Petros Grivas: Hello. I am Petros Grivas. I am a medical oncologist at Seattle Cancer Care Alliance and associate professor of medicine, at the University of Washington, and associate member of the Fred Hutchinson Cancer Research Center. I’m really honored and thrilled today to host Dr. Shilpa Gupta. Dr. Gupta is an associate professor of medicine at the University of Minnesota, and she’s a leader in the field of urothelial cancer. Welcome, Shilpa.

Shilpa Gupta: Thank you, Petros, glad to be here.

Petros Grivas: It’s great to have you and I would like to pick your brain regarding the emerging data across the spectrum continuum of bladder cancer landscape. Let’s start the discussion about neoadjuvant therapies. We all know that cisplatin-based chemotherapy is a standard of care, as neoadjuvant therapy in patients who can tolerate cisplatin. But some patients may not be fit enough for cisplatin and that some others, may not respond. What are your thoughts about emerging clinical trials in this neoadjuvant space?

Shilpa Gupta: So we saw the data from the ABACUS trial using atezolizumab, a single agent which showed encouraging activity, and we also saw the data from the PURE trial with pembrolizumab. It wasn’t in a cisplatin-ineligible population, but those patients did not get cisplatin, and we saw encouraging data. Your trial of combination I-O therapies will gain more insight into this field, but I think that’s a good field to try immunotherapy combinations, prior to cystectomy and we’ll see what the data shows.

Petros Grivas: I agree with you, it’s a very exciting field and we do this trial with a combination of nivolumab and lirilumab, looking at the NK cells and T-cells, but you have a clinical trial that just finished accumulating, is that correct?

Shilpa Gupta: Yes, so that’s the BLASST-1 trial, which is a Bladder Cancer Signal Seeking Trial. That is for cisplatin-eligible patients. We added nivolumab to the standard of care GemCis, four cycles prior to cystectomy, and we just completed accrual of 41 patients and we are really excited about the preliminary data, and looking forward to seeing the final data once everyone has cystectomy.

Petros Grivas: That’s exciting, and this also provides a plethora of opportunities for biomarker development, and I’m sure you’re going to look at different biomarkers in this study, right?

Shilpa Gupta: Yes, absolutely. We did the whole genome sequencing, we did the molecular subtypes, PD-L1 assay. We also have stored plasma for our circulating for DNA, and we’ll get a lot of insights into which patients are really the responders and who are resistant to these combinations.

Petros Grivas: That’s very exciting and all these neoadjuvant trials provide the platforms to potentially aligning some of those biomarker assays down the road.

Shilpa Gupta: Right, absolutely.

Petros Grivas: I agree with you. So if you think about adjuvant trials, we have the three large randomized trials with pembrolizumab and AMBASSADOR trial that Dr. Apolo is running, we have atezolizumab and nivolumab trials. These are not, of course, reported yet, but there is a significant … I would say interest in the adjuvant setting, then we have the POUT trial, in the upper triangular urothelial cancer with adjuvant chemotherapy. Any comments about those trials that somewhat are ongoing some others are reported.

Shilpa Gupta: Yeah, I think it would be really exciting to see what the adjuvant immunotherapy trials show because so far, the adjuvant chemotherapy trials and bladder cancer haven’t really provided a great guidance. The POUT trial was really a landmark trial. For the first time, we saw an upper tract disease benefit of platinum-based regimens but, everybody who gets a nephroureterectomy may not be eligible for cisplatin-based chemotherapy. So, it’s not necessarily applicable to all patients. So I think looking at what the immunotherapy adjuvant trials will provide us with would be very important moving forward.

Petros Grivas: I agree with you and I know there is some discussion about the adjuvant use of carboplatin-based on the POUT trial, but there was a small proportion of patients, and there was a discussion about the interaction test not impacting which regimen confer benefit. But if you look at the first plot, the confidences of all cross to one, do you use adjuvant carboplatin or not in your practice for upper tract resected disease in the upper tract?

Shilpa Gupta: I don’t use it that much. But when I can use cisplatin and I try to use it for the upper tract adjuvant.

Petros Grivas: Otherwise you go for a clinical trial if someone is not fit enough for cisplatin.

Shilpa Gupta: Right.

Petros Grivas: Got you. I think as you mentioned before, cisplatin-based chemotherapy is indeed the standard of care in the neoadjuvant setting. And for the adjuvant setting, it has it all for patients with a high stage.

Shilpa Gupta: Yes.

Petros Grivas: Maybe PD3, PD4 or node-positive disease.

Shilpa Gupta: Yeah.

Petros Grivas: If they never received neoadjuvant chemo. So chemotherapy-naive patients.

Shilpa Gupta: Right.

