Immunotherapy for Genitourinary Cancers Still in Infancy

Susan F. Slovin, MD, PhD

As part of our coverage of the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting held May 29 to June 2 in Chicago, today we are speaking with Susan F. Slovin, MD, PhD, attending physician, member of genitourinary oncology services at Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center, and professor of medicine in the department of medicine at Weill Cornell Medical College. At this year’s meeting, Dr. Slovin will be chairing an education session discussing immunotherapy for the treatment of genitourinary tumors.

 -Interviewed by Leah Lawrence 

Cancer Network: Dr. Slovin, thank you for taking the time to speak with us today.

Dr. Slovin: Thank you.

Cancer Network: The education session you are chairing discusses whether or not immunotherapy in the treatment of genitourinary cancers is ready for prime time. Generally speaking, where do immunotherapies stand in the treatment of genitourinary disease compared with other solid tumors?

Dr. Slovin: That is a great question. It is interesting to learn that over the course of probably 25 to 30 years we really have not had any major breakthroughs in immunologic therapies in genitourinary cancers. I would still say that it is in its infancy; however, our first indication that there might be a role for immunotherapy came in prostate cancer with the FDA approval of sipuleucel-T, otherwise known as Provenge. This is the first autologous cellular immunotherapy that was able to give a survival benefit almost comparable to that seen with hormonal therapy or chemotherapy.

What is very interesting now is that while we continue to pursue a variety of different approaches in immunotherapy for different solid tumors, particularly within genitourinary oncology, the checkpoint inhibitors appear to be making a relatively big impact on two cancers right now. The first is bladder cancer and the second is renal cancer.

We have always thought of immunologic cancers as being melanoma, because there have been spontaneous remissions as indicated either by the resolution of an abnormal mole or just a depigmentation that occurs where the skin suddenly becomes white, otherwise known as vitiligo, and that is associated with treatment response. In kidney cancer, for example, it has always been interesting that if you remove the primary cancer, the kidney, sometimes patients who had metastatic disease to the lungs actually had complete resolution of their lung lesions.

Bladder cancer was always thought to be an immunologic cancer by virtue of the fact that patients who had very small cancers within their bladder could respond by a local inflammatory response induced by the adjuvant BCG, Bacillus Calmette-Guérin. That has been known for many years. Nobody really thought about how checkpoint inhibitors would work in these malignancies.

What has changed is the way we are looking toward treating these malignancies, perhaps with less aggressive therapy, less inflammatory to the patient or the organ, by using checkpoint inhibitors. The recent approval of Opdivo [nivolumab], which is a human IgG4 anti–programmed death-1 (PD-1) monoclonal antibody, has really changed how we are going to go forward in the future with treating either kidney cancer, or even bladder cancer; we still don’t know where we are going to go with prostate cancer. It is an immunomodulator that works by blocking the ligand activation of a PD-1 receptor on activated T cells. In an earlier report in kidney cancer, it was associated with an overall 18-month survival at a very low dose of 0.3 mg/kg. What is now going into development is a combination of Opdivo, or nivolumab, with another checkpoint inhibitor, anti–CTLA-4 or ipilimumab.

In going over the history of immunotherapy, there is no question that we are making strides. The therapy is working with durable responses, but it is still in its infancy in terms of how we are going to go forward. It is one thing to combine two checkpoint inhibitors, but I think in going forward it will be the tyrosine kinase inhibitors, and the vaccines-all that will be used in combination.

I think the future is extremely exciting in going forward in the world of genitourinary oncology.

Cancer Network: Your portion of the session will focus specifically on prostate cancer. Can you briefly discuss where immunotherapeutics stand in treating men with this disease?

Dr. Slovin: The role of immunotherapy in prostate cancer has been taken under advisement in the last couple of years. We definitely had a major breakthrough with the FDA approval of sipuleucel-T, or Provenge, which is the autologous dendritic cell vaccine that has yielded an overall survival benefit, and in some cases it has been accompanied by a very small anti-tumor response. Where to integrate it into the armamentarium that we currently have in prostate cancer is still questionable, but for patients with minimally symptomatic or asymptomatic castration-resistant prostate cancer, it is still a very viable and well-tolerated alternative.

