OREANDA-NEWS. December 08, 2015. Bristol-Myers Squibb Company (NYSE:BMY) today presented extended follow-up data and a pre-specified interim overall survival (OS) analysis of Empliciti in combination with Revlimid® (lenalidomide) and dexamethasone (ERd) in patients with relapsed or refractory multiple myeloma from ELOQUENT-2. The follow-up data demonstrated that Empliciti in combination with Rd had an improvement in progression-free survival (PFS) with a hazard ratio (HR) of 0.73 (95% CI: 0.60, 0.89; p=0.0014) versus Rd alone. This result was consistent with the improvement in PFS that was observed at the time of the primary analysis (HR 0.70 [95% CI: 0.57, 0.85; p = 0.0004]).

The Empliciti combination delayed the need for subsequent myeloma therapy by a median of one year compared to Rd alone. A pre-specified interim analysis of OS found a positive trend favoring the Empliciti combination versus Rd alone (HR 0.77; [{95% CI: 0.61, 0.97; 98.6% CI: 0.58, 1.03}; p=0.0257]), though at the time of the interim analysis the OS endpoint had not reached the pre-determined threshold for statistical significance. Patients will continue to be followed for survival. Updated safety and tolerability data were consistent with previous findings. Common Grade 3 or 4 adverse events included neutropenia (26%), anemia (15%), fatigue (9%), and diarrhea (5%).

These data from ELOQUENT-2, a randomized, open-label, Phase 3 study (Abstract #28) were presented at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, FL.

“The Empliciti extended follow-up results provide physicians with additional insight into the potential benefit this new treatment may offer patients with relapsed or refractory multiple myeloma,” said Paul G. Richardson, M.D., Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute. “Empliciti represents a new approach in multiple myeloma treatment of directly activating the body’s immune system, and it is very encouraging to see these data demonstrate the efficacy benefit persisted in some patients up to three years, allowing patients to live longer without experiencing disease progression.”

Empliciti as combination therapy with lenalidomide and dexamethasone was approved by the U.S. Food and Drug Administration on November 30, 2015, for the treatment of patients with multiple myeloma who have received one to three prior therapies.

“The extended follow-up and overall survival data presented at ASH for our immunostimulatory antibody, Empliciti, reinforce our commitment to helping improve outcomes for patients with multiple myeloma,” said Michael Giordano, M.D., senior vice president, head of Development, Oncology, Bristol-Myers Squibb. “These data further demonstrate Empliciti as combination therapy provides improved efficacy compared to lenalidomide and dexamethasone alone.”

About ELOQUENT-2

ELOQUENT-2 (CA204-004) is a randomized, open-label, Phase 3 study evaluating Empliciti in combination with lenalidomide and dexamethasone (ERd) versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma. The trial enrolled 646 patients who had received one to three prior therapies. Patients were randomized 1:1 to receive either Empliciti 10 mg/kg in combination with Rd or Rd alone in 4-week cycles until disease progression or unacceptable toxicity. Baseline patient demographics and disease characteristics were well balanced between treatment arms and included a meaningful portion of patients who were ? 65 years old, had high-risk cytogenetics, and/or were refractory to the most recent line of therapy. The co-primary endpoints were PFS, as assessed by HR, and overall response rate. Results of the primary analysis of the ELOQUENT-2 study were published in The New England Journal of Medicine on June 2, 2015.

In the exploratory, extended follow-up analysis, the ERd regimen resulted in a 27% reduction in the risk of disease progression or death (HR 0.73 [95% CI: 0.6, 0.89]) and a 44% relative improvement in the PFS rate at three years compared to Rd alone. The benefit observed was consistent with the pivotal two year analysis which showed ERd resulted in a 30% reduction in the risk of disease progression or death compared to Rd alone (HR 0.70 [95% CI: 0.57, 0.85; p = 0.0004]) and a 52% relative improvement in PFS rate at two years. The extended follow-up analysis also showed ERd had a median delay of one year in the time to next treatment compared to Rd alone 33.35 months (95% CI: 26.15, 40.21) vs. 21.22 months (95% CI: 18.07, 23.20) (HR=0.62 [95% CI: 0.50, 0.77]). An interim analysis of OS found a positive trend favoring the Empliciti combination compared to Rd alone (HR 0.77; [{95% CI: 0.61, 0.97; 98.6% CI 0.58; 1.03}; p=0.0257]), though at the time of the interim analysis the OS endpoint had not reached the pre-determined threshold for statistical significance. Patients will continue to be followed for survival.

