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Sumanta Pal: Welcome to UroToday. My name's Monty Pal. I'm a GU medical oncologist at the City of Hope Comprehensive Cancer Center. 

I'm very fortunate today to be joined by my friend/brother/colleague, Petros Grivas, who is a world-famous, world-renowned genitourinary medical oncologist at the University of Washington Cancer Center. Dr. Grivas, welcome. 

Petros Grivas: Thank you so much for having me, for the very kind words. 

Sumanta Pal: Yeah. Well, I consider you to be an expert across disease spaces of bladder cancer. But, why don't we try to approach this in a logical way? Let's start in the neoadjuvant space. So, we know that Cisplatin-based chemotherapy is a standard in this particular setting but clearly I think we want to sort of get away from that. Can you talk to us about some of the newer approaches we're taking for neoadjuvant disease? 

Petros Grivas: It's a good question. As you mentioned, Monty, many patients may not be able to tolerate Cisplatin because they're not fit enough, or kidney function reasons, and other reasons. And, of course, some patients may not respond. So, there is an urgent unmet need for novel therapies and immunotherapy is trying to meet that unmet need through innovative clinical trials. Right now, we have data from two clinical trials, Phase II trials, that are not practice-changing but definitely are very interesting and promising. These two trials are the PURE-01 by Dr. Necchi and colleagues, with three doses of pembrolizumab in Cisplatin-fit patients, actually specifically. These trials show the pathological complete response rate. So, about 40%, regardless of PD-L1 expression. 

Similarly, Dr. Powles and colleagues in the ABACUS trial with Atezolizumab, two doses in the neoadjuvant setting. This one was in Cisplatin unfit/ineligible patients as compared to the PURE-01. So, a pathological complete response rate of about 30%, regardless of PD-L1 expression. So, definitely very promising data from the Phase II trials supporting further launching of Phase III trial designs that we're now starting to try to evaluate whether immunotherapy by itself or in combination with chemotherapy could potentially increase pathological complete response rate and becoming standard of care in the future. As I mentioned before, these are ongoing clinical trials and there is no established role of immunotherapy in terms of checkpoint inhibitors in the neoadjuvant space. 

The other idea is to try to combine these checkpoint inhibitors with other agents that impact the components of the immune system. In that context, we're doing a clinical trial and we have a trial in progress abstract, here at ASCO, combining Nivolumab, an anti-PD-L1 agent with a different agent called Ipilimumab, which is an activator of natural killer cells. So, we try to activate both the innate component of the immune system with natural killer cells and the adaptive component of the immune system with the PD1 inhibition. The question is whether the engagement of both immune system populations might potentially result in a high complete response rate, pathological complete response rate. This study is ongoing and hopefully, we're going to have results in the future but overall, the field is moving forward with many clinical trials in the neoadjuvant space. 

Sumanta Pal: Very interesting. So, we could probably keep going on that end for days but let's kind of shift gears a little bit. So, we talked a little bit about the neoadjuvant space. The metastatic space is the space that traditionally has just been in the hands of the medical oncologists. In that context, CIS/GEM has really been sort of been the industry standard for a very long time. I know that Johnathon Rosenberg has been trying to build on that. Tell us a little bit more. 

Petros Grivas: It's very interesting because we have been trying for a long time to target androgenesis across tumor types and specifically in urothelial cancer. We actually did a trial back in the day with Dr. Hussein and colleagues at the University of Michigan and other sites looking at Sunitinib as switch maintenance approach. Unfortunately, this was a negative trial and switch maintenance, Sunitinib did not add benefit after first-line chemotherapy. So, the question became, if you use anti-androgenic agents concurrently together with chemotherapy, for example, Dr. Johnathon Rosenberg's' trial, Gemcitabine and Cisplatin with or without the Bevacizumab, whether you improve outcomes. The Phase II trial was very promising. Unfortunately, the Phase III trial did not show overall survival benefit with the addition of Bevacizumab in the Gemcitabine/Cisplatin backbone. It showed progression-free survival benefit but I think the primary endpoint of overall survival was not met. 

