8 Questions With a Physician: Immunotherapy in Genitourinary Cancers

Immunotherapy is continuing to enter the treatment landscape of genitourinary malignancies such as renal cell carcinoma (RCC) and bladder cancer, thanks to recent pivotal findings in the field.

Such data include the CheckMate-025 study results presented during the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, which showed that approximately one-third of patients with advanced RCC who were treated with single-agent Opdivo (nivolumab) in the second-line setting or later were still alive at four and five years. This was found in long-term follow-up results of phase 1 and phase 2 clinical trials of the PD-1 inhibitor.

“For the majority of patients [with RCC], they will likely get immunotherapy at some point in the trajectory of their disease, whether it’s early as part of an ongoing clinical trial, in second-line with the indication of nivolumab, or [later],” explains Elizabeth Plimack, M.D.

In the field of bladder cancer, the FDA-approved PD-L1 inhibitor Tecentriq (atezolizumab) has generated excitement as a promising immunotherapy agent, while clinical trials have explored the durable activity of others, including durvalumab and Opdivo. Opdivo was granted a breakthrough therapy designation by the FDA in this space in June 2016.

In an interview with CURE, Plimack, who is the director of Genitourinary Clinical Research at Fox Chase Cancer Center, discussed some of the most impressive advancements with immunotherapy agents in the fields of RCC and bladder cancer, as well as remaining questions with the use of these treatments.

Focusing first on kidney cancer, what are some exciting data we have seen recently with [Opdivo] in this space?

Editor's note: The following has been edited. Dr. Plimack used generic drug names in her answers, but we've used trade names — in brackets — for clarity.The most exciting data with [Opdivo] that was presented at the 2016 ASCO Annual Meeting was looking at long-term survival from some of the very earliest studies — phase 1/2 studies — that are the first studies to test [Opdivo] in kidney cancer. [Opdivo] is now approved by the FDA for kidney cancer, but long-term follow-up requires a lot of time.

Now we have had, in some cases, four to five years of follow-up on the patients on these trials. What is really impressive to us is that one-third of patients are alive at four and five years. It looks like the term “durable responses” is actually one we can say now, knowing that we are looking at those long-term survival rates.

The other interesting thing is that those long-term benefits occurred in patients regardless of their initial response to therapy. These are progressors, including those with stable disease and response. It occurred regardless of risk group, even those poor-risk patients who typically have the worst prognosis. In some of those, the trajectory of their cancer can really be turned around, it seems, by [Opdivo].

What other questions with [Opdivo] still need to be answered in kidney cancer?

Some of that long-term survival is contributed to by additional developments in the world of kidney cancer. Some of those patients either have or will get these other drugs that have been developed over this long period of time. However, all of it just indicates significant progress in the field of kidney cancer, which we’re excited about.There are many, many other questions. The CheckMate-025 study, which was a randomized phase 3 trial of [Opdivo] versus [Afinitor] (everolimus), is a prime opportunity for biomarker development. When you have a randomized trial, you can look to see what is predictive over prognostic. That is one opportunity.

We are looking at how adverse events related to response is critical, to see if those patients tend to do worse or better. We need to also conduct a variety of other secondary analyses. For example, treatment beyond progression was a hot topic at this year’s ASCO. There is a lot to still learn to optimize how we use this drug.

The second piece is, is it best used alone or in combination? Those studies are cooking and, hopefully, we will be talking about that next year at ASCO.

What are your thoughts on Cabometyx in this setting?

What sequencing challenges can we expect?

Should community oncologists feel confident using immunotherapy agents? How should associated toxicities be handled?

Now, we know there is an OS benefit with [Cabometyx] (cabozantinib) over [Afinitor] in kidney cancer. I don’t think any of us were surprised by that, based on the way the curves were looking earlier, but the recent [METEOR findings] confirm that. This is now FDA approved for kidney cancer and now it is in the clinic.That’s the question we’re getting, and I don’t think anyone knows the answer. This is optimistic, but the reality of what we’re seeing now is patients are living longer with kidney cancer, living better — for the most part — in terms of the treatments we have, and I am treating more and more patients with fourth-, fifth- and sixth-line therapies, because they’ve done so well sequentially on many others. Most patients are probably going to get all of these agents—at least [Cabometyx] and [Opdivo]. It is just a matter of which to try first. That’s what we’re all trying to figure out; until we have concrete data, there is no clear answer to that.What is interesting is that the community oncologist probably has more experience using immunotherapy than the genitourinary oncologist. This is because they’ve been using [Yervoy] (ipilimumab) in melanoma and PD-1 inhibitors in melanoma and lung cancer because they’ve been approved for those indications. Now, kidney cancer comes along.

While it is new, it is something that spans multiple tumor types, so gaining familiarity with the particular side effects and how to manage them is a challenge. It was for all of us who used these in the first clinical trials. This is a challenge they’ll quickly get experience with.

Do you tend to use immunotherapy for all patients or for specific populations?

Switching to bladder cancer, what has been the impact of immunotherapy in this setting?

There are really good online resources, especially for [Opdivo], which I have the most experience with in kidney cancer. [The resources explain] “If you see this, these are the next steps with treatment.” If toxicities are caught early and steroids are started quickly for autoimmune-related adverse events, almost all of them are reversible. The one exception to that is the endocrine effects—hypothyroidism or adrenal insufficiency. Those can require lifelong replacement.There are very few patients who aren’t candidates for immunotherapy. There is some data that show that patients with autoimmune diseases are predisposed to the autoimmune phenotype that makes it more dangerous to use them. For those patients, I probably would use something else.In bladder cancer, the PD-1/PD-L1 inhibitors are emerging. [Tecentriq] got the first approval in the class for bladder cancer, which is great news. That is really the second-line standard of care, post-platinum therapy for bladder cancer. At ASCO, we saw data from [Opdivo] and durvalumab, which are two others that seem better than the chemotherapy standard we had before. Those data are pretty clear. We’ll see how those agents evolve.

What ongoing studies have the potential to change practice?

There was an abstract [at ASCO] looking at [Tecentriq] in the first-line cisplatin-ineligible population. These are patients who were ineligible mostly because of their renal function, and cisplatin is the standard of care in that setting. Those patients received [Tecentriq] on this trial, and although the response rates weren’t as good as chemotherapy, the OS was better. Therefore, future settings are really needed to explore this group of patients. Those will be important to look for.In clinical trials for bladder cancer, many of them exclude patients who received prior immunotherapy. Of those that allow prior immunotherapy, very few of them are looking at giving those patients another immunotherapy approach. There is really no reason to say that one immunotherapy won’t work after another, or that a combination approach wouldn’t work. We need to really expand that eligibility to answer some of those questions.