Highlighting Clinical Trials | Advanced/Metastatic Bladder Cancer

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Jun 26, 2018 - atezolizumab plus bevacizumab, which is a VEGF antibody and comparing it to atezolizumab alone in the fir
Highlighting Clinical Trials | Advanced/Metastatic Bladder Cancer Part I: The Basics of Advanced/Metastatic Bladder Cancer Clinical Trials June 26, 2018 Presented by: Dr. Arjun Balar is Assistant Professor of Medicine in the Department of Medicine and Genitourinary Medical Oncology program in NYU Langone Perlmutter Cancer Center. He leads a team of medical oncologists, nurse practitioners, social workers and other care providers who are dedicated to treating those who have genitourinary cancers, particularly bladder cancer. Dr. Balar's research focuses on bladder cancer and immunotherapy, treatments that harness the body's own immune system to fight the cancer, as well as molecularly targeted therapies.

Dr. Balar: I'm joined by Dr. Apolo and we'll hopefully over the next 45 minutes we'll give you, all of the attendees on this webinar a flavor of how we approach clinical trials and therapeutics in bladder cancer, where the field is headed over the next several years and how we hope to ultimately improve the lives of patients who are diagnosed with this awful disease. You know, my opening slide that I have here really highlights the history of bladder cancer therapy over the past 30 years, leading up until, you know, the advent of some of the more exciting drugs involving the immune system. And what we have on this particular slide are survival curves for what we call our best treatments for patients who have advanced bladder cancer who are treated in the first-line setting, and that's the curve that you see up top, which is treatment with cisplatin-based chemotherapy showing that on average patients survive about 12 to 15 months with cancer when they receive cisplatin chemotherapy. And then what you see on the bottom is that for the patients who initially respond to cisplatin chemotherapy but then their cancer ultimately progresses, you know, this was the context and the background that we had leading up to the immune agent showing that for many of our patients the

Highlighting Clinical Trials | Advanced/Metastatic Bladder Cancer Dr. Andrea Apolo, Dr. Arjun Balar & Rick Bangs

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outcomes were not any better by giving second line chemotherapy. What you see here is a survival curve for patients who are treated with vinflunine, which is a medication that's really only used in Europe. But showing that it was hardly much better than receiving what's called best supportive care. That's what BSC stands for on its own. And this was a backdrop where we were really enthusiastic and excited about developing new treatments because the outcomes, you know, before immunotherapy weren't so great. So, you know, let's fast forward to about two or three years ago when some of the first trials, clinical trials involving new immunotherapy drugs were first being tested. A lot of research has been conducted over the last two or three years. It's virtually impossible to cover everything, but I wanna cover some of the high points that, you know, lead us to where we are today. And one particularly important clinical trial was a Phase 2 Imvigor 210 trial, which tested atezolizumab, which is a PD-L1 immunotherapy drug in patients who had advanced bladder cancer and who had progressed on platinum chemotherapy showing that patients had responses to treatment, which means that the cancer shrunk, and that for a sizable population of these patients, their cancer actually stayed shrunk, which means that, you know, we could have long-lasting responses. It appeared from this trial that patients who had high levels of the PD-L1 protein in their tumor expressed on immune cells had the best survival. And so, this was a promising first step in improving the outcomes of patients who have advanced bladder cancer. The next clinical trial that really proved to us that immunotherapy was better than traditional chemotherapy after progression on platinum was the Phase 3 KEYNOTE 45 trial. And in this particular trial, patients who had advanced bladder cancer who had progressed on prior platinum chemotherapy were randomized to receive pembrolizumab immunotherapy, which is a PD-1 antibody versus standard chemotherapy, which is what we used previously in the past. And what we found in this particular trial is that the survival for patients was significantly better if they received pembrolizumab rather than chemotherapy. And what's also particularly noteworthy is that in this particular curve, and this is a survival curve, what it shows is

