In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On November 30, 2015, elotuzumab (Empliciti) was approved for use in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.1,2
Supporting Efficacy Data
Approval was based on findings of improved progression-free survival and response rate in an open-label phase III trial in which 646 patients were randomized to receive elotuzumab in combination with lenalidomide and dexamethasone (n = 321) or lenalidomide plus dexamethasone alone (n = 325).2,3 Patients continued treatment until disease progression or unacceptable toxicity.
Patients had a median age of 66 years (range = 37–91 years, 57% ≥ 65 years); 60% were male; 84% were white; Eastern Cooperative Oncology Group performance status was 0 or 1 in 91%; disease stage was I in 43%, II in 32%, and III in 21%; 32% had del(17p) and 9% had t(4;14); the median number of prior therapies was two; 35% had refractory disease and 65% had relapsed disease; and prior therapies included stem cell transplant (55%), bortezomib (Velcade; 70%), melphalan (65%), thalidomide (Thalomid; 48%), and lenalidomide (6%).
Median progression-free survival was 19.4 months (95% confidence interval [CI] = 16.6–22.2 months) in the elotuzumab group vs 14.9 months (95% CI = 12.1–17.2 months) in the control group (hazard ratio [HR] = 0.70, P = .0004). The overall response rate was 78.5% vs 65.5% (P = .0002).
How It Works
Elotuzumab is a humanized IgG1 monoclonal antibody directed against signaling lymphocyte activation molecule family 7 (SLAMF7). SLAMF7 is present on myeloma cells independent of cytogenetic abnormalities and is also expressed on natural killer cells, plasma cells, and, at lower levels, on specific immune cell subsets of differentiated cells in the hematopoietic lineage. Elotuzumab directly activates natural killer cells through both the SLAMF7 pathway and Fc receptors. It targets SLAMF7 on myeloma cells and facilitates interaction with natural killer cells to mediate killing of myeloma cells through antibody-dependent cellular cytotoxicity. In preclinical models, the combination of elotuzumab and lenalidomide resulted in natural killer cell activation greater than that with either drug alone and increased antitumor activity in vitro and in vivo.
How It Is Used
The recommended dose/schedule for elotuzumab is 10 mg/kg via intravenous (IV) infusion on days 1, 8, 15, and 22 for the first two 28-day cycles and on days 1 and 15 in every subsequent cycle until disease progression or unacceptable toxicity. Lenalidomide is given at 25 mg daily orally on days 1–21. Dexamethasone is given on days of elotuzumab infusion at 8 mg IV and 28 mg orally; on days 8 and 22 of the third and subsequent cycles, when elotuzumab is not given, dexamethasone is given at 40 mg orally. On days that elotuzumab is given, oral dexamethasone should be given at 3–24 hours before and IV dexamethasone at 45–90 minutes before elotuzumab. In addition to dexamethasone, patients should be premedicated 45–90 minutes prior to elotuzumab infusion with an H1 blocker (diphenhydramine 25–50 mg orally or IV or equivalent), an H2 blocker (ranitidine 50 mg IV or 150 mg orally or equivalent), and acetaminophen (650–1,000 mg orally).
In the first dose of the first cycle, elotuzumab infusion should be started at a rate of 0.5 mL/min; if no infusion reaction is observed, the rate can be increased to 1 mL/min during minutes 30–60 and to 2 mL/min during the remainder of the infusion. During the second dose in cycle 1, infusion can be started at 1 mL/min during the first 30 minutes and increased to 2 mL/min in the absence of infusion reactions. All subsequent doses can be given at 2 mL/min. In patients who have received four cycles, the infusion rate may be increased to a maximum of 5 mL/min.
For grade ≥ 2 infusion reaction, infusion should be interrupted and appropriate medical and supportive measures instituted. With resolution to grade ≤ 1, infusion may be restarted at 0.5 mL/min and increased at a rate of 0.5 mL/min every 30 minutes as tolerated to the rate at which the infusion reaction occurred. The escalation regimen can be resumed if there is no recurrence. If a reaction recurs, infusion should be stopped and should not be restarted on that day. Patients who have an infusion reaction should have vital signs monitored every 30 minutes for 2 hours after the end of infusion. Severe infusion reactions may require permanent discontinuation of elotuzumab and emergency treatment.
If dosing of one drug in the regimen is delayed, interrupted, or discontinued, treatment with the other drugs may continue as scheduled. However, if dexamethasone is delayed or discontinued, the decision whether to administer elotuzumab should be based on clinical judgment (ie, risk of hypersensitivity). Dose delays and modifications for dexamethasone and lenalidomide should follow the prescribing information for these drugs.
Safety Profile
In the phase III trial, the most common adverse events of any grade occurring with a ≥ 5% higher incidence in the elotuzumab group were fatigue (62% vs 52%), diarrhea (47% vs 36%), pyrexia (37% vs 25%), constipation (36% vs 27%), cough (34% vs 19%), and peripheral neuropathy (27% vs 21%). Grade 3 or 4 adverse events included pneumonia (14% vs 10%), fatigue (13% vs 12%), lymphopenia (9% vs 3%), and cataracts (6% vs 3%).
Other important adverse reactions included infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with determination of complete response. Infections occurred in 81% vs 74% of patients, including grade 3 or 4 infections in 28% vs 24%, and fatal infections occurred in 2.5% vs 2.2%. Opportunistic infections occurred in 22% vs 13%, including fungal infections in 9.7% vs 5.4% and herpes zoster in 13.5% vs 6.9%. Second primary malignancies occurred in 9.1% vs 5.7%, including hematologic malignancies in 1.6% vs 1.6%, solid tumors in 3.5% vs 2.2%, and skin cancer in 4.4% vs 2.8%. Hepatotoxicity occurred in 2.5% vs 0.6%.
The most common grade 3 or 4 lab abnormalities were lymphopenia (77% vs 49%), leukopenia (32% vs 26%), thrombocytopenia (19% vs 20%), hyperglycemia (17% vs 10%), and hypocalcemia (11% vs 5%). Vital sign abnormalities were more common with elotuzumab, including systolic pressure ≥ 160 mm Hg (33% vs 21%), diastolic pressure ≥ 100 mm Hg (17% vs 12%), systolic pressure < 90 mm Hg (29% vs 8%), and heart rate < 60 bpm (66% vs 31%).
Serious adverse events occurred in 65% vs 57% of patients, with the most common in the elotuzumab group being pneumonia (15.4% vs 11%), pyrexia (6.9% vs 4.7%), respiratory tract infection (3.1% vs 1.3%), anemia (2.8% vs 1.9%), pulmonary embolism (3.1% vs 2.5%), and acute renal failure (2.5% vs 1.9%). Adverse events led to discontinuation of any component of treatment in 6.0% vs 6.3%.
Elotuzumab carries warnings/precautions for infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with determination of complete response. Elotuzumab can interfere with assays used to monitor M protein, which can affect the ability to determine complete response. Patients should have liver function monitored, and elotuzumab should be stopped if hepatotoxicity is suspected. Pregnancy risk with use of elotuzumab is unknown; lenalidomide can cause embryofetal harm and is contraindicated for use in pregnancy. ■
References
1. U.S. Food and Drug Administration: Approved drugs: Elotuzumab. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm474719.htm. Accessed January 9, 2016.
2. Empliciti (elotuzumab) for injection, for intravenous use, prescribing information, Bristol-Myers Squibb Company, November 2015. Available at http://packageinserts.bms.com/pi/pi_empliciti.pdf. Accessed January 9, 2016.
3. Lonial S, Dimopoulos M, Palumbo A, et al: Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373:621-631, 2015.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
