Expert Highlights Biological Advancements in Bladder Cancer Field

Brant Inman, MD

The 5 FDA approvals of checkpoint inhibitors in the bladder cancer paradigm over a 2-year period are largely due to the improved understanding of the disease on a biological level, according to Brant Inman, MD.

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

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 2 or more checkpoint inhibitors.

OncLive: 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 during the 2017 OncLive^® State of the Science Summit^TM on Genitourinary Cancers.Inman: I spoke about 3 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.

What is important for clinicians to know about these 5 PD-1/PD-L1 inhibitors we have available?

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.Right now, the big message is that, for patients with metastatic bladder cancer whose tumors did not respond to chemotherapy, they should consider using one of the checkpoint inhibitors. I don't think we can recommend one over the other right now.

The other situation is for patients who are ineligible for cisplatin. If [a patient cannot receive] cisplatin, the likely best choice right now is to consider a checkpoint inhibitor.

What is imperative for clinicians to know regarding the evolution of bladder cancer treatment?

In terms of what is coming [down the road], it is combinations. This is either combinations of 2 checkpoint inhibitors or, more likely, chemotherapy combined with checkpoint inhibitors. There are a number of combinations being tested in early-phase studies and even later-phase trials, too. That is where it is going. It is going towards combinations of novel agents with existing therapies, novel chemotherapies, or new checkpoint inhibitors.The big thing with bladder cancer is that we had about 30 years of no developments and no progress and, in the last 18 months, we have seen 5 new drugs and a whole lot of clinical trials. This is a field where change is rapid, and the biggest thing for clinicians to take home is that the stuff that you used to do is not the same stuff you’ll be doing today—[and] it is going to be very different in the next year or 2.