The Basics Behind Bladder Cancer Treatment Gains

Brant Inman, MD

Thanks to a better understanding of bladder cancer on a biological level, there have been five FDA approvals of checkpoint inhibitors within a two-year span to treat the disease.

“It is not so much that the biology is changing; it’s that our knowledge of the biology is improving,” said Brant Inman, M.D.

As for the future of treating patients with bladder cancer, Inman stated that it lies in combinations. Such regimens with checkpoint inhibitors coupled with chemotherapy are being explored in clinical trials, but there may be potential for combinations with two or more checkpoint inhibitors.

Can you please provide an overview of your discussion on bladder cancer?

Inman, who is a surgical oncologist, urologic oncologist and urologist at Duke Cancer Institute, discussed the biology of bladder cancer, the evolving role of checkpoint inhibitors and the future of chemotherapy in an interview with CURE.I spoke about three things: the biology of bladder cancer and how it has changed the way we are managing patients, the standard of care right now for managing muscle-invasive bladder cancer, and the role of chemotherapy with or without surgery, as well as the types of chemotherapy regimens we should be using.

How are we seeing the understanding of bladder cancer biology change?

Also, some of the biomarkers that are coming out may help us to choose who should receive what type of chemotherapy—and [we spoke about] if there are some people who should not be receiving chemotherapy at all. The last thing I talked about was the new data that have come out in the last year on checkpoint inhibition in bladder cancer. This is mostly in metastatic disease, but I mentioned the clinical trials that are available in nonmetastatic disease.This is [happening] mainly with genetics. Genome sequencing and RNA sequencing have really allowed us to characterize bladder cancer into several different molecular subtypes. Those molecular subtypes are important; they seem to affect prognosis and the response to chemotherapy.

What do you envision for the role of chemotherapy going forward?

In particular, there are now clinically available tests to check for these subtypes that may become important in the future. We can classify patients into different types, such as basal and luminal cancer, and that may be important for us in choosing who gets chemotherapy and who doesn't. Right now, not everyone benefits from chemotherapy, and if they get it, a patient may be subject to the toxicity for no benefit. Ideally, we would like to match the treatment with the patient, so that the patient who would really benefit from that would receive [chemotherapy]. There have been many chemotherapy combinations tried, and, to be honest, there hasn’t been a whole lot beyond gemcitabine/cisplatin or MVAC. The big innovation that’s not that big is compressing the MVAC into a dose-dense or accelerated format. It allows us to give the chemotherapy over a shorter period of time, but it requires a little bit more growth factor support and it is more toxic. That is the big change in chemotherapy in terms of the regimens that are given.

What biomarker-driven trials are being conducted in the field?

The bigger change is in the use of immunotherapy in combination with chemotherapy. That is being tested in clinical trials and it’s being tested after chemotherapy fails in advanced settings, as well as in earlier settings. There are not many good biomarkers of immunotherapy activity right now. It is interesting that the molecular subtypes of bladder cancer also predict response to immunotherapy, at least in one of the clinical trials. Therefore, I suspect that these biomarkers are telling us more about the biology of the tumor than whether it is going to respond specifically to that treatment.

In terms of clinical trials, there is a SWOG trial right now that is going to test a COXEN drug predictor of chemotherapy response. [COXEN] is a predictor that was developed in cell lines testing many different cancer cell lines against a variety of drugs and then developing a panel of RNA signatures—which predict which cancers should respond to which drugs. That is now being tested in bladder cancer in a clinical trial.