Defining BCG-Unresponsive and The Pathway to Clinical Trials in Treating NMIBC - Ashish Kamat

June 5, 2019

Ashish Kamat, MD discusses the focus of the International Bladder Cancer Group, discussing the pathway to developing the definition of BCG-unresponsive. Today the unified definition of BCG-unresponsive disease essentially denotes those patients for whom any more BCG is futile.  This has opened the door to many ongoing clinical trials.  The discussion moves to review these trials, including Nadofaragene firadenovec (Adstiladrin®) therapy, a modified vector that is put into the bladder and allows the patient's bladder to make its own interferon alpha. The phase two study results had really exciting response rates at about 30 to 35%, but low toxicity. The phase 3 study was completed. We should have the data in the near future. They also discuss KEYNOTE-057 and SWOG-1605.  It is an exciting time in the development of treatments to improve patient outcomes in NMIBC.  


Petros Grivas MD, Ph.D. a medical oncologist at Seattle Cancer Care Alliance with expertise in genitourinary cancers such as bladder cancer, prostate cancer, and testis cancer. He is the Clinical Director, of the Genitourinary Cancers Program at the University of Washington Medicine and an Associate Professor of the Department of Medicine, Division of Oncology at the University of Washington School of Medicine.

Ashish Kamat, MD, MBBS, President, International Bladder Cancer Group (IBCG), Professor of Urology & Cancer Research, MD Anderson Cancer Center, Houston, Texas

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Petros Grivas: Hello, I'm Dr. Petros Grivas. I'm a Medical Oncologist at the University of Washington and the Clinical Director of the Genitourinary Cancers Program at the University of Washington and the Fred Hutchinson Cancer Research Center. It's my pleasure and honor to host today Dr. Ashish Kamat who is the Professor of Urology at MD Anderson Cancer Center, and he's also the President of the International Bladder Cancer Network as well as International Bladder Cancer Group, and a true leader in the field, so we're very honored to have him here today. 

Ashish, welcome.

Ashish Kamat: Thank you for having me. 

Petros Grivas: It's a pleasure to have you here today, and there is so much going on in the field of bladder cancer. Just to set some context here for the audience, can you talk a little bit about your work with International Bladder Cancer Group, defining the different endpoints and status of disease in non-muscle invasive bladder cancer and different benchmarks and metrics of success for different drugs and agents in this status of disease based on your recent publication a few years ago.

Ashish Kamat: I'm glad you asked that question because there's been an explosion of clinical trials and studies in this field, and a lot of it is obviously because we understand the biology of the disease a lot better. To be honest with you, their biggest roadblock to clinical trials and drug development was the fact that the disease was not clearly understood from a regulatory standpoint. Our group, the International Bladder Cancer Group, along with a group from GU ASCO several years ago, led by Seth Lerner, came together at the behest of the FDA, actually, and came up with unified definitions to kind of make the playing field in noninvasive disease level for the different players that wanted to come in. One of the biggest advances that we made and, again, helped the FDA that has incorporated this into that draft guidance that now is final as of February, is the definition of what is BCG-unresponsive disease. Before this, any patient that failed BCG or had a tumor recurrence after BCG therapy was considered a BCG failure and that, as you know, is a very heterogeneous mix of patients. It's hard to develop clinical trials. It's hard to make sense of results from clinical studies, whether they're intravesical immunotherapy or systemic immunotherapy. Because of that, the unified definition of BCG-unresponsive disease essentially denotes those patients for whom any more BCG is futile.

Those are patients who have had adequate BCG, so at least five or six of the induction course of BCG and at least two of three of a maintenance course of BCG and then still have persistent or recurrent high-grade tumor within6 to 12 months. If you take that cohort of patients, in those patients a single arm study is acceptable by regulatory agents such as the FDA because the only control arm truly is radical cystectomy and you can't probably randomize in a blinded fashion, do radical surgery versus intravesical or systemic therapy. It really was the introduction of the definition and the creation of this pathway to a drug approval that has helped our field and will help our patients.

Petros Grivas: I fully agree. I think it's an important context for any discussion that is being done, in the non-muscle invasive bladder cancer setting because before that consensus and there was significant confusion, to your point, about the field and what benchmark we should use. Could you tell us a little bit more about the metrics and specific complete response rates, the rates of survival? What is meaningful that you think it meets the high bar or of regulatory approval across the board for specifically BCG-unresponsive disease?

Ashish Kamat: I think one way to look at that is clearly what is beneficial to our patients and what do we as clinicians think is beneficial to the field. That coupled with a certain bar that is relatively arbitrary, and has been set by different experts and the FDA, has to all factor in the risk/benefit ratio. If you look at absolute numbers as a clinician, what we think is meaningful is about a 50% response rate at 6 months, that's durable to 30% at a year and 25% in 18 months. But again, we have to take that into context looking through the eyes of our patients. If we have a drug that is only 20% effective but there's a biomarker that can help us identify which 20% that is effective in, then personally I think that drug is something that we should have used, available for use and approved. On the other hand, if we're looking at a drug that has a 50% response rate and you can't tell which patients would respond or not respond, then I think the durability of the response is very important and that's why most studies that present initially a 6 month or a 3 month response rate, it's too early to really say whether the drug will be useful and we need to wait for the longer term results, 12, 18 months follow up.

Petros Grivas: That's a great point. With that background and very relevant context, I want to ask your opinion about the study that you have been involved in and you have done great work with regarding the KEYNOTE-57 trial that is being presented in various meetings. We saw some results in ESMO, and SUO, and GU ASCO. What's your opinion about the study and the study results so far?