Highlighting Clinical Trials | Advanced/Metastatic Bladder Cancer Dr. Andrea Apolo, Dr. Arjun Balar & Rick Bangs

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that the patients who received pembrolizumab immunotherapy, which is the turquoise line, that there is a flattening of the curve. And what this indicates to us is that there are patients who are surviving for a long period of time, many months, two years or more with cancer, indicating that with immunotherapy we can lead ... This can lead to durable shrinkage of cancer that can be long lasting. And so, over the last several years, we've seen a dramatic change in how we treat bladder cancer, and there's only more changes to come. In the past three years what we have seen is the advent of five different immunotherapy drugs in the second line setting after progression on platinum chemotherapy. And then more recently, the approval of two of these immunotherapy drugs, atezolizumab and pembrolizumab, as first-line treatment in particular for patients who can't receive our so-called gold standard best chemotherapy cisplatin. What we are starting to see is that for a sizable population of patients, if they respond to immunotherapy, the responses can be quite long lasting. This is a slide that really just highlights the five different drugs, you know, where their current lines of indication are. So, with atezolizumab and pembrolizumab, which are the first and the last drugs mentioned here, the current indications by the U.S. FDA are for first and second line treatment. In the first line setting they are restricted to patients who are not eligible for cisplatin based chemotherapy. And then three other agents that target PD-1 or PD-L1 are all approved in the second line setting and these include nivolumab, durvalumab and avelumab. And the evidence from all the trials that were conducted that led to the approval of these drugs show that the outcomes in terms of how well they work and how safe the drugs are appear to be very similar across the trials. So obviously, the next question we ask is that, so we've made a lot of advancements over the last two or three years. What are the next steps? And this is where you know, our continuing research efforts through clinical trials are quite particularly important. What we have learned over the last you know, 30, 40 years of doing research in cancer is that we always need to be testing new agents or new combinations or new approaches to cancer, and we use our evolving technology as well as understanding of science to help guide that approach. What we know now from many studies is that between individual patients the mechanisms for cancer to evade the immune system is quite varied. And that certainly explains why, you know, patient number one may respond to the immunotherapy drug but patient number two who has the same so-called same bladder cancer doesn't respond to immunotherapy drug or other drug. There's certainly differences between both the individual patients as well as their individual cancers that explains these differences. And so, the critical thing here is that rational combinations will absolutely be required to be able to generate an effective anti-tumor immune response in those patients.

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And there's several ways of approaching this. And we can only find out the right answer through clinical trials. Some of the ways of doing it is through combining with other checkpoint inhibitors, so the drugs that are approved are ones that block the PD-1 pathway. But then there's also reason to combine with traditional chemotherapy, and what we are learning from lung cancer clinical trials in particular is that combining immunotherapy with chemotherapy is actually particularly active and shows that it actually improves survival. Radiation is an interesting combination. There are other targets, including angiogenesis, which is the mechanisms by which cancer cells [derive 00:11:47] blood vessels for growth. And then also targeted therapy. And targeted therapy is a term reserved for drugs that target specific genetic defects that are present in cancer. And there's a great deal of science that supports using any of these approaches to improve the outcomes of patients with cancer, and then ultimately, we test this in clinical trials. So, what I'm going to do over the next two or three slides is simply highlight some of the larger national or multinational clinical trials that I believe will lead to some major improvements in either how we treat patients or major improvements in terms of how we understand cancer and perhaps may lead to newer treatments in the future. So broadly speaking, you know, I have grouped on this particular slide immuno-immuno based combination which means using multiple immunotherapy drugs together. And then also at the bottom we have immuno-chemo based combinations where we're combining immunotherapy with chemotherapy to see if that actually is a way forward in terms of improving outcomes. So CTLA-4 for those on the webinar that may not be familiar with this drug. So CTLA-4 is also another immune checkpoint that is present on T cells and is another negative regulator of the immune system. What we know is that when we target a CTLA-4 and the PD-1 pathway together, that it improves outcomes not only in melanoma, which we know about, but also in kidney cancer, as well as in lung cancer. And so, we're now testing this combination in two randomized Phase 3 trials in advanced bladder cancer and in the first-line setting. And so, in these slides that I'm presenting, I'm reviewing clinical trials that are currently ongoing that are testing whether using combination immunotherapy is better than chemotherapy in the first line setting.

