Immunotherapy Advances Again Propel Progress in GU Malignancies

Randy F. Sweis, MD

Across the fields of renal cell carcinoma (RCC), bladder cancer, and prostate cancer, immunotherapy agents are moving through the pipeline and impacting patient outcomes—some quicker than others.

“Now, we see that anti—PD-1 therapy has taken off,” explains Randy F. Sweis, MD. “Suddenly, GU has come at the forefront of immunotherapy again and we are all excited about that.”

Sweis, who gave a lecture on bone-targeting agents in prostate cancer during the 2016 OncLive State of the Science Summit on GU and Prostate Cancer, has a keen research interest in immunotherapy in GU malignancies—and understanding why some patients are resistant to them.

OncLive: How have you seen an evolution toward immunotherapy in GU cancers?

In an interview with OncLive during the meeting, Sweis, a clinical instructor at the University of Chicago Medicine, covers the immunotherapy advancements in prostate cancer, RCC, and bladder cancer, and what refinement lies ahead in each of these areas.Sweis: GU cancers have had an interesting historical course, where initially, BCG [bacillus Calmette-Guérin], which is an immunotherapy instilled intravesically in the bladder, was the second immunotherapy ever approved by the FDA. That occurred after interferon-alpha, so it was at the forefront of immunotherapy.

Can you discuss the IMvigor 210 study, and how those results led to the FDA approval?

Then, there was sort of a lull where, for decades, we did not have much—especially in bladder cancer. In RCC, we saw the development of the tyrosine kinase inhibitors and, in prostate cancer, we saw a lot of secondary androgen-targeted agents. However, bladder cancer sort of remained with no new FDA-approved drugs until atezolizumab (Tecentriq). Therefore, it is an exciting time.In IMvigor 210, we saw a lot of interesting durability to the responses, and I think that is what people are most excited about. My research interest is understanding resistance mechanisms, and although we are all excited about the responses we saw, the response rate is still not where we want it, especially in PD-L1—negative patients. There is definitely a subset of patients who are not having the responses we want.

What clinical trials should be done in an effort to get more patients responding to therapies?

Overall, when taking all comers with bladder cancer, there are probably one-quarter of patients who will have a response to PD-1, which is shown on the survival curves. There is impressive durability—sort of the tail on the curve that is noted at the end—but the majority of patients are still having disease progression, which is where there will be a lot of work going forward. To temper some of the excitement about the approval, there is still a lot of work to be done.A lot of this is already happening. I have recently heard of as many as 500 different clinical trials where there are combinations of PD-1 targeted therapy with other agents. Results will likely rely heavily on some preclinical data and the understanding of immune biology—and that is critical. There are a lot of drugs that are active.

Chemotherapies are active still, so we are looking at potentially combining immunotherapies with chemotherapies. Radiation, of course, is of interest. We have a phase I study in our Developmental Therapeutics Program combining radiation with an anti—PD-1 drug. We also have targeted therapies.

How is the FDA approval of atezolizumab going to shake up the treatment landscape of bladder cancer?

In RCC, we have had many targeted tyrosine kinase inhibitors that have been approved in the past decade. How do they fit in with immunotherapy? These are questions that are ongoing and we are going to learn a lot in the next decade.It is going to be a dramatic change. It has been a difficult discussion in clinic for patients who have had no response or had a response, but had had a recurrence to chemotherapy. We do not have many therapeutic options to offer that are highly effective and minimally toxic, and this is now one of them. It is very exciting for a patient who is sick, but still has a good performance status, and is eager to get some kind of treatment for their disease, and there was previously not much else to give them. This new approval will offer something different and will be more widely available outside of clinical trials, now that we have it FDA approved.

In RCC, are there other types of immunotherapy agents that you would like to see explored?

It will also impact how clinical trials are done. Many of the patients are going to be coming to us who have already had immunotherapies. We have already anticipated that, and I am sure that there are trials at other institutions designed specifically for those who have had recurrences while on PD-1 immunotherapy. These trials are typically combining other immunotherapies to see if that resistance can be reversed.There is a whole host of immune-targeted drugs on the horizon, some of which might be promising in RCC. Going back to the combinations, it may be a combination of traditional VEGF-targeted therapy—and there are ongoing studies evaluating those combinations—but also other markers that have been identified as immune suppressive that occur as sort of natural breaks in the immune system, or conversely stimulating receptors that might activate the immune system.

The toxicities that are associated with immunotherapy are very different from the adverse effects associated with targeted therapies. How are these adverse effects managed?

For example, there are trials with agonists for OX40 in combination with PD-1. All of these immunotherapy combinations are fair game for renal cancer, and we will have to see how they play out. Many of these are still in phase I studies, so we will not know for quite some time. However, referring a patient who has had immunotherapy and has not had a response, or has a recurrence after a response to such a study in phase I, would be reasonable.One critical aspect of these new immune-based therapies is to educate the patient. This is still very new to even physicians, let alone the patients who are learning about how immunotherapy works and what to expect.

Sometimes, patients may develop symptoms and not think that it is related to the drug, because they are used to the typical adverse effects of chemotherapy or even targeted therapy, which are different.

We have seen immunotherapy positively impact the landscape of RCC and bladder cancer, but what about prostate cancer?

A big part of what I do in the clinic is educating the patient on things to look for. We look for autoimmune-related effects, which might mean rash, diarrhea, or changes in their breathing, so we are monitoring closely for those. It is critical to identify these early because they are treatable and often reversible—almost always with cessation of the drug and/or treatment with steroids, or other ways that temper the immune system.Prostate cancer has been a challenge, but we are also remembering that sipuleucel-T (Provenge) is an immunotherapy that has been approved in prostate cancer; that has shown a benefit. There is an immune response in prostate cancer, but it is different, and it is going to be a challenge to understand the tumor microenvironment in prostate cancer. Most of the 90% of the metastases are to the bone, and that is quite different from other cancers.

While there has been excitement with immunotherapy, there are obviously challenges. What are they?

Also, the microenvironment—the immune interface—is something that is not fully understood. We also have some work going on in prostate cancer where we are trying to understand the potential molecular markers of resistance to immunotherapies. If we learn more about that, we may be able to target them and reverse some of the resistance to anti—PD-1, CTLA-4, or other immune checkpoints.The challenges with GU cancers are somewhat applicable to all cancers with immunotherapies, and that would be biomarkers. That is the key. The majority of patients are not responding to PD-1 therapy. Although, it is great when we do see it. It can be durable, and it is associated with very low toxicity.

However, we need to be able to figure out who those patients are, not just to identify them to direct them to other therapies, but also to potentially identify why they are not responding. That is the way discovery happens; that is how we find new targets to combine and to maybe overcome that resistance. Therefore, biomarker development and identification of resistance mechanisms are the 2 areas that are critical going forward with GU immunotherapies, now that we have FDA-approved drugs.