ASCO 2017: Bladder Cancer: 'Novel' Becomes the Norm

Chicago, IL ( Dr. Rosenberg gave an elegant summary of the abstracts 4500- Dr. Seth Lerner, 4501- Dr. Dean Bajorin, 4502- Dr. Peter H. O'Donnell and 4503 – Dr. David C. Smith. Dr. Rosenberg started with a short introduction, stating that the development of immune checkpoint blockade (ICB) in urothelial carcinoma (UC) has led to significant progress and new treatment options.

It has transformed the treatment of previously treated and cisplatin ineligible UC patients. There are a total of 5 approved ICB drugs in US – Atezolizumab, Nivolumab, Durvaumab, Avelumab and Pembrolizumab (Pembro). However, despite dramatic advances, outcomes are still suboptimal for most patients. The Objective response rate (ORR) remains between 14.8-21.1% in the 2nd line setting and median survival is still less than 1 year.

Dr. Rosenberg continued with his take on abstract 4501: Survival analysis from phase 3, open label study of Pembrolizumab versus chemotherapy in advanced UC. This study showed an ORR occurring rapidly with generally durable response. Furthermore, safety and tolerability of Pembro  was better than for 2nd line and 3rd line chemotherapy. Overall data from this study supports the use of Pembro in patients following platinum chemotherapy as a new standard of care.

The next abstract discussed was abstract 4502 – Biomarker findings and mature clinical results for 1st line Pembro in cisplatinum ineligible advanced UC patients. This was a single arm phase 2 study demonstrating an ORR of 29% with 7% complete response. 67% of responses were still ongoing at a median follow-up of 9.5 months. Toxicity data appeared to be modest in the older and sicker population. In summary, Pembro should be considered a standard of care for cisplatin ineligible UC metastatic patients.

Abstract 4503 was the next discussed, titled: Epacadostat (Epac) plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037. Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient survival. Epac is an oral small molecule targeting IDO1 enzyme. In this study 40 patients were treated with the combination of Pembro+Epac with an ORR of 35%. Most responders were PD-L1 positive with a similar tolerability to PD-1 therapy alone. In summary, results were promising with an ORR worthy of further investigation in a large randomized clinical trial. 

Finally, Dr. Rosenberg addressed abstract 4500 – Comprehensive molecular characterization and analysis of muscle invasive UC, presented earlier by Dr. Seth Lerner. This was a continuation of a prior study, already published in Nature,1 on 412 patients. Results demonstrated that higher somatic mutation and neo-antigen load appear to be prognostically significant.  APOBEC proteins are cytidine deaminases that are capable of inducing DNA damage, and are responsible for most of the mutational burden in bladder cancer. However, it may play a role as a predictive biomarker in bladder cancer. A total of 58 significantly mutated genes were identified, mutated in more than 10% of the samples. Prospective trials should be performed to validate these retrospective results.

Dr. Rosenberg concluded his presentation stating this is a time for rapid change in the field of UC. New approaches are rapidly integrated into the treatment paradigms and we need to understand mechanisms and spectrum of immunotherapy resistance to rationally design combination therapy.  

Presented By: Jonathan E. Rosenberg, MD, Memorial Sloan Kettering

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA

1. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507(7492): 315-22.