Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from Houston at MD Anderson Cancer Center. And it's my distinct privilege and pleasure to be joined today by a good friend and an expert when it comes to all things bladder cancer, Andrea Apolo, who's Chief of the Bladder Cancer Section at the NCI and is here today taking time off from her busy schedule to talk to us about the changing landscape of systemic therapy for urothelial cancers. Thank you and welcome, Dr. Apolo.

Andrea Apolo: Thank you so much for inviting me to be here today. I'm really excited to talk about all the new therapies that are out there right now. The way that I like to divide this talk is by the management of bladder cancer. And I like to do that by nonmuscle-invasive bladder cancer, muscle-invasive bladder cancer, and metastatic bladder cancer. And usually, drug development starts in the metastatic setting. And for decades, all we've had is combination chemotherapy for patients with metastatic bladder cancer. But in 2016 and 2017, the FDA approved five checkpoint inhibitors, including atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab which the NCI took part in its clinical development for the second-line treatment of metastatic urothelial carcinoma. And also two of these were approved for patients that are cisplatin-ineligible.

In 2019, erdafitinib was approved and also enfortumab vedotin was approved. And this year pembrolizumab was also approved for patients with BCG unresponsive nonmuscle-invasive bladder cancer with carcinoma in situ, ineligible for, or refusing cystectomy.

Let's go into the data of the approvals. For the second- and third-line therapy for metastatic urothelial carcinoma, back in 2018, the Phase II data of erdafitinib was presented for patients with metastatic urothelial carcinoma with FGFR3 alterations. And these are the waterfall plots and we saw a remarkable 40% response in patients that harbored these alterations with the treatment of erdafitinib. And the median duration of response was 5.6 months. Based on this data, in April 2019, the FDA granted accelerated approval of erdafitnib for platinum-refractory metastatic urothelial carcinoma patients with FGFR2 and 3 genetic alterations.

Enfortumab vedotin was the next agent to be approved. This is an antibody-drug conjugate that targets nectin-4 with the payload of MMAE. The study initially, the updated was presented at ASCO 2018. And again, it showed this also was remarkable finding, a 40% response, but this was in all-comers. These were all patients with metastatic urothelial carcinoma that were treated with enfortumab vedotin in the second-line setting, showed a 40% response. And what was remarkable was that a lot of these patients had visceral metastases, including liver metastases and they were showing a response. And this patient population is usually very difficult to treat. The median duration of response was 5.75 months. And based on this data, the FDA granted in December of 2019, accelerated approval for enfortumab vedotin for platinum and checkpoint inhibitor refractory metastatic urothelial carcinoma.

Another antibody-drug conjugate is sacituzumab govitecan that has also shown promising results in metastatic urothelial carcinoma. This is also an antibody-drug conjugate. However, it's directed toward Trop-2, an epithelial antigen expressed on many other solid tumors. And with the payload of SN-38, which is similar to irinotecan. This agent was tested in the second-line setting in metastatic urothelial carcinoma and it showed also very nice response with a 31% response in patients in the second-line setting.

Moving on to first-line therapy for metastatic disease. There are several trials asking the question, okay, so chemotherapy is the first-line therapy for patients with metastatic urothelial carcinoma. What about if we combine checkpoint inhibitor with chemotherapy versus just giving the immunotherapy by itself? How does it do compared to chemotherapy? And there are several trials asking this question.

At ESMO 2019, the IMvigor130 trial, which was asking this question about atezolizumab alone, atezolizumab with chemotherapy versus chemotherapy presented its preliminary results of the combination of chemotherapy plus atezolizumab versus chemotherapy. Those two arms predominantly. And what we saw was that there was an improvement in progression-free survival from 6.3 months to 8.2 months when atezolizumab was added. There was also an improvement in overall survival in the early data that we saw with the 11-month follow-up with a median overall survival of 13.4 months with the chemotherapy arm and 16 months with the combination arm. But we do need longer follow up in order to interpret this data.

Recently, there were two press releases regarding the two other large trials in the first-line setting combining chemotherapy with checkpoint inhibitor. The first one was the DANUBE press release. And this is a study of durvalumab in PD-L1 high patients versus durvalumab plus tremelimumab versus standard of care chemotherapy. And unfortunately, the press release said that the trial did not meet its primary endpoint of overall survival with durvalumab alone in PD-L1 high patients or the combination with tremelimumab versus chemotherapy.

