Improving Patient Selection Key to Optimizing Novel GU Cancer Treatments

Sumanta Kumar Pal, MD

As the fields of renal cell carcinoma (RCC) and bladder cancer continue to dramatically progress with the approval of novel agents—both immune-based and targeted therapies—oncologists need to improve their methods of selecting patients to receive such available therapies.

This point was made in a paper published in the Journal of Clinical Oncology by Sumanta Kumar Pal, MD, who spoke to the ever-changing paradigm in bladder cancer and supported the recently released NCCN Bladder Cancer Guidelines, which advocate for molecular profiling in advanced bladder cancer. With greater use of genomic testing, Pal notes that patients will be guided to more rationale therapies and also be better selected to enroll on clinical trials.

OncLive: What are some of the key issues right now with the available treatment approaches in renal cell carcinoma?

You described IL-2 is waning in treatment. Why is that?

Are we researching ways to select patients better, or are we just moving on to different treatment methods?

What are the latest updates with some of these newer agents?

How do you approach your first-line patients?

In an interview with OncLive, Pal, medical oncologist, assistant clinical professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses advancements occurring in the treatment landscape of RCC and bladder cancer, the promise (yet caution) with immunotherapy, and guidelines that practitioners should use when choosing between immunotherapy and targeted agents for their individual patients. Pal lectured on this topic during the 2016 OncLive State of the Science Summit on GU Cancer.Pal: In metastatic kidney cancer, there is a whole host of different treatment decisions that we need to make. In the first-line setting, there is a huge debate regarding whether or not interleukin-2 (IL-2) remains the standard of care. I would suggest that a lot of the data out there implicates that use of IL-2 is really waning. In contrast, we see a rise of trials that actually juxtapose VEGF inhibitors against novel immunotherapeutic strategies, and that likely represents the most en vogue approach right now.The big challenge with IL-2 is that, to date, we really haven’t developed objective criteria to pick appropriate patients. With some of the other drugs that we use in this category— VEGF inhibitors, for example—we tend to apply those across the board and across different study populations. The criteria that we are using now for picking patients with IL-2 remain somewhat arbitrary. My feeling is that that the new classes of therapy, the PD-1/PD-L1 inhibitors, may actually represent the new wave of agents that may potentially replace the approach of IL-2. IL-2 is not a particularly sophisticated approach. It really prompts generalized immune stimulation, whereas PD-1 and PD-L1 inhibitors can really promote immune stimulation in a much more organized fashion.As in many other cancers, what we’re seeing is that PD-1—based therapy has been introduced for renal cell carcinoma. Now, the agent nivolumab (Opdivo) is FDA approved for use in the second-line setting, following VEGF-directed therapies. What we’re probably going to see, in coming years, is incorporation of PD-1–based therapies in the frontline setting, but it will require clinical trials that compare these agents against VEGF-directed therapies. Those may mature over the next couple of years.Great question. In the context of first-line therapy for metastatic RCC, there are a number of different choices that are available. The NCCN guidelines, for instance, offer category 1 recommendations to agents such as sunitinib (Sutent), pazopanib (Votrient), bevacizumab (Avastin) with interferon, and temsirolimus (Torisel) in select cases.

With all of these agents available, how do sequence treatments while keeping the patient’s goals in mind?

By and large, I tend to prefer sunitinib and it really hinges on a practical decision. Usually, when I approach patients for frontline therapy, I’m offering them a clinical trial. These studies often times offer a control arm of sunitinib therapy versus a novel immunotherapeutic approach. It’s very hard to really restructure the conversation after that and offer an agent other than sunitinib in that setting.It’s so challenging to really optimize sequencing of therapy. Right now, we have a lot of data that overlaps to some extent, and we’re forced to juxtapose, side-by-side, different phase III clinical trials to compare data—and that’s never ideal.

Having said that, what I try to emphasize in my practice is clinical trials. That probably sounds a little bit cliché but when I look at the treatments that we have right now for metastatic RCC—even though I would concede that we’ve made major advances—most of our treatments really fall into 3 categories. These are VEGF-targeted agents, mTOR-directed therapies, and immunotherapies.

As an oncologist, what is your approach to determining what treatment is best suited for a patient?

With that in mind, the patient is probably going to run out of treatment options at some point in time. Sandwiching in clinical trials early and offering new pathways and new treatments that exploit those pathways is a great way to optimize outcomes overall.In the second-line setting, for instance, I tend to be fairly dogmatic in my patients with metastatic RCC. I tend to use cabozantinib (Cabometyx) more or less across the board. Cabozantinib is a dual VEGFR inhibitor and MET inhibitor. It also appears to act against a receptor called AXL. Moreover, cabozantinib has shown to have a survival benefit against everolimus (Afinitor) in a randomized phase III study.

