| Abstract: | Baseline patient characteristics and prognostic factors are important considerations in oncology when evaluating the impact of immunogenicity on pharmacokinetics (PK) and efficacy. Here, we assessed the impact of anti‐drug antibodies (ADA) on the PK of the immune checkpoint inhibitor atezolizumab (an anti–PD‐L1 monoclonal antibody). We evaluated data from ≈ 4500 patients from 12 clinical trials across different tumor types, treatment settings, and dosing regimens. In our dataset, ~ 30% of patients (range, 13–54%) developed treatment‐emergent ADA, and in vitro neutralizing antibodies (NAb) were seen in ~ 50% of ADA‐positive (+) patients. Pooled time course data showed a trend toward lower atezolizumab exposure in ADA+ patients, which was more pronounced in ADA+/NAb+ patients. However, the atezolizumab concentration distributions overlapped, and drug concentrations exceeded 6 µg/ml, the target concentration required for receptor saturation, in greater than 95% of patients. Patients had sufficient exposure regardless of ADA status. The dose selected to allow for dosing over effects from ADA resulted in a flat exposure‐response relationship. Analysis of study results by ADA titer showed that exposure and overall survival were not affected in a clinically meaningful way. High tumor burden, low albumin, and high CRP at baseline showed the greatest association with ADA development but not with subsequent NAb development. These imbalanced factors at baseline can confound analysis of ADA impact. ADA increases atezolizumab clearance minimally (9%), and its impact on exposure based on the totality of the clinical pharmacology assessment does not appear to be clinically meaningful. Study Highlights - WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Anti‐drug antibodies (ADA) to anticancer therapeutics, including atezolizumab, might affect pharmacokinetics (PK) and drug efficacy. - WHAT QUESTION DID THIS STUDY ADDRESS?
How do treatment‐emergent ADA impact atezolizumab exposure, and is there association between baseline prognostic factors and the development of ADA? - WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Based on a dataset of ~ 4500 patients, we showed that decreased atezolizumab exposure accompanying ADA and neutralizing ADA (NAb) development does not meaningfully impact drug concentrations required for receptor saturation. Further, differences in atezolizumab concentrations seen prior to ADA development demonstrated that baseline prognostic factor imbalances other than ADA can affect the drug exposure. Notably, baseline tumor burden, albumin, and C‐reactive protein can influence ADA development. - HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The traditional approach of using univariate analysis to analyze PK or efficacy by ADA status alone may be inadequate, and confounding from baseline covariates should be considered or accounted for in ADA studies. The impacts of ADA on atezolizumab exposure are not expected to be clinically relevant. |
