Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies - Beyond the Abstract

Immune-oncology therapies have significantly changed the treatment landscape of advanced urothelial carcinoma (aUC) in recent years. Five immune checkpoint inhibitors are FDA-approved after platinum-based regimen, while two of them are available for cisplatin-ineligible patients not previously treated with chemotherapy for aUC who either have “positive” PD-L1 tumor tissue expression or can’t even tolerate carboplatin-based therapy. However, the clinical outcomes of patients progressing on these agents is undetermined, esp. outside the context of clinical trials.

In our study published in Targeted Oncology (Barata et al. 2018), we present the clinical data of 79 consecutive patients with aUC treated with atezolizumab, the first immune checkpoint inhibitor to be available for this disease. Most patients (75%) had progressed on prior systemic treatment and were treated with atezolizumab for a median of fewer than 3 months. The best response included 18% partial response rate and 29% stable disease rate, which was not very different than prior clinical trial experience with this agent. At the time of data analysis, less than one third (29%) of patients were still on atezolizumab while slightly more than 40% were referred to hospice or died, while only 18% of patients were able to receive subsequent systemic treatment for a median of 1.8 months (95%CI 0-5)

The findings of that study are clinically relevant. Despite the several limitations of that retrospective analysis in a single institution, it represents one of the first assessments of the post-checkpoint inhibitor outcomes in a sizable cohort of patients outside the setting of a clinical trial. Unfortunately, a great proportion of patients were unable to receive further systemic treatment following atezolizumab, mainly due to clinical deterioration. Moreover, the responses of patients who could receive subsequent therapy were modest. This is probably in line with the modest benefit of the existing chemotherapy options in that salvage, refractory to prior therapies, space. 

In the absence of validated predictive biomarkers to help to select the great responders in the salvage setting it is expected that most patients will receive an immune checkpoint inhibitor given the favorable safety profile and comparable response rate with salvage chemotherapy and the potential durable responses that a subset of the patients obtains. There is a plethora of clinical trials evaluating further salvage therapies in aUC, e.g. antibody-drug conjugates, targeted therapies (FGFR inhibitors, PARP inhibitors, etc.), vaccines and other immunotherapies. Preliminary data from early phase trials appear very promising as shown at the recent Annual ASCO Meeting. Moreover, ongoing clinical trials that investigate the best timing of immunotherapies and the optimal sequence of active agents will hopefully further improve outcomes in aUC, and also explore the potential clinical utility of predictive and prognostic biomarkers.

Written by:
Pedro C. Barata, MD MSc, Cleveland Clinic, Taussig Cancer Institute
Petros Grivas, MD Ph.D., Associate Professor, Department of Medicine, Division of Oncology, Medical Director, Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center

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