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

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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 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.

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Acknowledgements

Professional medical writing and editorial assistance was provided by Matthew Thomas at Caudex and was funded by Bristol-Myers Squibb. PK and immunogenicity analyses were performed at Covance (formerly Tandem Labs) with oversight by Debbie Hilliard and Tonya Felix, including a significant contribution from Linda Zislin and Pathanjali Kadiyala. NAb assessments were performed at Bristol-Myers Squibb by Marina Juhel and Mike Sank.

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Authors and Affiliations

  1. Bristol-Myers Squibb, Princeton, New Jersey, USA

    Chaitali Passey, Johanna Mora, Robert Dodge, Jennifer Sheng, Amit Roy, Akintunde Bello & Manish Gupta

  2. QuantPharm LLC, North Potomac, Maryland, USA

    Leonid Gibiansky

Authors
  1. Chaitali Passey
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  2. Johanna Mora
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  3. Robert Dodge
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  4. Leonid Gibiansky
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  5. Jennifer Sheng
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  6. Amit Roy
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  7. Akintunde Bello
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  8. Manish Gupta
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Corresponding author

Correspondence to Manish Gupta.

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Supplementary Figure 1

ADA status and baseline M-protein concentration in patients from ELOQUENT-2 and studies 005 and 007. Box plots represent 25th and 75th percentiles, bold lines within the box represent median values and whiskers represent 1.5 interquartile range. ADA, anti-drug antibody. (GIF 16 kb)

High resolution image (EPS 766 kb)

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Passey, C., Mora, J., Dodge, R. et al. An Integrated Assessment of the Effects of Immunogenicity on the Pharmacokinetics, Safety, and Efficacy of Elotuzumab. AAPS J 19, 557–567 (2017). https://doi.org/10.1208/s12248-016-0033-9

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