Abstract 664: Analytical validation and clinical utility of an immunohistochemical PD-L1 diagnostic assay for treatment with durvalumab in urothelial carcinoma patients
Authors: Zajac M , Boothman A M. , Ben Y , Gupta A , Antal J , Jin X , Nielsen A , Manriquez G , Barker C , Wang P , Patil P , Schechter N , Rebelatto M , Walker J 
Published: July 2017

Abstract
Background: A high quality programmed cell death ligand-1 (PD-L1) diagnostic may help to identify patients (pts) most likely to respond to anti-PD-L1/programmed cell death-1 (PD-1) therapy. Here we describe a PD-L1 immunohistochemical (IHC) diagnostic test developed for urothelial carcinoma (UC) pts treated with durvalumab.
Methods: The IHC assay uses an anti-human PD-L1 rabbit mAb optimized for detection of both tumor cell (TC) and tumor-associated immune cell (IC) PD-L1 expression with the OptiView DAB IHC Detection Kit on the automated VENTANA BenchMark ULTRA platform. The assay was validated for intended use in UC formalin-fixed, paraffin-embedded samples in a series of studies that addressed sensitivity, specificity, robustness and precision and implemented in Study CD-ON-MEDI4736-1108 (NCT01693562). Pts were evaluated using the VENTANA PD-L1 (SP263) Assay at a prespecified PD-L1 expression cut-off. Efficacy was analyzed in pts with PD-L1 low/negative (defined as TC &lt;25% and IC &lt;25%) UC and in pts with PD-L1 high (defined as TC ≥25% or IC ≥25%) UC.
Results: The VENTANA PD-L1 (SP263) Assay met all the predefined acceptance criteria (average positive agreement and average negative agreement &gt;85%), showing analytical specificity, sensitivity and precision. It demonstrated ≥97% and ≥85% inter-reader precision agreement for TC and IC respectively. For intra-reader precision, it demonstrated &gt;96% and &gt;87% agreement for TC and IC respectively. For intra-day performance, the assay demonstrated ≥96% agreement for TC and IC and for inter-day performance, it demonstrated ≥98% and 100% agreement for TC and IC respectively. Precision studies for inter-antibody lot, inter-detection kit lot and intra-platform demonstrated &gt;97% agreement for both TC and IC. Inter-laboratory testing was performed at 3 external laboratories and demonstrated an overall agreement rate of 92.3%. The VENTANA PD-L1 (SP263) Assay was implemented in Study CD-ON-MEDI4736-1108 and durvalumab demonstrated clinical activity and durability of response in both PD-L1 high and PD-L1 low/negative subgroups, yet with different response rates. In addition, given the high negative predictive value of the assay, it is especially helpful in evaluating the likelihood of response to durvalumab; pts who were classified as PD-L1 high with the VENTANA PD-L1 (SP263) Assay tended to have a higher objective response rate per RECIST v1.1 than pts who were PD-L1 low/negative.
Conclusions: These data show that determination of PD-L1 expression in TC and IC in UC pts using the VENTANA PD-L1 (SP263) Assay is precise and highly reproducible and highlight the utility of the assay in a clinical setting. The VENTANA SP263 Assay is especially helpful in informing pts and physicians on the likelihood of response to durvalumab, but not for the purpose of restricting treatment to only PD-L1 high pts.
Citation Format: M Zajac, A M. Boothman, Y Ben, A Gupta, J Antal, X Jin, A Nielsen, G Manriquez, C Barker, P Wang, P Patil, N Schechter, M Rebelatto, J Walker. Analytical validation and clinical utility of an immunohistochemical PD-L1 diagnostic assay for treatment with durvalumab in urothelial carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 664. doi:10.1158/1538-7445.AM2017-664