Highlighting Clinical Trials | Advanced/Metastatic Bladder Cancer

Highlighting Clinical Trials | Advanced/Metastatic Bladder Cancer Part II: Current Advanced/Metastatic Bladder Cancer Clinical Trials June 26, 2018 Presented by: Dr. Andrea Apolo is the head of the Bladder Cancer section at the National Institutes of Health and a Lasker Clinical Research Scholar. Her research involves designing and implementing clinical trials to test novel agents for the treatment of urologic cancers. Her primary research interest is in developing targeted therapies for bladder cancer and rare genitourinary tumors, including angiogenesis inhibitors, agents that target MET, and immunotherapies and identifying molecular alterations that serve as targets for individualized treatment strategies.

Dr. Apolo: I'm gonna also talk about combination therapy, which I think is very important to reiterate because that's essentially what we're gonna be doing in the future is taking two things that work and combining them. And really what we're looking at when we're doing these trials is, can it be tolerated. What are the side effects? If we take one thing that works and another thing that works, then we don't always presume that it's gonna work better, but what we're seeing is that there's definitely additive effects and potentially even synergistic effect. Essentially what I wanted to talk about are the agents that can enhance the immune response. And Dr. Balar did a really great job discussing these, and these include other immunotherapies. Other immunotherapies can be vaccines, CTLA-4 inhibitors, which are also checkpoint inhibitors, adoptive cell transfer or other things. Radiation therapy so combining the checkpoint inhibitor, the immunotherapy with radiation therapy. We saw here the clinical trial that Dr. Balar was talking about combining immunotherapy with chemotherapy and combining immunotherapy with tyrosine kinase inhibitors. So can we make a tumor more immunogenic? So we had talked about the agents that can enhance the immune system. And the answer is yes. We can make a tumor more immunogenic by using the combination approach, and what this does we think is makes the tumor inflamed. It surrounds the tumor with immune cells, therefore making it more susceptible to treatment with checkpoint inhibitors. So this picture here shows a picture of all the clinical trials that are ongoing, and this essentially is changing and growing every day because there are new clinical trials that we are doing and that are being opened for combination therapy. But these are combination clinical trials. The purple shows clinical trials that are using immunotherapy plus immunotherapy. So we had talked about before CTLA-4

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

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inhibitors, vaccines, adoptive cell transfer, those are some of the immunotherapies that are being combined together. Immunotherapy plus chemotherapy, that's the light blue, and Dr. Balar touched on some of the ones that are being used in the front line setting. These are also being studied in the second line setting in the muscle-invasive setting and in the non-muscle-invasive setting. I had talked a little bit about cabozantinib, which is a tyrosine kinase inhibitor, and that's also being combined with immunotherapy, that's the orange slice. And then the red slice are other agents that are being combined with immunotherapy, such as radiation therapy or other novel agents. And the outside rim shows the second line therapies and then the inside rim is the first line therapies, so some of the trials that Dr. Balar talked about are in there. And then these combinations are being brought even to earlier states of disease, like muscle-invasive and non-muscle-invasive tumors. We have a clinical trial, a Phase 1 trial of cabozantinib plus nivolumab. Cabozantinib is a tyrosine kinase inhibitor. It's a pill that you take every day in combination with PD-1 nivolumab and this we call the doublet combination and that's the first green square. And there's also a triple combination arm that we have, and that's cabozantinib plus nivolumab and ipilimumab. And ipilimumab, we learned earlier is a CTLA-4 inhibitor. There have been studies with nivolumab and ipilimumab by itself in other tumors, and it seems that using these two immunotherapies together you can see some higher activity. But you can also see more toxicity, which is something that we have to consider. So one of the approaches that we have is how about adding another drug, capozantinib and doing a triple approach and seeing if we can potentially enhance even the already higher activity that we see with the double immunotherapy. And this is a Phase 1 trial that was presented recently and showed


