Predicting Response in Kidney and Bladder Cancer Remains in a State of Flux

As treatment regimens for bladder cancer and renal cell carcinoma (RCC) continue to expand, experts are still navigating biomarkers to identify which patients will best respond to treatment.

What is taking place in the field of RCC and bladder cancer?

In an interview with CURE, Sumanta Kumar Pal, co-director of the Kidney Cancer Program at City of Hope, discusses the state of biomarker development in the field of genitourinary malignancies.In kidney cancer, there are some caveats to the way that we treat the disease. For instance, we use targeted therapies—drugs that affect VEGF and mTOR—but we really don’t use biomarkers to apply these therapies. It is very different from lung cancer or colon cancer. How might we get there?

Bladder cancer is a very different landscape than kidney cancer. In contrast to kidney cancer, where we have had 10 drug approvals over the past decade, we really are still stuck with cisplatin-based chemotherapy in bladder cancer. We are very little beyond that.

What biomarkers are available in kidney cancer? Which ones are in development?

For the practicing urologist, it is a little bit different. Right now, there are some biomarkers that are at their disposal. There is an Oncotype-like test available for kidney cancer, which uses a 16-gene recurrence score. These genes straddle various pathophysiological domains of kidney cancer, including vascular and inflammatory genes. This gene score was validated across both Cleveland Clinic and a French-derived cohort. It predicts risk associated with metastases. If you have a patient with localized kidney cancer, you can get some symbol of their risk score for developing metastases down the line.

For the medical oncologist, it’s a little trickier. We do have some emerging biomarkers. For instance, if you’re running mutational panels, there are certain alterations that may potentially predispose a response to VEGF-directed therapies, while others may potentially predict response to mTOR-directed therapies.

For VEGF, we think that there are alterations in a gene called KDM5C, which may potentially lend itself to longer clinical benefit for a VEGF inhibitor. There has also been some great research from Dr Toni Choueiri and colleagues from Dana-Farber Cancer Institute suggesting that, if you have mutations in mTOR such as TSC1 or TSC2, these are genes that are related to the mTOR pathway that may potentially respond to agents such as Afinitor (everolimus) or Torisel (temsirolimus).

What is the evidence for PD-L1 as a biomarker in RCC or bladder cancer?

Certainly, PD-L1 plays a role in bladder cancer responsiveness to various immune-based treatments, including PD-1/PD-L1 inhibitors. Thus far, the data is most soundly attributed to atezolizumab, where we know the response rates are concordant. For instance, 3+ staining is intense staining for PD-L1, while 1+ staining is low staining for PD-L1.

We don’t quite have an accurate estimate of whether or not those patients who lack PD-L1 expression will have zero response to immunotherapy. There is still a story to be told there. That’s where other surrogates, such as mutational load, could potentially come in handy.

In general, why does it seem that many promising biomarkers are stuck in the discovery phase of research and not progressing to clinical phases?

There is a desire on the part of pharma, on the part of investigators and on the part of patients to get drugs sent to the clinic quickly. I certainly wouldn’t disagree with that enthusiasm. It is clinically important that we segue drugs from the lab to the clinic very quickly.

One of the challenges observed in RCC, where we have a multitude of different targeted therapies and now immunotherapies, is we don’t quite know how to apply them.

What should the next steps entail?

If we were to turn back the clock a couple of years, perhaps a more sensible way to design these trials would be to embed a lot of biomarker-based research. Then, we can better understand how we can select these patients who will have a better response to Opdivo (nivolumab) over Cometriq (cabozantinib) and vice versa.The real key is, as time as goes on, we’re going to have to focus our efforts on embedding biomarkers prospectively in clinical trials for genitourinary oncology. We have not done a great job of these to date.

There are certainly some great examples of trials that have incorporated biomarkers early on. However, we need to really employ biomarkers in prospective fashion and stratify patients based on the presence or absence of PD-L1 or specific genes, for example, which can produce a predicted response to therapy. Unless we do that, we will never really have an understanding of which patient will benefit the most from any given therapy.

There is a really interesting trial being conceived right now within the Alliance for Clinical Trials in Oncology. This study will randomize patients to either a VEGF inhibitor or PD-1 inhibitor. One of the primary endpoints of this study will be to ascertain the potential role of biomarkers in predicting response. I think that will be an excellent example of a study design that we can use moving forward in this domain.