Similarly, just this month, there was a press release for KEYNOTE-361 that discussed that pembrolizumab also did not meet its pre-specified dual primary endpoint of OS and PFS compared with standard of care chemotherapy. We're yet to see this data. And the hope is that we'll be able to see it really soon as it's presented in upcoming meetings.

Moving on to maintenance therapy for metastatic bladder cancer. At ASCO 2020, the JAVELIN Bladder 100 study was presented. And this study took patients with metastatic urothelial carcinoma that were treated with chemotherapy cisplatin gemcitabine or carboplatin and gemcitabine and achieved a response. It could be a CR, a PR or stable disease, and randomized these patients to receive avelumab versus best supportive care with the primary endpoint of overall survival. This is the data that was presented. There was a survival benefit to receiving avelumab immediately after completion of chemotherapy in this patient population versus best supportive care.

Moving on to perioperative therapy for muscle-invasive bladder cancer. There are three large trials right now, three large Phase III trials asking the question about adjuvant checkpoint inhibitor in patients with muscle-invasive bladder cancer. I'm running one of them through the Alliance. That's the AMBASSADOR trial that asked the question of pembrolizumab versus observation after a cystectomy in high-risk muscle-invasive bladder cancer patients.

The IMvigor010 had data presented at ASCO 2020. And what it showed, unfortunately, was that IMvigor010 did not meet its primary endpoint of disease-free survival. Overall survival follow-up is still ongoing, but this trial was essentially negative.

Moving onto BCG unresponsive high-risk nonmuscle invasive bladder cancer. The KEYNOTE-057 study was a single-arm trial of pembrolizumab in patients with nonmuscle-invasive bladder cancer with high-risk disease that are BCG refractory that have either carcinoma in situ with papillary disease, with or without papillary disease or papillary disease alone. The patients receive pembrolizumab and were evaluated for a complete response. The data showed that in 102 patients, there was a complete response in 40% of the patients that were evaluated at three months. And based on this data, the FDA granted approval of pembrolizumab for BCG unresponsive high-risk nonmuscle-invasive bladder cancer with carcinoma in situ, with or without papillary tumors who are ineligible or refuse cystectomy.

This is the summary of the new treatment options for patients with bladder cancer. With the approval of checkpoint inhibitors back in 2016 and 17, we have two new approvals, erdafitinib, and enfortumab vedotin as of last year and possibly another approval of another antibody-drug conjugate. And in the first-line setting, we have atezolizumab and pembrolizumab and a new approval of pembrolizumab for nonmuscle-invasive bladder cancer with carcinoma in situ in BCG unresponsive patients that are ineligible for or are refusing cystectomy. And the question for this year is what's next? Avelumab maintenance and maybe chemotherapy in combination with checkpoint inhibitor in the first-line setting. With that, I'll stop and we can discuss a little bit more what these findings mean for our community.

Ashish Kamat: Thank you so much, Andrea. That was a really nice succinct summary of all the recent approvals and advances in bladder cancer. If I could ask you a couple of questions, with everything that's now available for our patients, it's obviously great for them to have all these choices and it's great for us to be able to offer these choices, but could you take us through how you go through the counseling session with your patient now that we have all these different options available for patients with, let's say metastatic first-line bladder cancer?

Andrea Apolo: Yeah. That's a good question. How do you put this into clinical practice? And I think for the second-line treatment, these are standard and we've been giving these for a while with treatment with checkpoint inhibitor. For patients in the second-line setting when they harbor an FGFR3 alteration, I favor erdafitinib because this is a select group of patients that have an extra treatment option. I do favor doing erdafitinib first before moving onto enfortumab vedotin which is a treatment option. And then enfortumab vedotin would be a third treatment option. And this is really important because there are a lot of clinical trials right now in the metastatic setting so you do have to make sure that unless you're offering these agents in addition to something else, if you're going to offer something different, make sure that the patients have received a checkpoint inhibitor if they're FGFR3 positive, erdafitinib and enfortumab vedotin before moving on to a clinical trial.

Now, in terms of avelumab, that one that's a really, really new data. And does it change practice? I think is kind of what's on everybody's mind right now. It doesn't apply to patients that did not respond to chemotherapy, which is a population that really doesn't have a lot of treatment options. If you don't respond to platinum-based chemotherapy, the tumor tends to be very aggressive and often these patients may not respond to subsequent therapies like checkpoint inhibitors. And we don't know yet about how these patients do with erdafitinib or with enfortumab vedotin. But in terms of offering immunotherapy immediately after receiving chemotherapy, if they did have a response, which is what the data was in, I still think that it warrants a discussion with the patient about the data.

