ASCO 2018: Optimization of PD-L1 Algorithm for Predicting OS in Patients with Urothelial Cancer Treated with Durvalumab

Chicago, IL (UroToday.com) Durvalumab is an anti-programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitor that has been tested in patients with advanced urothelial bladder cancer. In a phase I/II open-label study, 191 patients who had progressed on or were ineligible for chemotherapy were administered durvalumab IV 10 mg/kg every two weeks for up to 12 months or until progression or unacceptable side effects [1]. Over a median follow-up was 5.8 months (range, 0.4-25.9), the ORR was 17.8% (95%CI 12.7%-24.0%), including 7 complete responses. Responses were observed as follows with regard to PD-L1 expression: high expression (n=27) - ORR 27.6%, 95%CI 19.0%-37.5%, and low/negative expression (n=4) – ORR 5.1%, 95%CI 1.4%-12.5%. The median progression-free survival (PFS) and overall survival (OS) were 1.5 months (95%CI 1.4-1.9 months) and 18.2 months (95%CI, 8.1 months-NR), respectively, and the 1-year OS rate was 55% (95%CI 44%-65%). Indeed, PD-L1 expression is a useful biomarker in predicting response to PD-1 and PD-L1 directed immunotherapies in a variety of tumor types, including urothelial carcinoma. In urothelial carcinoma, PD-L1 expression in tumor cells and tumor-infiltrating immune cells have clinical utility, but the relative importance of each cellular compartment and the most predictive algorithm and PD-L1 expression cutoff remain unclear. At today’s ASCO 2018 annual meeting, Magda Zajac and colleagues presented results of their optimization of PD-L1 algorithm for predicting OS in patients with urothelial cancer treated with durvalumab.

For this study, the authors used data from 188 patients with urothelial carcinoma treated with durvalumab [1]. PD-L1 expression data were assessed and regression models were used to evaluate the impact of PD-L1 expression in tumor cells or tumor-infiltrating immune cells on the outcomes of OS, PFS, objective response rate (ORR), best percentage tumor change and tumor shrinkage 15 months after last subject randomization. Kaplan–Meier plots were generated to explore the impact of single biomarker and combined (tumor cells or tumor-infiltrating immune cells [% PD-L1 positive immune cells within immune cell area]) algorithms on OS.

Both tumor-infiltrating immune cells and tumor cell PD-L1 were linked to higher ORR, and PD-L1 tumor-infiltrating immune cells were associated with better survival in patients treated with durvalumab. Interestingly, PD-L1 tumor-infiltrating immune cells had a higher impact on response to durvalumab than PD-L1 tumor cell, demonstrating a significant association with OS, PFS, ORR, and tumor shrinkage. The results of several algorithms combining PD-L1 tumor cell and tumor-infiltrating immune cell cutoffs and the effect on ORR and median OS are as follows:
UroToday ASCO2018 Optimization PD L1 PredictingOS Urothelial Cancer


Biomarker-driven precision medicine is desired when possible. Since testing of immunotherapy agents started, PD-L1 expression has routinely been measured and results stratified by PD-L1 expression levels, however, the desired expression level and components has not been uniformly agreed. The results of this study for patients treated with durvalumab for bladder cancer suggest that a cutoff/algorithm using PD-L1 tumor cell 25%/PD-L1 tumor-infiltrating immune cell 25% (TC25%/IC25%) provides optimal predictive value based on efficacy and prevalence of the biomarker. 

UroToday ASCO2018 Optimization of PD L1


As Magda Zajac notes, since these results are limited to patients treated with durvalumab, additional data from randomized trials utilizing other agents are needed to confirm these findings. 


References:
1. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncol 2017;3(9):e172411.

Presented by: Magda Zajac, AstraZeneca, Cambridge, United Kingdom
Co-Authors: Jiabu Ye, Pralay Mukhopadhyay, Xiaoping Jin, Yong Ben, Joyce Antal, Ashok Kumar Gupta, Marlon Rebelatto, J. Andrew Williams, Jill Walker; AstraZeneca, Cambridge, United Kingdom; AstraZeneca, Washington, DC; AstraZeneca, Gaithersburg, MD; DAIICHI SANKYO, Potomac, MD; AstraZeneca (currently at BioAtla, San Diego, CA, USA), Gaithersburg, MD; MedImmune (currently at G1 Therapeutics Inc, Research Triangle Park, NC, USA), Gaithersburg, MD; MedImmune, Gaithersburg, MD

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA
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