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Confounding Factors in Exposure-Response Analyses and Mitigation Strategies for Monoclonal Antibodies in Oncology
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  • Sonoko Kawakatsu,
  • Rene Bruno,
  • Matts Kågedal,
  • Chunze Li,
  • Sandhya Girish,
  • Amita Joshi,
  • Benjamin Wu
Sonoko Kawakatsu
Genentech Inc

Corresponding Author:[email protected]

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Rene Bruno
Genentech Inc
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Matts Kågedal
Genentech Inc
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Chunze Li
Genentech Inc
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Sandhya Girish
Genentech Inc
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Amita Joshi
Genentech Inc
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Benjamin Wu
Genentech Inc
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Abstract

Dose selection and optimization is an important topic in drug development to maximize treatment benefits for all patients. While exposure-response (E-R) analysis is a useful method to inform dose-selection strategy, in oncology, special considerations for prognostic factors are needed due to their potential to confound the E-R analysis for monoclonal antibodies. The current review focuses on three different approaches to mitigate the confounding effects for monoclonal antibodies in oncology: (1) cox-proportional hazards modeling and case-matching, (2) tumor growth inhibition-overall survival (TGI-OS) modeling, and (3) multiple dose level study design. In the presence of confounding effects, studying multiple dose levels may be required to reveal the true E-R relationship. However, it is impractical for pivotal trials in oncology drug development programs. Therefore, the strengths and weaknesses of the other two approaches are considered, and the favorable utility of TGI-OS modeling to address confounding in E-R analyses is described. In the broader scope of oncology drug development, this review discusses the downfall of the current emphasis on E-R analyses using data from single dose level trials, and proposes that development programs be designed to study more dose levels in earlier trials.
17 Aug 2020Submitted to British Journal of Clinical Pharmacology
18 Aug 2020Submission Checks Completed
18 Aug 2020Assigned to Editor
24 Aug 2020Reviewer(s) Assigned
14 Oct 2020Review(s) Completed, Editorial Evaluation Pending
14 Oct 2020Editorial Decision: Revise Minor
03 Nov 20201st Revision Received
04 Nov 2020Submission Checks Completed
04 Nov 2020Assigned to Editor
04 Nov 2020Review(s) Completed, Editorial Evaluation Pending
08 Nov 2020Editorial Decision: Accept
Jun 2021Published in British Journal of Clinical Pharmacology volume 87 issue 6 on pages 2493-2501. 10.1111/bcp.14662