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very nice responses. And we call responses when the tumor shrinks more than 30%. Very nice responses in bladder cancer and other genitourinary tumors like kidney cancer and something that I'm very interested in is also studying rare bladder tumors. And we saw very nice responses in rare bladder tumors. So this is an example of a combination approach that we take two active drugs, and we know capozantinib by itself in bladder cancer is active and we put them together and we look at the side effect profile. Is this manageable? Can the patient tolerate this? What's the quality of life? And can we use it potentially all together to see if we can get a better response? And there's trials also that are looking at well, what about sequencing these agents if the doublet doesn't work, what about adding a triple drug at that point instead of starting all together at the same time. So those are approaches that are currently ongoing right now for combination immunotherapy. So, bladder cancer has one of the highest number of mutations that when you look at the absolute number of mutations and compare it to other solid tumors. So this seems to ... We think that this is one of the reasons that it is responsive to immunotherapy, and we're learning more and more about what these mutations are. And data from the Cancer Genome Atlas project has shown that a lot of these mutations are DNA damage response gene, so these are genes that help, when the DNA is damaged, help repair the DNA. And work done here at the NCI looking at these DNA repair genes found that about 30% of patients with bladder cancer have alterations or mutations in DNA repair gene. And this can be either within the tumor or mutations that they're born with. So taking advantage of that, we can use agents that target the DNA repair gene pathway. An agent like that is called a PARP inhibitor and it's already approved in other cancers, such as ovarian cancer for patients that have BRCA1 and BRCA2 mutations and alterations. And potentially we're trying to test it now in bladder cancer, so this is an ongoing trial at the NCI where we give patients that have certain alterations that are within the DNA repair gene pathway, we give them olaparib to see if we get responses. So this is a novel targeted approach based on the DNA of the patient.


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So again, like we had mentioned earlier, when you take two things that potentially work and you combine them, maybe you'll get a higher response. And this is a trial that's currently ongoing right now of avelumab in combination with talazoparib. Talazoparib is a similar drug to olaparib, which is a PARP inhibitor to see if we can get an enhanced response in using this combination. So anyway, so this is ... COXEN is a mathematical algorithm that we're using within a clinical trial. What it does is it takes data from cell line that have been tested against certain drugs and it applies that data to tumors to see if we can predict what the tumor is going to respond to in terms of therapy. We have a clinical trial at the NCI with using COXEN where we biopsy a patient and then we look at the gene expression of the tumor and then we run it through the COXEN algorithm, and we essentially get a waterfall plot. You see here, there's the blue and then there's the red. And the blue means all the agents that are that the tumor is potentially sensitive to and the red are the agents that the tumor is potentially resistant to. And we meet as a molecular tumor board, and we decide from the blue can we use a combination approach, use multiple agents from the blue to see if we can treat the patient with these agents that were given to us by the COXEN algorithm. So this is a personalized approach to treating cancer, and this is an ongoing trial at the NCI right now.


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Another common alteration is the fibroblast growth factor receptor, FGFR3 alteration. Urothelial carcinoma or bladder cancer has a high rate of alterations of the FGFR3 pathway. There's currently no approved targeted therapies for bladder cancer using these kinds of approaches, but FGFR agents that target FGFR alterations have been studied in bladder cancer, and there have been preliminary results showing that these agents are potentially active. Because FGFR3 again, like I said, is prominently found in bladder cancer. About 15 to 20% of bladder tumors have FGFR3 mutations. So, this year at GU ASCO initially we saw the Phase 1 results of an agent, erdafitinib, that's an FGFR agent that was tested at multiple doses. And if you look at the overall response rate, that's circled in red, we see regimen number three had the highest response rate at 42%, and that was the highest dose that was tested. So therefore, next slide ... At ASCO, which is our yearly oncology meeting, one of the largest meetings that we have where we discuss these findings, this trial, a Phase 2 trial of erdafitinib this FGFR3 agent, was reported. And what I have here is the results. If you look at the orange are the results of the erdafitinib. In 99 patients receiving the highest dose level we see a 40% response rate. Now that's something for us to get excited about because when you look at the overall response rate for pembrolizumab, which is the standard of care and I'm using the Phase 3 data that was published in the New England Journal of Medicine, where pembrolizumab was compared to chemotherapy and the overall response rate was 21%. Erdafitinib, now this is in a select group of patients that have the FGFR3 alteration, the pembrolizumab trial was in all comers, they had, the pembrolizumab showed a 21% response rate and with the erdafitinib, this FGFR3 agent, we saw an overall response rate of 40%. So that was really exciting.


