Treating Advanced Bladder Cancer - Petros Grivas

July 5, 2019

Petros Grivas, MD Ph.D. and Alicia Morgans discuss the rapidly changing landscape in the treatment of advanced urothelial cancer.  Dr. Grivas discusses the era of immunotherapy in advanced bladder cancer and the development of new drugs, new combinations, and biomarkers.  


Petros Grivas, MD, Ph.D. is an Associate Professor and the Clinical Director of the Genitourinary Cancers Program at the University of Washington, and an Associate Member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center with expertise in genitourinary cancers such as bladder cancer, prostate cancer, and testis cancer.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois. 

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Alicia Morgans: Hi. I'm thrilled to have here with me today Dr. Petros Grivas, a medical oncologist and Associate Professor of Medicine at the University of Washington, where he is also the Program Director of the Genitourinary Cancer Program at the University. So thank you so much for being here.

Petros Grivas: Very honored to be here. Thanks for having me, Alicia.

Alicia Morgans: Of course. So, Petros, we have talked before, always really exciting conversations. I would love to hear your take today on the landscape that we're looking at, particularly as it comes to immunotherapies, how we're thinking about the current trials, future trials and how we are aiming for ultimately getting to that regulatory process. What are the endpoints we're looking for? So, why don't you start us off?

Petros Grivas: I think it's a great question and we live in an era where immunotherapy has attracted so much attention. In specifically, urothelial cancer, we have the data with immunotherapy in advanced disease, platinum-refractory advanced urothelial cancer with five checkpoint inhibitors approved by the FDA. Two of them are approved for cisplatin-unfit patients in the advanced urothelial cancer first-line setting. So definitely significant data there. Now we have combinations are being evaluated in clinical trials we have biomarkers, and they're being tested PD-L1 and beyond, tumor mutational burdens in expression profiling, DNA repair gene mutations which is great. Now the field is moving to try to incorporate immunotherapy earlier on in the disease setting.

So, the usual paradigms you start in advanced disease and if you have some good data you try to extrapolate and to move this earlier. So in the neoadjuvant and adjuvant space of muscle-invasive disease, but also in the non-muscle invasive disease space. Briefly, we'll mention it; we have some very interesting promising data, not practice-changing yet, but very promising in the non-muscle invasive disease setting with pembrolizumab in the Keynote-057 trial, we had data that was presented at ESMO and also GU ASCO. Great presentations by Arjun Balar and colleagues around the wheat and others in the Keynote-057 trial, suggesting activity with a clinical complete response rate of about 40%. It goes specifically, I think 39% for patients who got pembrolizumab for BCG unresponsive, high-risk, non-muscle invasive disease after having received adequate BCG therapy-

Alicia Morgans: At 12 weeks, is that what that was or-?

Petros Grivas: -This was, exactly right Alicia, this was early on, and the question that you're alluding to is; what is the durability of response or duration of response?

Alicia Morgans: Yes.

Petros Grivas: Because the FDA is going to look at the data at 12 months, and that's why the benchmark is there. Based on the data from the International Bladder Cancer group, [inaudible 00:02:44] and others have published a nice paper, looking at clinical response rate about one year, in 12 months, and 30% or so is the benchmark. I think the question is whether the durability of response exists. So we'll have to wait.

There's also a trial with atezolizumab. The SWOG, I think S1605 trial, in that setting, that Peter Black and Parminder Singh, the thing they are leading in, in SWOG with atezolizumab in the same disease irresponsive high regional muscle-invasive diseases heading.

So very interesting data, not practicing yet but definitely worth looking forward to it in the future.

Alicia Morgans: Absolutely.

Petros Grivas: And to your point, you know if you move to neoadjuvant or adjuvant setting, there are multiple clinical trials.

So, just to put some context in our discussion, right now, who is the center of care? For patients who are fit, eligible for cisplatin, neoadjuvant cisplatin-based combination chemotherapy, is still the standard of care. And if you have a clinical trial, great, you can go for it. If not, I tend to use either accelerated or dose-dense M-VAC, about four cycles, for node-negative disease in the neoadjuvant setting, dose-dense M-VAC is given every two weeks and I tend to give all the drugs on day one for convenience, the accelerated fashion, and then give growth factor on day two-

Alicia Morgans: -and I think that's actually, for us we do the same. I think that's actually quite well tolerated. Just to mention that clinical pearl particularly, I think patients appreciate doing it all on the same day and tolerate it quite well.

Petros Grivas: I fully agree with you and you have had good success with that so far?

Alicia Morgans: Very good success, yes, we've been using it for a few years.

Petros Grivas: Absolutely. And the other regiment that I'm sure you have used is gemcitabine with cisplatin. Are you using the every 21-day cycle with days one and eight?