So, I think this is not a practice-changing trial. It adds to the body of literature that you have a promising Phase II but may have a negative Phase III. The question is why this happens. Is that a matter of choosing the right agent? Or patient selection? Or other reasons? I think patient selection is probably very relevant and I think we have to work harder to identify biomarkers to select those patients who might benefit from androgenesis inhibition. We have, of course, other agents that we're thinking about evaluating in that context. We have some early data from Nick Vogelzang and colleagues looking at Lapatinib in combination, potentially with immunotherapy as another approach in Cisplatin unfit patients. This idea might be tested in clinical trial designs. So, I think the concept of anti-androgenesis in urothelial cancer is not gone but I think we have to think very, very carefully how we're going to combine this agent, potentially not with chemotherapy but maybe with immunotherapy. Maybe that different partner might have something to do with efficacy because if you combine androgenic inhibition with immunotherapy you might change the vasculature and potentially impact on T-cell trafficking and might get more T-cell infiltration in the tumor microenvironment. Under this context of ideas, we might have some good rationale to combine androgen inhibition with immunotherapy.

The other interesting data set is a range phase-III trial by Dan Petrylak that showed, again, PFS but no overall survival benefit in the patients who were previously treated with platin-based chemotherapy. Again, this was not a selectable collection, it was all comers. So, overall, we have some lessons to learn from all those trials and try to learn from those particular mechanisms and try to inform our decisions for future clinical trial designs. 

Sumanta Pal: Wow. I asked you a 30-second question. I got everything I needed to know about metastatic disease there. That's fantastic. But, one topic we didn't cover in entirety, you eluded to it, is switch maintenance therapy. So, at this meeting, Matt Galsky is going to report at a Hoosier study looking at maintenance pembrolizumab. And you, along with Tom Powles, are running a major international trial looking at the same concept. Can you tell us a little bit more about that? 

Petros Grivas: The switch maintenance design is very interesting across tumor types and specifically in urothelial cancer. The notion is that Cisplatin-based chemotherapy, even Carboplatin-based chemotherapy can achieve responses and the responses can be in the neighborhood of 60% or 50% with Cisplatin-based chemotherapy and maybe 40% with Carboplatin-based chemotherapy. The problem is that those responses are not lasting forever, are not durable responses and the median progression-free survival is about seven to eight months. So, if you have a less toxic way to continue sustaining the benefit achieved with chemotherapy with a less risky or toxic combination, or single-agent therapy, you might prolong progression-free and potentially overall survival. In that context, there were two main switch maintenance trials. One is being presented by Dr. Galsky colleagues here at ASCO 2019 showing actually progression-free survival benefit which was a prominent point of the study with pembrolizumab versus placebo. In the switch maintenance design, patients who finished chemotherapy with Gemcitabine/Cisplatin or Gemcitabine/Carboplatin and had responsive stable disease. They got randomized to pembrolizumab or placebo and this trial did show progression-free survival benefit. The trial was small, about 100 patients or so. It had a crossover design, so I think it will be very hard to show overall survival benefit but the question is whether this PFS benefit is clinically meaningful.

Of course, in the context of the larger trial, the JAVELIN trial that we're doing with Dr. Powles and the team, we have a Phase III design, very similar. After first-line chemotherapy patients who have no progression, meaning stable disease or response, get randomized to Nivolumab, anti-PD-L1 agent versus observation and supported care. This trial, Phase III is powered to show overall survival benefit as a primary endpoint and progression-free survival as a secondary endpoint. So, I think these two trials are going to give us very valuable information. The question is, from the regulatory standpoint, whether overall survival is needed or not and that's something we'll have to discuss as a group now with emerging data by Dr. Galsky. 

