There are currently ongoing trials attempting to overcome resistance to single agent anti PD1/PDL1 therapy. These trials include Checkmate 901 (assessing Gemcitabine+platinum vs. Nivolumab+Ipilimumab), IMvigor 130 (assessing Gemcitabine+platinum+Atezolizumab vs. Atezolizumab alone vs. Gemcitabine+platinum+placebo), Danube trial (assessing Durvalumab vs. Durvalumba+Tremelimubab vs. Gemcitabine + cisplatinum), and Keynote 361 (assessing Gemcitabine + platinum+ Pembrolizumab vs. Pembrolizumab alone vs. Gemcitabine + Platinum). There are also ongoing trials attempting to determine the optimal order of chemotherapy and immunotherapy. Importantly, one of the major advantage of these drugs, is their very acceptable side effect profile.
Some of the drug combinations include immune anti-angiogenesis combinations. This means co-targeting both VEGF and PD1/PD-L1. Other combinations include immune-immune combinations. This includes the CTLA4-PD1 pathway, which unfortunately does harbor significant toxicity, but multiple different classes are being tested.
There is now also a trend of moving earlier in the natural history of the disease, in an attempt to increase cure rates. There are currently ongoing adjuvant trials after surgery. Additionally, there are multiple trials testing anti-PD1-PD-L1 therapy in the muscle invasive (MIBC) and non-muscle invasive bladder cancer (NMIBC) population. Furthermore, there are several phase 2 single arm trials in BCG unresponsive bladder cancer patients. Lastly, there are trials in xenograft models assessing TGFb inhibition, which will hopefully lead to improved response to ICP blockade.
Dr. Rosenberg summarized his encompassing talk stating that multiple approaches are being tested in NMIBC, MIBC and metastatic disease. The number of combinations is daunting, not only by number of classes, but also by multiple agents within a class. There is a need for rational approaches to combinations. Biomarker work on patient samples will hopefully identify druggable resistance mechanisms. Finally, we should expect considerable more data to arrive over the next few years.
Presented by: Jonathan Rosenberg, MD, New York, USA
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan, at the 18th Annual Meeting of the Society of Urologic Oncology, November 29-December 1, 2017 – Washington, DC