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In Journal for immunotherapy of cancer ; h5-index 0.0

BACKGROUND : Although several therapeutic options for patients with renal cell carcinoma (RCC) have been approved over recent years, including immune checkpoint inhibitors, considerable need remains for molecular biomarkers to assess disease prognosis. The higher pharmacokinetic (PK) clearance of checkpoint inhibitors, such as the anti-programmed death-1 (PD-1) therapies nivolumab and pembrolizumab, has been shown to be associated with poor overall survival (OS) across several tumor types. However, determination of PK clearance requires the collection and analysis of post-treatment serum samples, limiting its utility as a prognostic biomarker. This report outlines a translational PK-pharmacodynamic (PD) methodology used to derive a baseline composite cytokine signature correlated with nivolumab clearance using data from three clinical trials in which nivolumab or everolimus was administered.

METHODS : Peripheral serum cytokine (PD) and nivolumab clearance (PK) data from patients with RCC were analyzed using a PK-PD machine-learning model. Nivolumab studies CheckMate 009 (NCT01358721) and CheckMate 025 (NCT01668784) (n = 480) were used for PK-PD analysis model development and cytokine feature selection (training dataset). Validation of the model and assessment of the prognostic value of the cytokine signature was performed using data from CheckMate 010 (NCT01354431) and the everolimus comparator arm of CheckMate 025 (test dataset; n = 453).

RESULTS : The PK-PD analysis found a robust association between the eight top-ranking model-selected baseline inflammatory cytokines and nivolumab clearance (area under the receiver operating characteristic curve = 0.7). The predicted clearance (high vs low) based on the cytokine signature was significantly associated with long-term OS (p < 0.01) across all three studies (training and test datasets). Furthermore, cytokines selected from the model development trials also correlated with OS of the everolimus comparator arm (p < 0.01), suggesting the prognostic nature of the composite cytokine signature for RCC.

CONCLUSIONS : Here, we report a PK-PD translational approach to identify a molecular prognostic biomarker signature based on the correlation with nivolumab clearance in patients with RCC. This composite biomarker signature may provide improved prognostic accuracy of long-term clinical outcome compared with individual cytokine features and could be used to ensure the balance of patient randomization in RCC clinical trials.

Wang Rui, Zheng Junying, Shao Xiao, Ishii Yuko, Roy Amit, Bello Akintunde, Lee Richard, Zhang Joshua, Wind-Rotolo Megan, Feng Yan

2019-Dec-11

Clearance, Composite signature, Cytokine, Nivolumab, Renal cell carcinoma, Translational PK/PD analysis