Petros Grivas: Moving to metastatic disease, a lot of excitement there, multiple trials are ongoing. And in that context, you have also done some trials in this particular space. Any comments regarding some novel targets beyond PD-1 and PD-L1?

Shilpa Gupta: Yeah, sure. So immunotherapy has been the game-changer for metastatic disease, but we know that bladder cancer is a very heterogeneous disease and there’s a lot of promising targets. We have been exploring the role of androgen receptor in bladder cancer.

Petros Grivas: Interesting.

Shilpa Gupta: And we did a phase I/Ib trial exploring the use of enzalutamide targeting AR and GemCis in first-line metastatic urothelial cancer. And we found that the standard dose is of enzalutamide and GemCis were well tolerated. There were no DLTs. And interestingly we found that, the patients with a high level of AR expression, had really very good clinical activity. We had one female patient who had a complete response, and she stayed on enzalutamide maintenance for over 10 months and now she’s complete responsive, complete remission for over three years since stopping the trial.

Petros Grivas: Oh wow.

Shilpa Gupta: So we want to now explore in our perspective, a bigger trial combining enzalutamide with immunotherapy and or chemotherapy because we do believe that, androgen receptor is a valid target. And as a companion study, we are looking at molecular efficacy of enzalutamide pre clinically, looking at fresh bladder cancer tissues and doing ex vivo organ cultures and looking at enzalutamide. And we’ll gain a lot of insights with our basic science colleagues from that.

Petros Grivas: That’s very exciting. And having this opportunity, to take fresh tissue from the patients and do the ex vivo work in organoids or PDX models can be very useful. And this is just to clarify, metastatic tissue or primary tissue?

Shilpa Gupta: So these patients are the ones who are undergoing TURBT or a radical cystectomy.

Petros Grivas: Okay.

Shilpa Gupta: So these are not metastatic patients.

Petros Grivas: Got you.

Shilpa Gupta: But we want to establish a proof of principle about if enzalutamide can target the androgen receptor and how active is androgen receptor.

Petros Grivas: Very interesting. So these are patients who have localized disease and they may get surgical procedure.

Shilpa Gupta: Right,

Petros Grivas: You get the tissue to do all this ex vivo work and evaluate the target activity.

Shilpa Gupta: Right.

Petros Grivas: Outside the clinical context and then pull it together with a clinical trial data separately.

Shilpa Gupta: Absolutely.

Petros Grivas: Very interesting work.

Shilpa Gupta: Thank you.

Petros Grivas: And of course here at ASCO we have very exciting data sets. We have, for example, data from Dr. Rosenberg looking at the CALGB or Alliance trial. Looking at the phase 3 randomized design of gemcitabine cisplatin combination chemotherapy with or without bevacizumab. Anti-angiogenesis. Any comments on this trial and how do you perceive the results of this study?

Shilpa Gupta: Yeah, I think the trial did not meet the primary endpoint overall survival benefit, but it does provide us a lot of insights because we’ve known that VEGF is a very valid target, and you yourself have done work with sunitinib in bladder cancer. And it’s an exciting target. It’s expressed in bladder cancer. So it would be good to gain insights from this trial, to which patients can derive benefit and offer a personalized approach.

Petros Grivas: I agree with you and to one of those examples that you have a very promising phase to try out, with a promising overall survival signal. But the phase 3 trial unfortunately did not meet the overall survival benchmark, and so progressive overall benefit but not overall survival benefit.

Shilpa Gupta: Yes.

Petros Grivas: So, it seems like you will not change practice, but to your point, it’s going to provide useful insights and that we should congratulate the author as you said.

Shilpa Gupta: Yes.

Petros Grivas: For that results. And biomarkers would be very useful to know and, in the future data set to look at biomarkers and see if, whether some subsets of those spaces may benefit.

Shilpa Gupta: Absolutely.

Petros Grivas: Switching gears from the first line to the suites maintenance design.

Shilpa Gupta: Mm-hmm (affirmative).

Petros Grivas: And they’re two big trials. One is the phase III trial with avelumab, versus best supportive care. Which has finished accrual reversal pending in the smaller trial, but by Dr. Galsky, looking at pembrolizumab versus placebo in cross over design as a switch maintenance approach, and the data is being presented here at ASCO. Any comments on this trial?

Shilpa Gupta: Yeah, absolutely. We were fortunate to participate in both the trials at our institution and I’m a collaborator on Dr. Galsky’s trial. It’s the first trial in the field to show that, using switch maintenance with immunotherapy early on, after patients get first-line chemotherapy and achieve at least stable disease, can confer a PFS benefit. And I think that makes a lot of sense because, as a standard of care, patients who have some response to first-line chemotherapy, we only offer them surveillance and we know most of these patients recur. And using immunotherapy early on in a switch maintenance setting is a very effective strategy, and this trial will suddenly propel the field forward for more combinations.