Sumanta Pal: So, let me ask you, pretend you're talking to an oncologist colleague of yours out in the outskirts of Washington. They can't send their patient into the University of Washington for your trial. So, based on the data that Matt's presenting here, what would you recommend to them? They have a patient who's had stable disease on Carboplatin/Gemcitabine. Should they segue right onto Pembrolizumab? Or should they wait based on the data you're seeing here? 

Petros Grivas: It's a great question. I think these dilemmas are going to be more robust after the data's been presented. I think there're some considerations. Number one, how will the patient, himself or herself, perceive the benefit of delaying progression or death with no known impact of how long this patient will live? That's the perceived benefit of progression-free survival has to be balanced against the potential risk of toxicity. Toxicity can be, in terms of side effects, immunotherapy-related adverse events and also potential cost, financial toxicity, especially for the healthcare system. 

Sumanta Pal: How about maybe more of a yes or no? What would you say to that oncologist out there? 

Petros Grivas: I think it's a good question. Practically, I think, before we change practice, I think have to see the results of a larger trial. So, I would probably, in that particular patient, most likely wait until they have progression and treat at that time. The question, of course, is what is value defined by me or you may be different by the value being defined by a patient. So, I think the question is whether PFS is the right endpoint. Just for me, hard to believe that the small but very important trial like this will change practice with only PFS data. So, most likely, we don't have the answer of early versus late in a definitive overall survival benefit way, so most likely, these patients, in my opinion, will continue to be observed but I am very open to see what the discussion is after the data's been presented. 

Sumanta Pal: Okay. So, you're saying no. More or less-

Petros Grivas: More or less. 

Sumanta Pal: More or less. Okay, very good. I didn't mean to pin you down. 

Petros Grivas: Practically it's a very important you were raising. What would you do? I make this comment on purpose because these are important considerations that people have to take into account why they make a decision. So, it's important for the audience to listen to the discussion and think for themselves. What is value? And value can be defined differently from different individuals. But, the practical answer is most likely I would observe this patient. 

Sumanta Pal: Let me ask you one other question. This happens to us in clinical practice. Let's say you're dealing with that octogenarian. Creatine clearance is very modest. You talked about this great data for Pembro/Atezo in the upfront setting, for muscle-invasive disease. Let's say patient in practice, and this has happened to me before, absolutely refuses to get chemotherapy, refuses to get surgery, refuses to get anything in that particular context. Would you give this patient without any metastatic disease PD1 or PD-L1 inhibitor? 

Petros Grivas: This scenario comes every week in our clinical practice and I have been hesitant to give checkpoint inhibition to someone with localized only disease, unless they have locally advanced unresectable disease because I'm not sure how it will benefit this patient in terms of his overall or her overall survival if they have only localized disease not amenable to any surgical intervention or even radiation intervention because this patient may potentially get chemoradiation as a localized disease for blood preservation. We have many patients who get localized chemoradiation, or sometimes radiation alone if they can't tolerate chemotherapy for localized bladder cancer. But, I'm hesitant giving checkpoint inhibition for localized resectable disease just because I cannot give any other therapy. 

Sumanta Pal: That's fair. That helps me, that's something I've been struggling with. Dr. Grivas, thank you so much. I'm thrown some tough dilemmas at you, you've answered beautifully. 

Petros Grivas: One scenario I can just think of right off my head right now, you happen to have a patient who really wants to achieve a milestone, attend an important event, maybe the wedding of a kid or a grandkid. This patient has a particular time set. This patient might potentially choose to get on a maintenance therapy to delay progression to cut that particular event to-

Sumanta Pal: Oh, so we're back to the maintenance case? 

Petros Grivas: Yeah. The maintenance question. ... In his or her life. So, that can be a scenario whether a maintenance approach could be considered, but these, of course, are unique scenarios. Again, most patient, might be [inaudible 00:14:03]. 

Sumanta Pal: Awesome. Thank so much, Dr. Grivas. 

Petros Grivas: My pleasure. Thank you for having me.