Infusion reactions occurred in 10% of patients treated with ERd; these adverse events were Grade 3 or lower and occurred during the first treatment cycle. The most common adverse reactions in ERd and Rd, respectively (?30%) were infections (83%, 75%), fatigue (48%, 40%), diarrhea (48%, 37%), anemia (41%, 37%), pyrexia (38%, 25%), constipation (36%, 28%), cough (33%, 19%), muscle spasms (30%, 27%), and neutropenia (34%, 43%). Adverse events of special interest in ERd and Rd, respectively, included gastrointestinal disorders (81%, 68%), respiratory disorders (63%, 53%), renal/urinary disorders (25%, 18%), peripheral neuropathy (15%, 9%), hypertension (10%, 7%), deep vein thrombosis (8%, 4%) and cardiac failure (1%, 2%). Updated safety and tolerability data were consistent with previous findings.

About Empliciti

Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities. Prior to approval, Empliciti was granted Breakthrough Therapy Designation by the FDA for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received one to three prior therapies. According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation requires preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

About Multiple Myeloma

Multiple myeloma is a hematologic, or blood, cancer that develops in the bone marrow. It occurs when a plasma cell, a type of cell in the soft center of bone marrow, becomes cancerous and multiplies uncontrollably. Common symptoms of multiple myeloma include bone pain, fatigue, kidney impairment, and infections.

Despite advances in multiple myeloma treatment over the last decade, less than half of patients survive for five or more years after diagnosis. A common characteristic for many patients is that they experience a cycle of remission and relapse, in which they stop treatment for a short time, but eventually return to a treatment shortly after. It is estimated that annually, more than 114,200 new cases of multiple myeloma are diagnosed and more than 80,000 people die from the disease globally.

EMPLICITI (elotuzumab) INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATION

EMPLICITI™ (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

  • EMPLICITI can cause infusion reactions. Common symptoms include fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.
  • Premedicate with dexamethasone, H1 Blocker, H2 Blocker, and acetaminophen prior to infusing with EMPLICITI.

Infections

  • In a clinical trial of patients with multiple myeloma (N=635), infections were reported in 81.4% of patients in the EMPLICITI with lenalidomide/dexamethasone arm (ERd) and 74.4% in the lenalidomide/dexamethasone arm (Rd). Grade 3-4 infections were 28% (ERd) and 24.3% (Rd). Opportunistic infections were reported in 22% (ERd) and 12.9% (Rd). Fungal infections were 9.7% (ERd) and 5.4% (Rd). Herpes zoster was 13.5% (ERd) and 6.9% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Monitor patients for development of infections and treat promptly.

Second Primary Malignancies

  • In a clinical trial of patients with multiple myeloma (N=635), invasive second primary malignancies (SPM) were 9.1% (ERd) and 5.7% (Rd). The rate of hematologic malignancies were the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd). Monitor patients for the development of SPMs.

Hepatotoxicity

  • Elevations in liver enzymes (AST/ALT greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were 2.5% (ERd) and 0.6% (Rd). Two patients experiencing hepatotoxicity discontinued treatment; however, 6 out of 8 patients had resolution and continued treatment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered.

Interference with Determination of Complete Response

  • EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

Pregnancy/Females and Males of Reproductive Potential

  • There are no studies with EMPLICITI with pregnant women to inform any drug associated risks.
  • There is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide and it is contraindicated for use in pregnancy. Refer to the lenalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.

Adverse Reactions

  • Infusion reactions were reported in approximately 10% of patients treated with EMPLICITI with lenalidomide and dexamethasone. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion reactions occurred in 1% of patients.
  • Serious adverse reactions were 65.4% (ERd) and 56.5% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15.4%, 11%), pyrexia (6.9%, 4.7%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
  • The most common adverse reactions in ERd and Rd, respectively (>20%) were fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%, 24.6%), constipation (35.5%, 27.1%), cough (34.3%, 18.9%), peripheral neuropathy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper respiratory tract infection (22.6%, 17.4%), decreased appetite (20.8%, 12.6%), and pneumonia (20.1%, 14.2%).