Petros Grivas, MD
Immunotherapeutic developments in the advanced bladder cancer space have resulted in a number of ongoing combination trials with chemotherapy, targeted therapy, vaccines, and more that could shift the landscape once again.
“It's very interesting to see the ongoing combination trials looking at chemotherapy and immunotherapy together. Beyond these, there are many other potential combination therapies that are worth looking at,” said Petros Grivas MD, PhD, who added there is additional biomarker research being conducted in the field.
In an interview during the 2018 OncLive®
State of the Science SummitTM
on Genitourinary Cancers, Petros Grivas, MD, PhD, director, University of Washington Medicine’s Genitourinary Cancers Program, associate professor, Oncology, University of Washington, Seattle Cancer Care Alliance, discussed ongoing clinical trials exploring novel approaches with the potential to change practice in advanced bladder cancer.
OncLive: How has the management of advanced bladder cancer changed?
: We are living in a very exciting era with multiple advances in the field of advanced urothelial cancer. Over the last couple of years, we've had significant developments in understanding the molecular biology of advanced urothelial cancer. There have also been developments with immune checkpoint inhibitors. Now, we have 5 approved checkpoint inhibitors for patients with platinum-refractory advanced urothelial cancer. Two of them have been FDA approved for patients with a cisplatin-unfit phenotype.
We have developed data regarding emerging biomarkers in advanced urothelial cancer. A recent press release by the FDA commented on the potential role of PD-L1 immunohistochemistry testing. PD-L1 may be used to try to predict whether patients would respond better or worse to immune checkpoint inhibitors based on PD-L1 expression. This is something we have not done for a long time.
Whether we should look further into that biomarker expression is another debate. For the time being, it is not a companion diagnostic. However, it is something to look for along with the plethora of other putative biomarkers, such as tumor mutational burden, gene expression profiling and subtypes, DNA damage response, and circulating tumor DNA. Many others are being developed and are going to be looked at in prospective clinical trials to evaluate their clinical utility.
In addition to the development of biomarkers, we have therapeutic advances. Clinical trials have evaluated the utility of targeted therapies. We have not been successful with targeted therapies so far. In my opinion, this is a result of improper patient selection. With the advent of more thorough and more accurate next-generation sequencing, we are now able to identify potential targets and/or predictive biomarkers that can help us position these targeted agents in the right clinical trial context.
Right now, we are conducting trials to evaluate whether targeted therapies, such as FGFR inhibitors, may have activity in this disease. Early data from phase I trials in well-selected patients look very promising. Moreover, we have other agents that target the EGFR, HER2, and HER3 family. This is relevant because we can develop potential biomarkers to help us select our patients.
We have data with antibody-drug conjugates. These are toxins that are linked to an antibody that can target a particular protein in urothelial cancer cells. This can lead to the internalization of the toxin, which can potentially kill the cancer cells. Three antibody-drug conjugates have been tested in clinical trials. Two have shown interesting results that are being moved to larger phase II and III trials.
It's important to know that antiangiogenesis agents are being evaluated. There is a pending trial looking at the combination of gemcitabine and cisplatin with or without the anti-VEGF agent bevacizumab (Avastin). The combination will be evaluated in the first-line setting in cisplatin-eligible patients. The trial has been going on for a while but has still not read out yet, which is interesting. There may be less events because people are living longer.
We also had recent results of the RANGE phase III trial looking at ramucirumab (Cyramza) in comparison with docetaxel. The trial met the primary endpoint of progression-free survival benefit. However, the overall survival (OS) data are not mature yet.
Overall, we have plenty of new targets. The other interesting development is our knowledge about DNA damage response (DDR) mutations. DDR alterations could be a target, especially with the development of PARP inhibitors. PARP inhibitors are a very promising compound.
There are trials in urothelial cancer that look very promising that are looking at the potential utility of PARP inhibitors, either in all-comers or patients selected by DDR alterations. These trials are being done alone or in combination with immunotherapy.