Alicia Morgans: We do, I actually tried to get M-VAC to everybody that I possibly can. So it's a rare patient that I give gem/cis but we do the 21-day regimen, yes.

Petros Grivas: Interesting, and you're saying when you use M-VAC, you use the accelerated in two weeks?

Alicia Morgans: Yes. Yes, every time.

Petros Grivas: So both of those regimens are used and there is a very interesting trial ... we're awaiting the results from it. It is a so-called SWOG 1314 COXEN trial.

Alicia Morgans: Yes.

Petros Grivas: The results are pending and I think it's an interesting trial because it's randomized, patients are getting either gem/cis, or dose-dense M-VAC. It is not powered to compare to others regimens, but will give some insights and hints-

Alicia Morgans: Yes.

Petros Grivas: -and the prominent point of this COXEN trial is to validate the predictive value of a gene expression profiling biomarker and the tissue of the TURBT. So it will be interesting to have a look at, and in the context of clinical trials in this neoadjuvant space.

Alicia Morgans: Absolutely. And maybe we can identify patients who may not benefit from chemotherapy at all, really identify a subgroup that we need more interventions for, though of course those patients getting chemotherapy may still benefit from things like checkpoint inhibitor therapies in the neoadjuvant setting.

Petros Grivas: You're absolutely correct. And I think we look for the holy grail, which is biomarkers. And to your point, you know, we're doing so many studies, but it's hard to find their biomarker and it's in that such valuable, you know, tumor biology and heterogeneity of disease. However, to your point, Alicia, you mentioned immunotherapy and there are definitely clinical trials specifically in cisplatin-ineligible, cisplatin-unfit patients, right now they go straight to cystectomy because the data with carboplatin are not of high-level evidence. I personally ... I want to hear your opinion. I do not use carboplatin with a neoadjuvant or adjuvant setting for bladder cancer.

Alicia Morgans: I don't either. Unless there is a cry from the surgeon saying; "I absolutely need this" but even in that setting if they're not ultimately going to go to surgery, that's an unresectable patient who I may think about using checkpoint therapy, for example, or something else or you know, we can use carboplatin in that setting. It just depends on what you're PD-L1 status is going to be. Almost never use carboplatin in the local setting.

Petros Grivas: I agree. This question that you alluded to about locally advanced or resectable versus unresectable. In the latter category, you can potential justify carboplatin gemcitabine in that context or PD-1, PD-L1 inhibitor or of course clinical trial-

Alicia Morgans: Clinical trial, if you can, yes.

Petros Grivas: If you can, right. And, and this is ... we feel that we're very excited about and I discussed with you before about a trial we're doing through PrECOG, PrECOG is affiliated with ECOG-ACRIN and we're doing a trial looking at anti-PD-1 as a single agent and also anti-PD-1 compound with an anti-KIR antibody trying to activate both T cells and natural killer cells and K cells, and we're going to look at the cell density before and after the uterine cystectomy. We started on going in multiple sites right now, like UT Southwestern, Montefiore, I think Lee Moffitt and Virginia are open, and we're opening more sites including the University of Washington and Seattle Cancer Care Alliance. So we're very excited about those clinical trials.

Alicia Morgans: Absolutely. And I would say that some people would say, well, if you're using this in a setting where these patients are not eligible for cisplatin chemotherapy, you wouldn't want to delay their time to cystectomy by giving them this therapy. And you're really not. I think that was something that you were very conscious of as you were making the trial and it's only a few weeks I think of this neoadjuvant therapy before you end up going to cystectomy.

Petros Grivas: You're absolutely correct. We actually do only two doses, four weeks apart, so patients can be scheduled for surgery and there's a window of opportunity that you can give two doses of a checkpoint inhibitor alone or with a combination. Patients can still go for surgery soon after so it doesn't interfere with their trajectory in the time flow there and sometimes you're all just are very happy because they have scheduling logistics, challenges, and having this opportunity to do these trials is very, very important. This is corroborated by data that Dr. Andrea Necchi and Dr. Tom Powles presented recently with single-agent pembrolizumab or single-agent atezolizumab that have very promising pathologic complete response rates in patients in the neoadjuvant setting. The data is not practice-changing yet. However, they look very promising and they definitely support a further evaluation in Phase III trials.

Alicia Morgans: I agree. I think what's so interesting about those studies is that Andrea Necchi, for example, in the PURE-01 study actually enrolled patients who were cisplatin-ineligible, who are aware of that, but for various reasons in Italy that he mentioned, they don't necessarily get the standard of care, cisplatin regularly in the neoadjuvant setting, and so these patients were receiving at least something in the neoadjuvant setting were able to enroll in a clinical trial and even when cisplatin-eligible were given pembrolizumab in a neoadjuvant setting and had some really nice complete responses, which was impressive I thought.

