENT-2
ELOQUENT-2 (CA204-004) is an open-label, multicenter Phase III study evaluating elotuzumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with relapsed or refractory multiple myeloma. The trial enrolled 646 patients who had received one to three prior therapies and who were not lenalidomide-refractory. Patients were randomized 1:1 to receive either elotuzumab 10 mg/kg in combination with lenalidomide and dexamethasone (ELd) or lenalidomide and dexamethasone alone (Ld) in 28-day cycles to disease progression or unacceptable toxicity. The co-primary endpoints were progression-free survival, as defined by hazard ratio, and objective response rate. Median follow-up for this interim analysis was 24.5 months with 35% of ELd patients (n=113) and 21% of Ld patients (n=66) remaining on therapy. Key secondary endpoints included overall survival and pain severity/interference with daily life. Exploratory objectives included tumor response, duration of response, health-related quality of life, and safety.
Along with a 30% reduction in the risk of disease progression, which was sustained at two years, the median PFS in the ELd group was 19.4 months (95% CI, 16.6 to 22.2) versus 14.9 months (95% CI, 12.1 to 17.2) in the Ld group. The PFS benefit observed was consistent across all pre-specified subgroups. Patients in the ELd arm were exposed to treatment with lenalidomide 30% (or median of approximately five months) longer than patients in the Ld arm. Discontinuation was mainly due to disease progression (42% ELd, 47% Ld). The rate of discontinuation due to adverse events did not differ between arms. Grade 3-4 hematologic adverse events in the ELd and Ld arms, respectively, included lymphopenia (77% vs. 49%), neutropenia (34% vs. 44%), anemia (19% vs. 21%) and thrombocytopenia (19% vs. 20%), and the exposure-adjusted infection rate was the same in both arms. Infusion reactions occurred in 10% of patients with ELd; these were mostly Grade 1-2, and were manageable and resulted in discontinuation in only 1% of patients. A similar proportion of patients in each study group (2%) died due to an adverse event. As of this analysis, there were a total of 210 deaths in the study with 94 [30%] in the ELd group versus 116 [37%] in the Ld group. This represents a total of 49% of the 427 deaths required for the final analysis. Follow-up of longer-term outcomes, including overall survival, is ongoing.
About Elotuzumab
Elotuzumab is an investigational immunostimulatory antibody targeted against Signaling Lymphocyte Activation Molecule (SLAMF7), a cell-surface glycoprotein that is highly and uniformly expressed on myeloma cells and Natural Killer (NK) cells, but is not detected on normal solid tissues or on hematopoietic stem cells. Elotuzumab is being investigated to determine whether the compound may selectively target myeloma cells. It is believed that elotuzumab works through a dual mechanism of action: binding to SLAMF7 on NK cells, directly activating them and binding to SLAMF7 on myeloma cells, flagging them for NK cell recognition and destruction.
In May 2014, the U.S. Food and Drug Administration (FDA) granted elotuzumab Breakthrough Therapy Designation for use in combination with one of the chemotherapy treatments for multiple myeloma (lenalidomide, used in combination with dexamethasone) in patients who have received one or more prior treatments. Elotuzumab is an investigational compound and its safety and efficacy have not been evaluated by the FDA or any other health authority.
Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.