Petros Grivas: I think it’s a very exciting study. I fully agree with you. And if anything gives you some proof of principle that these agents could potentially be used sequentially, it’s a small study of course.

Shilpa Gupta: Yes.

Petros Grivas: And overall survival will be very hard to be shown with a small sudden crossover design, but definitely an interesting study to look at. And even if it does not change practice, it’s still I think is provoking and provides significant information.

Shilpa Gupta: Yes.

Petros Grivas: About the sequence of chemotherapy and immunotherapy, and definitely Dr. Galsky has to be congratulated with his team.

Shilpa Gupta: Yeah.

Petros Grivas: What about antibody-drug conjugates. Do you think that these agents are going to be in the armamentarium of advanced urothelial cancer?

Shilpa Gupta: Absolutely. We saw the data with enfortumab vedotin that Dr. Rosenberg presented and, looking forward to Dr. Petrylak’s data this meeting. But to see a drug that is active in heavily pretreated patients, including patients who had prior immunotherapy with around 44% response rate. That’s very exciting. Because the bar is really 20 to 25%, which we really get excited about. And I think the unique activity of this drug that we see clinically and in the data that has been presented so far is in the liver. Patients with liver metastasis who typically don’t respond to immunotherapy that well, but EV has a very specific activity in the liver metastasis.

We don’t know the details why it has to do with the mechanism of the drug, the way it’s delivered, but it’s really exciting to see even in patients who were pretreated with immunotherapy, this drug has significant activity because that’s an unmet need right now.

Petros Grivas: You said unmet need and I think with your point, having an agent that can target liver metastasis in this setting of previously treated patients, platinum-refractory, immunotherapy refractory disease is a big deal. So we look forward to Dr. Petrylak’s data and also there’s data from the other antibody-drug conjugate. The sacituzumab govitecan.

Shilpa Gupta: Yes.

Petros Grivas: Also has shown significant activity in those pre-treated patients.

Shilpa Gupta: Yes, and in the side effect profile of these two agents is different. But that is another antibody-drug conjugate that I think is promising and we want to see more of the phase II study that is ongoing. And I think because these two drugs have non-overlapping toxicities, one could still use both in sequence, and it would be good to see more data from that study.

Petros Grivas: You raise a good point because both the antibody, the linker, and the toxin are different. Different markers of factions. There is in theory at least, no reason to have cross-resistance between these two antibody-drug conjugates.

Shilpa Gupta: Yeah.

Petros Grivas: So potentially if those agents go forward in urothelial cancer, could both have a role, one after the other.

Shilpa Gupta: Yes.

Petros Grivas: So we’ll see how the phase II and phase III data pan out.

Shilpa Gupta: Yeah.

Petros Grivas: What about targeted therapies and FGF receptor inhibition?

Shilpa Gupta: Yeah, so now we have the first targeted therapy approved erdafitinib which is the FGFR inhibitor and, it’s very exciting to see the field moving forward. And we have as a practice for standard of care, started sequencing our patients, instead of waiting when patients actually progressed on other therapies. And I think it adds a good agent in our pool of drugs that we have especially for patients who have not responded to immunotherapy or don’t have any other options. So it’s exciting.

Petros Grivas: I fully agree with you. It’s very exciting. And in the field of urothelial cancer, we haven’t seen a lot of advances for almost three decades and now we have immunotherapy, targeted therapies, FGF receptor inhibitors, antibody-drug conjugates. So, the sequence might start to become a question that was not before, until recently. So let’s give you a scenario. In the absence of a clinical trial, let’s say someone is away from a clinical trial, there’s not eligibility, and you have a patient who already progressed on platinum-based chemotherapy after some … Let’s say stable disease or response in the second-line setting.

This patient can potentially get a checkpoint inhibitor or if they have a genomic alteration in FGF receptor 2 or 3, they might potentially get erdafitinib. So if someone has the same mutation, who has the highest response rate with the FGF receptor 3 mutation let’s say, would you give this patients second line in the absence of a clinical trial? Erdafitinib or checkpoint inhibition? Any thoughts about that?

Shilpa Gupta: That’s a very good point, Petros. I think we want to move towards more and more precision medicine and if a patient does have a molecular marker, you might want to try that drug first because checkpoint inhibitor can always be given later. And as you know, single-agent checkpoint inhibitors are great when they work, but they only work in about a quarter of patients. So, you want to get the maximum mileage for the drugs that have a higher probability of working. And I would want to extend the responses with the FGFR inhibitor and then resolve the checkpoint inhibitor for later.

Petros Grivas: I think it’s really exciting to have all this emerging data and I look forward to having more discussions with you in the future meetings. I would like to thank you again for coming here today, and I would like to thank the audience for our attention.