Clinical Trials Play Key Role in Future of Bladder Cancer

While the treatment landscape continues to grow in bladder cancer, researchers should continue to follow the evidence, but accrual of patients in clinical trials is also key, according to Petros Grivas, M.D., Ph.D.

At the 33^rd annual Society for Immunotherapy of Cancer (SITC) Meeting, Grivas — who is an oncologist at Seattle Cancer Care Alliance, clinical director of the Genitourinary Cancers Program and an associate professor at the University of Washington – discussed the use of immunotherapy in bladder cancer, and what more needs to be done in this space.

What is it about bladder cancer, biologically, that makes it respond so well to immunotherapy?

Usually I start this answer by just quoting data that shows that bladder cancer, and even upper tract urothelial cancer, has many mutations — or a high tumor mutational burden. This high number of mutations creates new proteins, which we call neoantigens, that can be potentially recognized by the immune system. Some of those neoantigens, qualitatively, can induce immunogenic responses.

It’s hard to find really strong, robust neoantigens — it’s much like trying to find a needle in a haystack – but the more mutations you have, statistically, the higher your chances of having these strong immunogenic neoantigens that can trigger the immune system. And I think that’s probably part of the answer why some patients may respond very well – it’s just hard to find where these new antigens are.

Higher tumor mutational burden is one of the biomarkers associated with high response rates to immune checkpoint inhibitors across tumor types including urothelial cancer. Also, we now have data that shows if you have mutations in DNA-damaged response genes like BRCA or other similar genes in the DNA repair pathway, you might have a higher chance of responding to immunotherapy. The question is whether the mechanism of that is because of genomic instability, which creates more mutations, or if there is some separate mechanism there, and that DNA response gene mutations can predict the response to immunotherapy.

There are other features I think that we have to delve into more, including some molecular subtype profiling data that show that some subtypes like luminal or basal may respond better to immune checkpoint inhibitors, and of course we have the PD-L1 expression in some patients. But in my opinion, we have to do a better job of validating biomarkers in the context of each other and not in silos. Ideally, we have to measure with the same platform across clinical trials to help develop biomarkers in a validation context.

We have variability and heterogeneity in biomarkers which is great for discovery, but when it comes to validation, we need some more alignment and standardization across clinical trials.

What do you think can be accomplished in the next couple of years?

I think it’s likely that we are going to have some approvals in the disease in the future. Of course, it’s hard to predict when and for which agents, so we have to wait for the trials to readout. If you look at the current landscape, we have only chemotherapy and immunotherapy that we’re currently using today. But if you look at the published and publicized information, there are two agents that the Food and Drug Administration (FDA) has designated as breakthrough status — an FGF receptor inhibitor and an antibody drug conjugate - that are being evaluated in clinical trials, so we’ll have to see how the trials readout.

My prediction is that in the next couple of years, we are going to have hopefully more therapies approved in this disease, we’re going to have more biomarkers, and hopefully we will soon be able to identify patients for the right treatment based on both clinical and molecular factors, whereas right now we just use clinical factors.

The last point to make is that we have to be cognizant of the high frequency of germline mutations in patients with urothelial cancer. Genetic counseling for patients and their families is very important, even more in upper tract urothelial cancer but also in other patients based on their age at diagnosis or personal and family history of cancer. There’s also more data on genomic sequencing, which we have to refine the role of in this disease.

All in all, much more information is coming, in addition to the interesting data we’ve seen at this meeting.

Is there anything you’d like to add?

Right now, we have to utilize the evidence in patients with muscle-invasive, localized bladder cancer. We also want to do clinical trials to improve upon cisplatin-based chemotherapy. If there’s no trial available, (neoadjuvant) cisplatin-based chemotherapy is the standard of care and immunotherapy is investigational in the localized, non-metastatic disease setting.

We have to support clinical trial accrual. That’s the message across the board in both the academic and community sides, that there are trials across the spectrum of disease with more trial slots than patients — meaning we have more opportunity to investigate this disease. So, the message is follow the evidence but also accrue in clinical trials.