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So, I wanted to talk a little bit about antibody-drug conjugates cause this was another trial that was presented at ASCO. Enfortumab vedotin is an antibody conjugate that targets Nectin-4. The antibodydrug conjugate is made up of three parts. The green here is the antibody. In this case it's again, antinectin-4. The payload is the active drug and that's the red, the little red circles. And then the linker in the yellow, it's what the red circles are attached to, and that's a really important part also of this agent because that has to hold onto the agent while it's [pulling 00:33:13] in circulation, and it doesn't release the agent until it's inside the cell. So, this antibody binds to the cell, gets engulfed by the cell and when it's inside the cell, poof, it releases the cytotoxic agent, and then that's how the tumor dies. So the goal of the antibody-drug conjugate is to highly select tumor antigen and to have less off-target effects, less side effects compared to chemotherapy. The payload, which is the red part, which is the active part, must be toxic to the cell. And nectin-4, which is highly expressed as a tumor antigen that's highly expressed in bladder cancer is really a great tumor antigen to use because it doesn't necessitate tumor screening. It can essentially be given to everybody because about 95% of bladder cancer tumors express nectin-4. And the payload, which in this case is MMAE plus the linker is the vedotin part. And it's a microtubule-disturbing agent that is essentially like a chemotherapy agent that is 200 times more potent than a chemotherapy vinblastine that we often use in bladder cancer in combination. So what was initially reported was last year at our meeting, at our yearly meeting, the results of enfortumab vedotin Phase 1 was reported and again they looked at different dosages. And they found that the highest dose level which is 1.25 mg/kilo, which is the second column, had the highest overall response rate with 53% of patients responding. That was really exciting.


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And this year at our annual meeting we had an update of 112 patients with bladder cancer that received the highest dose level of enfortumab vedotin, and we saw an overall response rate, so if you look at the orange column, of 40%. And that was really exciting to us because this is all comers. They weren't selected, and when we compare it to pembrolizumab again, this is comparing across trials. These are different clinical trials, but we're just comparing the results from the immunotherapy pembrolizumab. The overall response rate was 21% there, and the overall response rate we saw with the enfortumab vedotin was 40%. So that was really exciting. However, the duration of response was about 5.75 months, so six months compared to pembrolizumab where the duration of response of the responders, the patients that actually had tumor shrinkage was not reached. It was pretty long. So this slide shows the management of bladder cancer depending on stage. So the first one is the non-muscleinvasive. These are the localized bladder tumors. Then there are the invasive localized bladder tumor that's muscle-invasive disease, and then today our webinar has focused on metastatic bladder cancer. And we see here that in the first line setting we have atezolizumab and pembrolizumab as new agents that we can add to be used in the metastatic setting, and in the second line setting we have five immunotherapy agents, atezolizumab, pembrolizumab, nivolumab, durvalumab and avelumab as new agents that we're using now in the second line setting. And what is next? Well, we are very excited about the findings in erdafitinib, this FGFR3 agent that was reported at ASCO this year. So the FDA is also excited about it, so I think that we may be seeing an approval for this very soon, but this is still under review. And larger trials are currently ongoing right now to assess the efficacy with a control arm when you compare it to standard of care. Enfortumab vedotin possibly also may be an agent or contender that we may be seeing also being reviewed by the FDA right now for potential, what it's role is in second line treatment of metastatic bladder cancer. And combination therapy. And, you know, which combination is going to show the highest efficacy and tolerable toxicity. A lot of trials are currently ongoing to ask this question. So now I'm gonna talk about rare bladder cancer histology. So just really I wanted just to mention that bladder cancer is not only transitional cell carcinoma or urothelial carcinoma. It is predominantly urothelial carcinoma. 90% of bladder tumors here in the United States are urothelial carcinoma.


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But there are also some rare histology such as squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. And generally we manage these based on data from other tumor types with the same cell type even though we don't have data for bladder cancer rare histology itself because it's really hard to run clinical trials with really small numbers and accrue patients to these clinical trials. But what we are finding now is that more clinical trials are enrolling patients with rare tumors with rare bladder cancer histology, and we're learning a lot more about the activity. And we have found that checkpoint inhibitors are active in some of these rare bladder cancer histology. And since I had them enrolled in our clinical trial when I did the combination of cabozantinib, nivolumab and ipilimumab and I saw activity. We're currently working on opening a larger trial where we're gonna use this triple combination for these rare tumors and assess the efficacy. And this is one of many clinical trials that are kind of using this either, using immunotherapy alone or a combination approach in rare bladder tumors and rare GU tumors to see what the efficacy is. So this is actually a very exciting time where we're actually including these rare tumors in clinical trials, which I think is very important for us to learn more about how to treat these patients. So the last slide is the future of bladder cancer therapy. We know that so far immune checkpoint inhibitors are the most important clinical advancements in bladder cancer treatment over the last 30 years. In advanced bladder cancer clinical trials are now focused on enhancing the effectiveness of immunotherapy through combination. Another approach is to develop novel treatment methods for patients who do not respond to immunotherapy, including targeted therapy based on the tumor's DNA and antibody-drug conjugates, using a sophisticated drug delivery mechanism. And more bladder cancer clinical trials are now incorporating rare bladder tumor histology as exploratory arms to test new therapies.

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