One of the things and I'll go back to the slide where the JAVELIN 100 data was presented. One of the things about this study is that the patients that received best supportive care, only about half of them received checkpoint inhibitor at the time that they progressed. There may be multiple issues with that. It could be access. This was an international trial where checkpoint inhibitor as a second-line setting is not necessarily approved in that country or it could be that the disease progressed so quickly and the patient just wasn't able to get it.

Because with my patients, I do very close follow-up, I think it's reasonable to offer the data, tell them what the data is and offer them to either receive checkpoint inhibitor immediately afterward or just often to wait and enjoy their holiday and then they can go on to a checkpoint inhibitor therapy at the time of progression. Because I think the issue is access to checkpoint inhibitor and we don't really know the question that if you do have access to checkpoint inhibitor and a 100% of the patients in the arm in the best supportive care arm would have gotten checkpoint inhibitor, what the data look like. I think that data is still missing.

Ashish Kamat: That's a very interesting point that you raise and one that I was going to sort of ask you about because clearly, once patients are on chemotherapy and are eligible in some ways for avelumab, that's a little bit different from what is done in the US with atezo and pembro after chemotherapy. Do you think that there is a role to consider maintenance therapy with the other checkpoint inhibitors based on this data? Or would you need to see more clinical trials?

Andrea Apolo: Well, we do have data of the maintenance therapy with pembrolizumab and that data also showed an improvement in progression-free survival. It did not show an improvement in overall survival. It was a smaller study and it did allow crossover. The patients, as soon as they progressed, they were allowed to receive pembrolizumab, so it was a little bit of a different design. Honestly, I do think that all agents are similarly active. They have a little bit different half-lives, but in general, the activity is very similar. I do apply data from one trial to another checkpoint inhibitor if the data is available for one checkpoint inhibitor. Because sometimes it has to do with trial design, eligibility of a clinical trial, and exclusion criteria, how things turn out. But in general, these agents are very active and I've used all of them. And I've seen really terrific longterm activity with all of them.

Ashish Kamat: Right. Another question that often people bring up and comes to mind is, well, with all the activity that's going on with these agents and EV and then erda, what should be the practice of us in the field when we see our patients, as far as profiling of the tumors? And what do you do? Do you profile or send all tumors for analyses at the first meeting with the patient? Do you wait to see how they do on standard chemotherapy? What has been your practice?

Andrea Apolo: Well, my practice is a little bit biased in that I work in a research center. We've been sequencing patients for years and even before the data on erdafitinib came out, just because we do have a lot of targeted therapy clinical trials that could potentially become available to the patient if they have an alteration. I have a little bit of a biased view in that yes, I sequence everybody, but I have that technology available where I am at the NCI. Not all community practices have the sequencing technology available. But with the data that we have now, with the availability of erdafitinib as a second-line agent for patients with metastatic urothelial carcinoma, I do think that in the metastatic setting, patients should be sequenced because you don't want to miss this as a potential therapy for these patients.

Ashish Kamat: Excellent. Excellent point. In the interest of time, obviously you and I could chat forever, but in the interest of time, any closing thoughts for our audience or viewers?

Andrea Apolo: Yeah. I think there's a lot of clinical trials that are currently ongoing, both Phase II, Phase III, using immunotherapy in combination with targeted therapy, in combination with chemotherapy. And I think a lot of these are being done right now in the muscle-invasive setting, in the perioperative setting, either as neoadjuvant therapy or even in bladder sparing approaches. There's a lot of exciting data that is up and coming and we await the results of these trials because I really think although the landscape is changing, I think it's just, it's going to continue to change. And it's a really exciting time to be doing research in bladder cancer.

Ashish Kamat: Indeed. Absolutely. It's great for not just us, but especially our patients that we have so many choices to offer now. And once again, thank you so much for not only doing a lot of these trials but taking time off from your busy schedule to spend this time with us. Stay safe, Andrea.

Andrea Apolo: Thank you. And this was a pleasure. It's always fun to talk about bladder cancer and anytime you want to talk about bladder cancer, I'm more than happy to stop and chat.