How long one should monitor a patient after immune therapy remains unclear. Patients are very reluctant to wait more than 4 to 6 months to see if the therapy works because we have the biomarker PSA, or prostate-specific antigen, which tends to frighten patients and may often be a herald of things to come, particularly if the PSA starts to double or triple very quickly.

There have been several attempts to look at ipilimumab in prostate cancer in the phase I, phase II, and now, phase III trials. The results were published about a year ago. This was in patients who failed chemotherapy with docetaxel and went on to receive either radiation to either one or more sites in bone followed by either placebo or ipilimumab. The results suggested that it was approaching a survival benefit, but that it did not meet its overall survival endpoint. It became apparent quickly that those patients with visceral metastases actually did much worse. We don’t have the results of the recent study done in the pre-chemotherapy state. We are all looking forward to determining whether or not ipilimumab will be helpful.

PROSTVAC is another vaccine, otherwise known as TRICOM, which has three costimulatory molecules that are embedded into the vector. It is part of what we call a prime boost technology, using either cowpox or fowlpox to enhance the immune response. There had been a small overall survival benefit in the phase II trial, but the phase III trial, which was recently completed, is not available to us yet.

Why are we so focused on prostate cancer? Well, it seems that prostate cancer does not have the kind of robust responses that we have seen, for example, with the checkpoint inhibitors in renal cell cancer, bladder cancer, or, for that matter, lung cancer. Many people have suggested that perhaps cancers with a greater number of mutations, or cancers that are hypermutated, such as melanoma, lung cancer, renal cell cancer, or bladder cancer, may be much more responsive to checkpoint inhibitors. However, it is not uniform and it is unclear in those people who do have these hypermutated tumors why they may respond better than others. In other words, it is not a given that if you have a hypermutated tumor that you will respond. People who don’t have hypermutated tumors also can respond, but perhaps not as robustly. The problem with prostate cancer is that it is not hypermutated. We don’t understand why the checkpoint inhibitors do not have the same level of efficacy. There are two clinical trials out there now that are accruing, looking at those patients who have AR-V7 splice variants and have not responded well to either abiraterone or enzalutamide. These are patients who now will be tested with nivolumab. Another trial is looking at patients with castrate metastatic disease to see if nivolumab has any impact. Again, it is highly unclear why we don’t have that kind of robust response and durability that we have seen in other genitourinary malignancies.

In going forward with prostate cancer, it has been clear, at least to me, that single-agent biologics or single-agent vaccines, or even immunotherapies, are just not robust enough, and therefore it will probably be a combinatorial approach in the future. We are severely lacking in immunologic therapies. It is getting harder. I think most of the emphasis these days is on those cancers that have the brisk responses. The best we can do right now is try to continue our efforts in developing or at least trying to pursue those immunologic therapies that may have some potential in patients with prostate cancer.

Cancer Network: How does the clinical community decide whether the treatment approaches are ready for use in the clinic?

Dr. Slovin: That is probably one of the most important questions that we ask, and a lot of it has to do with several different issues. One has to be exportability. In other words, it can’t be a boutique type of treatment, meaning that it has to be custom-made for the patient. It has to be exportable, off the shelf. It has to have minimal toxicity, and the results have to be very reproducible. There also has to be an ease of administration and a clear rationale for giving the treatment. It is not enough to say, “We think it’s working in one cancer, therefore it will work in the other.” These are major concerns, not only for the consumer and the doctor, but also for the company because they have to package this and get it out to many sites to make it easier for the patients to receive the therapy.

Cancer Network:Thank you again for taking the time to speak with us today about immunotherapies and where they stand in genitourinary tumors.

Dr. Slovin: My pleasure.