Ashish Kamat: Just to summarize, KEYNOTE-57 is a study of pembrolizumab as a single agent in patients who have truly BCG-unresponsive disease. We presented this data at ESMO in 2018 for the first time, and it's being presented here in the US again. Essentially, it's looking at the first cohort of patients, the cohort of patients that had pure CIS in the bladder, not the papillary-only disease. That's relevant because this cohort of patients is the one that the FDA, for example, will look at in deciding whether a drug should be approved or not approved for the particular indication. They're roughly ...

Petros Grivas: This is CIS with or without papillary.

Ashish Kamat: Correct. It's carcinoma in situ with or without papillary disease, not pure papillary disease. In this cohort of patients, it's about 103 patients, when you looked at the 3-month data, and it's obviously not complete patient cohort yet, but in the initial evaluation of the data, the 3-month response rate was 38.8%, which is actually quite encouraging. It's not the 50% bar that we would like to see with intravesical agents, but it's quite encouraging because as we have seen in other studies with such agents, pembrolizumab and systemic disease, it appears to be a durable response. More than 80% of the patients who had a response at 3 months actually have a durable response for more than 9 months after treatment at the last time at follow-up. That's exciting data. Now clearly we have to weigh this with the potential systemic toxicities of these agents, which, as you know, is not negligible. Intravesical therapies sometimes have lower efficacy, but much lower toxicity. Systemic agents have sometimes higher toxicity and the efficacy might not seem to be meeting the benchmark, but it's the durability that really is exciting. Overall, exciting results. Early results, yet. We need to wait and see what the final data shows.

Petros Grivas: I agree with you, it's a very, very exciting data, still early but very, very promising. Again for context, there is a similar trial run by SWOG, the SWOG-1605, and you have been in SWOG for many years yourself. You have contributed a lot. What's your opinion about that study, and it's still enrolling from what I know, right?

Ashish Kamat: It is and it's actually enrolling really well at this point. It's run by Peter Black who's a urologist up in Vancouver. That study has a very similar design. It's BCG-unresponsive patients and atezo is the drug that's being used. The only difference is a little subtle difference. They have to wait until their 6-month results, and this is something again with discussions with the FDA. We don't have any data from that as of yet. It's because of the fact that they have to wait for 6 months and they're ongoing and enrolling. I really don't know what the data is at this point. I personally don't expect it to be different from the pembro study, but in other systemic studies, pembro appears to have more activity, so who knows. We really need to wait and see what it shows.

Petros Grivas: That sounds really, really interesting. Any other trials that you are interested in or awaiting results, especially phase 2 and phase 3 trials in that particular disease status of BCG-unresponsive patient?

Ashish Kamat: Oh gosh, there's so many. We don't have enough time to go through all of those, but if you look at the whole gamut of therapies, intravesical gene therapy, for example, is very exciting. There's the Nadofaragene firadenovec (Adstiladrin®) therapy, which is essentially ... It's not gene therapy, per se, but it's a modified vector that's put into the bladder and allows the patient's bladder to make its own interferon alpha. This and phase two results had really exciting response rates. Again, 30, 35%, but low toxicity. The phase 3 study was completed. We, again, don't have the data yet to present. We should have that in the middle of this year. There are other agents that are also being looked at that are oncolytic gene therapies. There's Interleukin 15. There is supercharged BCG, for example, which is relevant because we might be facing a BCG shortage in the next few months in the United States. There's a lot of activity going on.

In the systemic arena. There's also a lot of activity going on, and I really think that when we talk about checkpoint inhibitors and BCG-unresponsive disease, this 38, 40% response rate that we're seeing with single-agent systemic therapy is actually encouraging because it does provide a window of opportunity. Both Merck, and BMS, and AstraZeneca, everybody really with the different drugs have been developing trials, looking at systemic IO agents, combining it with an intravesical agent to help release the antigen and provide that local milieu. For example, the BMS folks have a study, 9UT that many of us are participating in that looks at both nivo as a single agent, but also nivo plus BCG in the BCG-unresponsive agents. That, again, is open, it's accruing and is one of the trials that I'm really excited about.

Petros Grivas: That sounds really exciting and dynamic field. After a long time of not that many developments in this disease state and non-muscle invasive disease. Now we see some potential options down the road, assuming the data look promising. What about BCG-relapsing and BCG-naïve setting? Anything there in terms of data we should look for?

Ashish Kamat: Yeah, you mentioned, you hit the nail on the head. There's so much activity going on in this space that actually in UroToday at the Bladder Cancer Center of Excellence, we have a special section dedicated to these trials just updating what trials are going on, on a periodic basis. I would recommend that our listeners go to that site and look at it because that field changes every week, as you know. In the BCG relapsing in the earlier phase, so not quite as dire consequences as BCG unresponsive disease, but the relapsers or the persistent disease, there too, similar studies are being developed. None of them are open yet but there's a lot of discussion in that space and similar agents, systemic, intravesical, are being looked at in earlier phase diseases. I think what's happened is because the FDA has created this clear pathway for registration, most people are focusing on that in order to get their drug studied, approved and into the market. But now that they've seen so much activity in that particular disease space, people are moving into the other disease spaces. So it's great times for both us and our patients.

Petros Grivas: I fully agree with you. You have done such a great job overall in the field and you have done a great job with UroToday summarizing this development, so I agree with you to encourage our listeners to go to that website and look at these weekly updates, as you mentioned. 

Ashish, it was a pleasure having you here today and hosting you. You are a true leader in the field, and I'm sure that many more developments will happen soon. Thanks again for having us and thank you for the listeners that you join us today. 

Ashish Kamat: Thank you, Petros.