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DANUBE is a randomized Phase 3 trial that is looking at single agent durvalumab, which is a PD-L1 antibody compared to durvalumab plus tremelimumab. And in this arm, tremelimumab is the CTLA-4 antibody. And then we're comparing to traditional chemotherapy, which is either cisplatin or carboplatin chemotherapy. And we're trying to see if here that the combination of immunotherapy drugs is better than chemotherapy. And this is the DANUBE study. The CHECKMATE 901 study is a similar study that is also testing combination immunotherapy, but the arms are a little bit different. And in this particular study it's nivolumab plus ipilimumab. Ipilimumab is the CTLA-4 antibody here, and it's being compared to nivolumab plus cisplatin chemotherapy with gemcitabine. And then finally all of those arms are being compared to standard chemotherapy alone, either with cisplatin or carboplatin based therapy. And so essentially what these two clinical trials are designed to do is to test if whether combination immunotherapy is a better way to treat patients with advanced bladder cancer compared to chemotherapy. Another particular area that I'm interested in is combining drugs that target the angiogenesis pathway, which is VEGF. It turns out the VEGF also has immune properties in the tumor microenvironment in terms of how the immune cells are able to recognize cancer as foreign. And there's some very interesting clinical trial data from kidney cancer showing that if you combine these two approaches, that, that also leads to improvement in responses against cancer as well as improvement in survival. So, we are testing this as part of a randomized study in advanced bladder cancer, also in the first line setting where we're combining atezolizumab plus bevacizumab, which is a VEGF antibody and comparing it to atezolizumab alone in the first line setting. And the hypothesis here is that combining both VEGF and PD-L1 blocking antibodies will improve outcomes in the first line setting for patients who have advanced bladder cancer.

Highlighting Clinical Trials | Advanced/Metastatic Bladder Cancer Dr. Andrea Apolo, Dr. Arjun Balar & Rick Bangs

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And so, the last slide I have here is to talk about immuno-chemo based combinations. As I mentioned before just a few minutes ago, we are learning some very exciting data from advanced lung cancer trials that platinum chemotherapy plus immunotherapy actually is better than chemotherapy alone. And certainly it may be the most attractive way to treat patients with advanced cancer because it leverages both the immune effects of the immunotherapy while it also leverages the ability for chemotherapy to get cancer quickly under control and then finally, it may leverage the ability of the two treatment paradigms to work together, and there's certainly some science to support that chemotherapy might potentiate immune responses and therefore allow the immunotherapy to work better. There are two very large clinical trials that are currently ongoing. One of those is KEYNOTE 361 and the other is IMVigor 130. They are essentially identical studies in terms of design, but both are testing two different immunotherapy drugs. In KEYNOTE 361 is pembrolizumab and in IMVigor 130 is atezolizumab. But the basic question here is to see if we can combine chemotherapy with immunotherapy as a path to improve outcomes for patients who have advanced bladder cancer. The most critical thing that you should take away from all of these clinical trials that I've presented to you is that in these clinical trials there is the opportunity obviously to receive, you know, what we believe is potentially the next future standard of care. But at the very least, there is nothing less than the standard of care that any patient receives on a clinical trial. And so, it always improves access to the most cutting edge therapies when your physician thinks that a clinical trial may be right for you. So, I'm gonna hand off the baton to Dr. Apolo, who will now be talking about other investigational approaches, including those in the second line setting. So, for those patients who have at least had prior chemotherapy and then are considering treatment after prior platinum chemotherapy.

BCAN would like to thank our sponsors for their support.

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