An Integrated Assessment of the Effects of Immunogenicity on the Pharmacokinetics, Safety, and Efficacy of Elotuzumab.

Elotuzumab is a humanized, immunostimulatory anti-signaling lymphocytic activation molecule F7 (SLAMF7) IgG1 monoclonal antibody indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma (MM) who have received 1-3 prior therapies. We assessed the immunogenicity of elotuzumab as a monotherapy and in combination with bortezomib/dexamethasone and lenalidomide/dexamethasone in patients with MM in five clinical studies, including the pivotal ELOQUENT-2 trial (NCT01239797). Anti-drug antibody (ADA) prevalence was determined using a validated bridging assay. The prevalence of neutralizing antibodies (NAbs) was assessed in ADA-positive samples from ELOQUENT-2. Data from four trials of elotuzumab combined with lenalidomide/dexamethasone or bortezomib/dexamethasone (n = 390 evaluable patients) demonstrated that nine (2.3%) patients were ADA positive in baseline assays, 72 (18.5%) were ADA positive on-treatment or during follow-up, and two (0.5%) developed persistent ADAs. Patients treated with elotuzumab monotherapy had a higher incidence of elotuzumab ADAs than those on the combination therapy. In general, ADAs developed early and resolved after 2-4 months. Of 45 on-treatment ADA-positive patients in ELOQUENT-2, 19 had NAbs. Population pharmacokinetic modeling demonstrated an apparent increase in target-mediated elimination (higher V max, lower K M) in ADA-positive versus ADA-negative patients. ADAs were associated with lower elotuzumab steady-state exposure; however, this result may have been confounded by differential myeloma protein levels. ADAs/NAbs were not associated with hypersensitivity, infusion reactions, or loss of elotuzumab efficacy. Using a novel visualization, we also demonstrate that there is no clear relationship between the occurrence and titer values of ADA/NAbs and progression-free survival and best overall response status in patients treated with elotuzumab.