Complex E–R relationship
immuno-oncology
single-dose PK model
therapeutic monoclonal antibodies
Characterizing Exposure–Response Relationship for Therapeutic Monoclonal Antibodies in Immuno-Oncology and Beyond: Challenges, Perspectives, and Prospects
Summary
- Recent data from immuno-oncology clinical studies show that the exposure–response (E–R) relationship for therapeutic monoclonal antibodies (mAbs) is often confounded by various factors.
- The complex interplay involves patient characteristics, disease, drug exposure, clearance, and treatment response, presenting challenges in E–R analysis.
- An integrative framework is proposed to understand the E–R relationship, involving an interconnected triangle of baseline factors, drug exposure, and treatment response.
- This framework identifies three components of the E–R relationship: exposure-driven E–R, baseline-driven E–R, and response-driven E–R.
- Strategies to decouple these components and mitigate confounding effects are reviewed, highlighting their merits and limitations.
- A roadmap for selecting strategies is proposed, including the use of single-dose pharmacokinetic models and multivariable or case control analysis in randomized studies.
- Discussion includes the importance of data from multiple dose levels, the role of prognostic and predictive factors, and the potential utility of baseline clearance and its changes over time.
Analysis of the exposure response (E–R) relationship has long been an important tool for dose selection and optimization and regulatory decisions during all stages of drug development. In general, it is assumed that the E–R relationship is driven by the exposure and, therefore, a positive E–R correlation suggests that a higher exposure at a higher dose would lead to a better response. However, several recent reports from clinical studies with therapeutic monoclonal antibodies (mAbs) in oncology or immuno-oncology field have shown that this is not always true...
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Complex E–R relationship, immuno-oncology, single-dose PK model, therapeutic monoclonal antibodies
