title: An Integrated Assessment of the Effects of Immunogenicity on the Pharmacokinetics, Safety, and Efficacy of Elotuzumab.
abstract: 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 Vmax, lower KM) 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.
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Chaitali
authors.initials: C
authors.lastname: Passey
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mora
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dodge
authors.affiliation: QuantPharm LLC, North Potomac, Maryland, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Gibiansky
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Roy
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Akintunde
authors.initials: A
authors.lastname: Bello
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA. Manish.Gupta-LVL@bms.com.
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D057134:Antibodies, Neutralizing / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D006801:Humans; D000077269:Lenalidomide; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; C546027:elotuzumab; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide
keywords: anti-drug antibodies; elotuzumab; immunogenicity; neutralizing antibodies; pharmacokinetics