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Clin Pharmacol Ther. 2019 Feb;105(2):486-495. doi: 10.1002/cpt.1198. Epub 2018 Sep 4.

A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.

Author information

1
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
2
Pharmetheus AB, Uppsala, Sweden.
3
Department of Clinical Pharmacology, Genentech, South San Francisco, California, USA.

Abstract

To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.

PMID:
30058723
PMCID:
PMC6704358
DOI:
10.1002/cpt.1198
[Indexed for MEDLINE]
Free PMC Article

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