Maximum elotuzumab serum concentration (Cmax) increased in a dose-proportional manner from 5 to 20 mg/kg. But nonlinear pharmacokinetics (area under the curve [AUC]) increased more than proportionally. The systemic clearance (CL) decreased and terminal phase half-life (T1/2λ) increased with increasing doses, indicating a saturation of target-mediated elimination. Saturation of CS1 receptor by elotuzumab on bone marrow plasma cells achieved 80% and 95% at doses of 10 and 20 mg/kg, respectively, without dose-limiting toxicity (DLT). Bortezomib addition did not affect CS1 receptor saturation. No clinically significant differences were found in the pharmacokinetics of elotuzumab based on age (37–88 years), gender, race, baseline lactate dehydrogenase, renal impairment, end-stage renal disease and mild hepatic impairment (the mean terminal half-life is 33 days).34,36
SAFETY AND TOLERABILITY
In Phase 1 study, the MTD of IV elotuzumab in combination with oral lenalidomide and dexamethasone is identified, 28 patients were enrolled. Three doses of elotuzumab were given, three patients each for 5 and 10 mg/kg and 22 patients for 20 mg/kg. There was no DLT at 5, 10 and 20 mg/kg of elotuzumab in first cycle. Elotuzumab in combination with lenalidomide and low-dose dexamethasone was, generally, well tolerated. Based on the efficacy data, 10 mg/kg of elotuzumab by IV infusion is recommended to combine with lenalidomide and low-dose dexamethasone.34
In Phase 3 ELOQUENT-2 trail, patients were randomly assigned to receive elotuzumab plus lenalidomide/dexamethasone (elotuzumab group), or lenalidomide/dexamethasone alone (control group). The median duration of treatment was 17 and 12 months in the elotuzumab and control groups, respectively. Serious adverse reactions were reported in 65% of the elotuzumab group and 57% in the control group. The most common grade 3 or 4 hematological AEs included lymphocytopenia in 77% versus 49% and neutropenia in 34% versus 44%, in the elotuzumab and control groups, respectively. The treatment-related AEs in the elotuzumab arm versus the control arm were fatigue (47% vs 39%), pyrexia (37% vs 25%), peripheral edema (26% vs 22%), nasopharyngitis (25% vs 19%), diarrhea (47% vs 36%), constipation (36% vs 27%), musculoskeletal or connective-tissue disorders included muscle spasms (30% vs 26%), back pain (28% vs 28%); the other disorders included cough (31% vs 18%) and insomnia (23% vs 26%).38
FUTURE DIRECTIONS AND CONCLUSION
Although MM remains incurable, treatment options have improved for patients during the past decade. Myeloma is a genetically diverse disease and thus has provided challenges for the implementation of precision medicine and targeted therapy. A better understanding of biomarkers that predict response to specific therapeutic regimens is needed to improve patient care.42 Utilization of CS markers specific for plasma cells has gained interest for directing the treatment of MM since additional targets and therapeutic antibodies are emerging. For example, daratumumab binds to CD38 which is highly expressed on MM cells and was recently approved for patients with MM. CD38 is less abundant on normal lymphoid and myeloid cells. Daratumumab exerts anti-myeloma activity by multiple immune-mediated mechanisms including complement-dependent cytotoxicity, ADCC and apoptosis induction.43,44 It is feasible that combined targeting of CD38 and SLAMF7 may improve anti-myeloma activity as downregulation of both receptors may represent a rare event and thus decreased probability of escape from ADCC.
The combination of elotuzumab with other mABs treatment is also being clinically evaluated. The PD-1 immune checkpoint inhibitor nivolumab, has antitumor immune response in various tumors and approval by the FDA for nonsmall cell lung cancer, melanoma, head/neck cancer, Hodgkin’s lymphoma and renal cell carcinoma. In a Phase III multicenter trial, patients with RRMM are randomly assigned to evaluate the clinical benefit and safety for the combination therapy of N-Pd group (nivolumab, pomalidomide and dexamethasone, the investigational arm), Pd group (pomalidomide and dexamethasone, the control arm) and NE-Pd group (elotuzumab, nivolumab, pomalidomide and dexamethasone, the experimental arm). This study is, currently, recruiting participants. (ClinicalTrials.gov Identifier: NCT02726581).
In summary, elotuzumab has shown promising early clinical results and understanding how to best combine targeting SLAMF7 in combination with other immune strategies as well as standard of care agents may lead to improved patient outcomes for the treatment of MM.
This work was supported by National Institute Health (award number: 1RO1CA159727-01_LAH) and National Institute General Medicine (award number: U54GM104942).
The authors report no conflicts of interest in this work.
Wei-Chih Chen,1 Abraham S. Kanate,2,3 Michael Craig,2,3 William P. Petros,1,3 Lori A. Hazlehurst1–3
1Department of Pharmaceutical Sciences, School of Pharmacy, 2Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University, 3West Virginia University Cancer Institute, Morgantown, WV, USA
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Source: Cancer Management and Research.
Originally published July 12, 2017.