Have we shifted more toward overall survival as a primary endpoint in trials?

Let’s transition to bladder cancer. What kind of treatment advances are we looking at in this disease?

Now, nivolumab has also done the same, but cabozantinib has the added benefit of demonstrating responses in progression-free survival (PFS). Therefore, as much as we shift away from PFS as a key endpoint in clinical trials, I feel that it really is clinically meaningful to patients.There certainly has been an emphasis on OS; however, in the comparison of cabozantinib and nivolumab in metastatic RCC, one of the challenges is that both agents have actually demonstrated and proven an overall survival benefit. Therefore, folks may really rely on data such as PFS, toxicity, etcetera, to make treatment-related changes.Bladder cancer is this very interesting domain where there really haven’t been advances in treating metastatic disease for the past several decades. We have known about the activity of cisplatin-based chemotherapy regimens for a long time and, by and large, we’ve stuck to that.

Are these immunotherapies slower to show efficacy and get approved in bladder cancer?

What we’ve really seen come across over the past year is the approval of the PD-L1—based therapy atezolizumab (Tecentriq). There is a whole host of PD-1 and PD-L1 inhibitors in clinical testing right now. These aren’t curative options for patients with advanced bladder cancer, but they certainly represent a big improvement over what we had previously.In bladder cancer, I actually believe that within the next couple of months we will probably see some major activity. Many large studies looking at PD-1/PD-L1—based therapies are projected to read out, and this may potentially affect the FDA approvals that we see in this space.

What will we see in the next 5 years in bladder cancer?

Therefore, I don’t necessarily think bladder cancer is behind, and there’s also good rationale for these novel immunotherapeutic drugs to work in bladder cancer. Bladder cancer, such as melanoma and other diseases where you really see immunotherapy work, has a very high mutational load. That can certainly predispose to a higher response.If I had to give you my 5-year perspective on bladder cancer, I certainly think that immunotherapy is going to play a big role and it will likely be combination immunotherapy. However, I do think that there is still going to be that population of patients who don’t respond to immunotherapy, and hopefully, we’ll have made some progress in treating those folks.

What needs to be done, from a research perspective, to get to a point where we are using more immunotherapy?

Which patients will likely not respond to immunotherapy?

This goes along with your point on it being necessary to test all patients with bladder cancer—to determine what their mutational load is?

I’m a big proponent of profiling patients. We just had a big article in the Journal of Clinical Oncology published a couple of weeks ago that really validated the approach of genomic testing for all patients with advanced bladder cancer. Targeted therapies may potentially address those patients who don’t respond to immunotherapy in many cases.We have invested a lot of our time and energy right now in immunotherapy, and we principally looked at single agents. The wave of the future is going to be combination therapies beyond PD-1/PD-L1, drugs targeting targets such as LAG3 and IDO. All of these hold incredible promise, but it is going to be important for us to acknowledge that there will be a subset of patients who do not respond to these therapies. For the field to move forward, we really can’t lose sight of those folks. Again, I really feel that targeted therapy and use of genomic profiling will address them.Right now, we don’t have any hints as to perfect biomarkers predicting who won’t and will respond to immunotherapy for bladder cancer. One of our leading hypotheses is that folks with a low mutational burden may not respond quite as well. With that in mind, that is probably a target population for us to focus on, first and foremost, in terms of patients who will be non-responders. Perhaps profiling in that population will yield some novel targets for which we could apply targeted therapy.I actually led recently a position paper published in the Journal of Clinical Oncology that offers justification for those community-based oncologists out there who are looking to perform genomic profiling on their patients with bladder cancer. I hope that it serves as appropriate justification. In doing that, perhaps you can actually tease out elements such as mutational load and moreover, specific mutations that may allow folks to enroll on clinical trials with targeted therapy.

Why aren’t all patients undergoing genomic profiling right now?

There are a number of avenues for this. ASCO, for instance, has unleashed the TAPUR trial, which is a study that allows for use of this Clinical Laboratory Improvement Amendments (CLIA)¬—certified molecular profiling tests to position patients into appropriate clinical trials with targeted therapy.It’s interesting. I’m not clear on why patients with bladder cancer aren’t getting more universally genomically profiled. In this particular setting, we might look at the one-time, upfront cost of genomic profiling as being prohibitive, but we’re not really focusing in those scenarios on a downstream cost of using cytotoxic agents that have very little effect. However, they may have a big economic cost, as well as toxicity cost, to the patient by virtue of that. Certainly, those costs may outweigh the potential benefits of that approach.

Reference

Pal SK, Agarwal N, Boorjian A, et al. National Comprehensive Cancer Network recommendations on molecular profiling of advanced bladder cancer. J Clin Oncol. 2016;34(27):3346-3348.