FDA Grants Empliciti Combination a Priority Review for Myeloma Treatment

The FDA has granted a priority review to a supplemental biologics license application (sBLA) for Empliciti (elotuzumab) for use in combination with Pomalyst (pomalidomide) and low-dose dexamethasone (EPd) for the treatment of patients with relapsed/refractory multiple myeloma following two or more prior therapies, including Revlimid (lenalidomide) and a proteasome inhibitor (PI).

The sBLA was submitted based on the phase 2 ELOQUENT-3 trial, in which the addition of Empliciti to Pomalyst and dexamethasone reduced the risk of disease progression or death by 46 percent compared with Pomalyst and dexamethasone alone for patients with relapsed/refractory multiple myeloma. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sBLA by Dec. 27, 2018.

In the ELOQUENT-3 trial, the median progression-free survival (PFS) was 10.3 months with the Empliciti combination compared with 4.7 months with Pomalyst plus dexamethasone. The PFS benefit associated with EPd was similar, regardless of whether patients had received two to three prior lines of treatment, or four or more lines of treatment.

The objective response rate (ORR) was 53 percent with Empliciti compared with 26 percent in the control arm. The rate of very good partial response or better was 20 percent versus 9 percent, with and without Empliciti, respectively.

“This file acceptance is an important step in BMS’s ongoing efforts to advance treatment options for patients with relapsed/refractory multiple myeloma,” said Jeffrey Jackson, Ph.D., hematology development lead at Bristol-Myers Squibb, which is co-developing Empliciti with AbbVie.

“Given the need for new, effective treatment options in this patient population, we look forward to working with the FDA with the hope of bringing this combination to patients with relapsed/refractory multiple myeloma whose disease progressed on previous therapies as quickly as possible,” added Jackson.

The phase 2 ELOQUENT-3 study enrolled 117 patients with relapsed/refractory multiple myeloma who were randomized to the Empliciti combination (60 patients) or Pomalyst and dexamethasone alone (57 patients). Empliciti was administered at 10 mg/kg intravenously each week during cycles 1 and 2 and at 20 mg/kg every four weeks thereafter. Pomalyst was given at 4 mg orally on days 1 to 21 of each cycle plus dexamethasone weekly at 40 mg for patients up to 75 years of age or 20 mg for those older than 75 years.

Eligible patients had received at least two prior lines of therapy, including Revlimid and a PI; patients receiving prior Pomalyst were excluded from the study. The median age of patients was 67 years and they had received a median of 3 prior treatments (range, 2-8). Prior treatments included bortezomib (100 percent), Revlimid (99 percent), Kyprolis (carfilzomib) (21 percent), Ninlaro (ixazomib) (6 percent) and Darzalex (daratumumab) (3 percent). More than half of patients (55 percent) had undergone stem cell transplantation and most patients were refractory to Revlimid (87 percent), a PI (80 percent) or both (70 percent).

The primary objective of the study was investigator-assessed PFS and secondary endpoints included ORR and overall survival (OS). At the Feb. 21, 2018, database lock, the median follow-up was 9.1 months, and 40 percent of patients receiving the Empliciti combination remained on treatment compared with 20 percent in the control arm.

Although OS results remained immature they suggested a trend favoring Empliciti. At the analysis, there was a 38 percent reduction in the risk of death in the Empliciti arm compared with the control group. At the data cutoff, there were 13 deaths in the Empliciti arm and 18 in the control arm.

Disease progression was the main cause of treatment discontinuation and occurred in 43 percent of patients in the Empliciti arm compared with 56 percent in the control group. Discontinuation due to adverse events occurred in 18 percent of patients in the Empliciti arm compared with 24 percent for the control group.

The rates of grade 3/4 neutropenia and anemia were lower with Empliciti versus the control arm, despite longer exposure (median number of cycles 9 versus 5). Pomalyst dose intensity was similar between groups. Grade 3/4 neutropenia was experienced by 13 percent of patients in the Empliciti group compared with 27 percent for the control arm and grade 3/4 anemia occurred in 10 percent versus 20 percent of patients, respectively. All-grade infections occurred in 65 percent of patients in both treatment arms. Five percent of patients in the Empliciti group experienced infusion reactions that were grade 1/2 in severity.

Empliciti is an immunostimulary monoclonal antibody that specifically targets the signaling lymphocyte activation molecule family member 7 (SLAMF7), which is expressed as a surface protein on myeloma cells, natural killer (NK), and plasma cells. Empliciti has a dual mechanism of action to directly stimulate the immune system via NK activation and to directly target SLAMF7 on myeloma cells for activated NK destruction via ADCC toxicity.

The FDA approved Empliciti in November 2015 for use in combination with Revlimid and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies.