FDA Grants Elotuzumab Priority Review in Multiple Myeloma

Michael Giordano, MD

The FDA has granted elotuzumab (Empliciti) a priority review for use in combination therapy in patients with multiple myeloma following the failure of one or more prior therapies, according to Bristol-Myers Squibb and AbbVie, the co-developers of the drug.

A separate regulatory filing for the same indication was accepted and given an accelerated review by the European Medicines Agency (EMA) in late July. The FDA and EMA reviews will both be based primarily on data from the phase III ELOQUENT-2 trial, with supporting data coming from the phase II study CA204-009.

“Bristol-Myers Squibb is delighted by the approach both agencies have taken to review the Empliciti applications as it underscores the unmet medical need in the treatment of multiple myeloma and the role Immuno-Oncology may play,” Michael Giordano, MD, senior vice president, head of Oncology Development, Bristol-Myers Squibb, said in a statement. “The acceptance of our applications by the FDA and EMA brings Bristol-Myers Squibb’s Immuno-Oncology science a step closer to helping patients with hematologic malignancies.”

The open-label phase III ELOQUENT-2 trial randomized 646 patients with relapsed/refractory multiple myeloma to lenalidomide and dexamethasone alone (n = 325) or in combination with elotuzumab (n = 321). Elotuzumab was administered at 10 mg/kg IV weekly for the first two cycles and then biweekly thereafter, and lenalidomide was dosed at 25 mg orally on days 1 to 21 of each cycle. Across the study, patients received 40 mg of oral dexamethasone in weeks without elotuzumab. In weeks in the experimental arm when elotuzumab was administered, dexamethasone was dosed at 28 mg orally plus 8 mg IV. The cycle length for all three drug regimens was 28 days, and treatment was administered until disease progression or unacceptable toxicity.

The median patient age in the trial was 66 years and patients had received a median of two prior therapies (range, 1-3) including bortezomib (70%), thalidomide (48%), and lenalidomide (6%). Thirty-five percent of patients were refractory to their most recent therapy; however, no patients were lenalidomide refractory. High-risk patient subgroups were identified, with 32% and 9% of patients having a 17p deletion (del[17p]) or t(4;14) translocation, respectively.

The primary outcome measures for the study were progression-free survival (PFS) and overall response rate (ORR). Overall survival (OS) was a secondary endpoint. Tumor response was assessed every 4 weeks and survival was assessed every 12 weeks following disease progression.

At a median follow-up of 2 years, PFS with the elotuzumab regimen was 19.4 months (95% CI, 16.6-22.2) versus 14.9 months (95% CI, 12.1-17.2) with lenalidomide and dexamethasone alone (hazard ratio [HR], 0.70; 95% CI, 0.57-0.85; P <.001). The 1-year PFS for the elotuzumab versus control arm was 68% versus 57%, respectively, with the difference in 2-year PFS rates increasing to 41% versus 27%.

Sagar Lonial, MD

“What I think is quite striking about this progression-free survival curve...is that the two curves do not appear to come back together with longer follow-up,” lead author Sagar Lonial, MD, said when discussing the results during a presscast held in advance of the ASCO 2015 Annual Meeting.

“This idea of the maintenance of benefit over time really speaks to the power of an immune-mediated based approach when we treat cancer. We’ve seen this, for instance, with PD-1 and other immune-based approaches,” added Lonial, who is chief medical officer of the Winship Cancer Institute of Emory University, and professor and executive vice chair of the Department of Hematology and Medical Oncology of Emory University School of Medicine.

The PFS benefit with elotuzumab in the overall study was observed across the high-risk del(17p) and t(4;14) subgroups, with HRs of 0.65 and 0.53, respectively.

ORR was 79% with elotuzumab and 66% for the control group (P = .0002). The OS data for the trial are not yet mature.

Elotuzumab was well-tolerated overall, according to Lonial. “The improvement in clinical parameters occurred without a significant increase in adverse events or toxicities. In fact, there was no reduction in quality of life for the group receiving the three drugs.”

At the time of the interim analysis, 35% of patients receiving the elotuzumab regimen and 20% of patients receiving lenalidomide and dexamethasone alone remained on therapy. The most commonly reported all-grade adverse events (AEs) in the elotuzumab arm versus the control arm were lymphocytopenia (99% vs 98%) anemia (96% vs 95%), thrombocytopenia (84% vs 78%), neutropenia (82% vs 89%), fatigue (47% vs 39%), diarrhea (47% vs 36%), and pyrexia (37% vs 25%).

Serious AEs occurred in 65% versus 57% of the elotuzumab versus control arms, respectively. Grade 3/4 lymphocytopenia rates were higher with elotuzumab at 77% versus 49%; however, high-grade neutropenia rates were higher in the control arm, at 44% versus 34%. Ten percent of patients (n = 33) in the elotuzumab arm had infusion reactions, most of which were grade 1/2 (n = 29).

Data from study CA204-009 were presented in June at the 20th Congress of the European Hematology Association (EHA). In the phase II trial, 152 patients with relapsed/refractory multiple myeloma received bortezomib plus dexamethasone with (n = 77 ) or without (n = 75) elotuzumab. The median patient age was 66 years and patients had received 1 to 3 prior therapies.

Treatment cycles 1 through 8 were 21 days, with all regimens administered on 28-day cycles thereafter. Elotuzumab at 10 mg/kg IV was administered weekly in cycles 1 and 2, on days 1 and 11 of cycles 3 to 8, and on days 1 and 15 thereafter; patients received bortezomib at 1.3 mg/m² either IV or subcutaneous on days 1, 4, 8, and 11 of cycles 1 to 8, then on days 1, 8, and 15 thereafter; dexamethasone was administered at 20 mg orally on “non-elotuzumab” days and 8 mg orally plus 8 mg IV on elotuzumab days.

All treatments were administered until disease progression or unacceptable toxicity. The primary endpoint was PFS. Based on the study design, a P value ≤.3 was considered statistically significant.

At the data cutoff, 18% of patients who received the elotuzumab combination remained on therapy, compared with 10% of patients in the control group. The median number of treatment cycles was 12 and 7, respectively.

The median PFS observed with the addition of elotuzumab was 9.7 months versus 6.9 months with bortezomib and dexamethasone alone (HR, 0.71; 70% CI, 0.58-0.87; P = .08). When adjusting for prognostic factors, the HR for PFS was 0.58 (70% CI, 0.47-0.72; P = .01). One- and 2-year PFS rates were 39% versus 32% and 24% versus 6%, respectively.

ORR was 66% with elotuzumab, compared with 63% in the control arm. Early survival data showed an HR of 0.61 (70% CI, 0.43-0.85) favoring the elotuzumab group, with 1-year OS rates of 85% versus 74% in patients receiving bortezomib and dexamethasone alone. OS follow-up is ongoing.

Sixty-eight percent of patients (n = 51) in the elotuzumab arm reported grade 3/4 AEs, compared with 60% (n = 45) in the control arm. The most common AEs of grade 3 or higher were thrombocytopenia (9% [n = 7] with elotuzumab vs 17% [n = 13] in the control arm) and infections (19% [n = 4] versus 15% [n = 11], respectively).

Grade 1/2 infusion reactions occurred in 7% of the elotuzumab arm; however, there were no infusion reactions at the maximum planned infusion rate of 5 mL/min.

Elotuzumab binds to the SLAMF7 protein found on the surface of both myeloma cells and natural killer (NK) lymphocytes in the immune system. “One of the unique attributes of elotuzumab is that it appears to have a dual mechanism through which it targets both the myeloma cell and appears to enhance the activation of natural killer cells,” Lonial said on the ASCO presscast.

Elotuzumab received a breakthrough therapy designation from the FDA in May 2014 for use in combination with lenalidomide and dexamethasone for patients with multiple myeloma following one or more prior therapies.

The ongoing phase III ELOQUENT-1 trial is examining elotuzumab plus lenalidomide and dexamethasone in the frontline setting for relapsed/refractory multiple myeloma. Other ongoing trials are examining elotuzumab in various other combinations with existing therapies.