Petros Grivas: I fully agree with you and initially I was telling Andrea that I was impressed that the IRB allowed-

Alicia Morgans: Yes.

Petros Grivas: -cisplatin-ineligible patients in that setting, but it went through and there was some difference between the PURE-01 in the ABACUS trial. If you look carefully, the stage, I think one of them allowed PT-4 - I think the ABACUS. While the PURE-01, I think it T-2 and T-3 there were some differences. Of course as you've mentioned already, Alicia, in cisplatin-eligible patients in the PURE-01 and cisplatin-ineligible unfading ABACUS. I think there was some differences, probably the PD-1 expression frequency and the cutoff and different tests being used-

Alicia Morgans: Yes of course.

Petros Grivas: -in the different trials and of course the number of cycles. I think, if I remember correctly, the PURE-01 had three doses when the ABACUS had two doses, so you know it's hard to compare across studies that I will not do that. But, I would say collectively, both trials support further evaluation of those agents and there is some data already from combination. Dr. Chris Goins, who is in Case Western, he did a study through [Who's There 10:24] Group, and he actually combined them set up in cisplatin and pembrolizumab and the pathologic downstaging defined as PT-1 or less, about 61%. So definitely encouraging data supporting, again, further evaluation even for chemo-immunotherapy combination in the Phase III design, in the future in the neoadjuvant setting.

Alicia Morgans: Very interesting. But I'm still very much tied to that pathologic complete response as being the most meaningful and the most, I guess, impactful in terms of thinking about prognosis. And when you think about endpoints and what we're aiming for, where are you in terms of thinking through that with the neoadjuvant setting and as we're kind of putting all of these trials into effect, particularly as ultimately the goal for some is to try to not remove the bladder, which means we'll never get a pathologic complete response. It will just be a clinical complete response that we have at the end of the day.

Petros Grivas: You raised some very important points and there are many challenges with staging in bladder cancer and you make a great point that clinical complete response might not necessarily be the same with pathologic complete response. I think it's a very cautionary tale here. However, you know, as we move forward in the modern era, we have clinical trials that look at patients, for example, DNA repair gene mutations, like ELCC 2, ATM, RB-1, you know, and [inaudible 00:11:45] genes based on work from Jonathan Rosenberg, Eli Van Allen and Betsy Plimack and others.

In those clinical trials, there are three of them right now, they evaluate the idea, always in the context of a clinical trial, I would not do it outside the trial, to potentially avoid cystectomy in patients who have a complete response, clinical complete response and they have DNA repair gene mutations that may portend sensitivity to cisplatin-based chemotherapy. These trials; one is led by Betsy Plimack and her colleagues, I think Dan Geynisman in Fox Chase; the other is by Matt Galsky, Mount Sinai; and the third is a corporate of good trial by Dr. [inaudible 00:12:21] at Memorial Sloan Kettering. All of these three trials are going to provide data for this question and they're going to evaluate the clinical complete response rate as a potential surrogate, but I, as I always say, we should not do anything like that outside the context of clinical trials.

Alicia Morgans: True. Agreed.

Petros Grivas: Moreover, to your point before, I think you know, think about the regulatory approval of in the neoadjuvant trials, we're struggling with that because we have some prognostic relations between a pathological complete response and overall survival from the neoadjuvant trials. In the past, for example, the SWOG-8710 trial. However, we don't have any, you know, contemporary ... let's say evidence of pathologic complete response, correlated with overall survival with immunotherapy that I call it was with chemotherapy neoadjuvantly. So I think it's a question and they're going to be workshops with FDA and NCI discussing further the idea of pathologic complete response as an endpoint, for registration and/or event-free survival or disease-free survival and whether maybe both of them can be relevant because of overall survival. It's a long one. It takes forever. And you know-

Alicia Morgans: Thank goodness in bladder cancer it's a long one now. I would say that hasn't necessarily always been the case, but it's transforming into one for sure. And especially if we're talking about neoadjuvant, it'd be really nice if we could move past even the pathologic complete response and if biomarkers ... people like you, can put together some biomarkers for us that can help define, you know, a test that does not require removal of the bladder to do this.

Petros Grivas: I think you have a great point there and you know, we all look for biomarkers. The challenge we have, Alicia, is among different clinical trials we have different biomarkers, different assays, different time points, different endpoints and it's hard to harmonize and align those. So, we have some discussions with the NCI and FDA on how to harmonize that in a clinical trial design and how can we learn collectively from different trials, from each patient and that's a really high bar but we should look for and track for it.

The other point to make is for blood preservation, and there are significant discussion ideas about concurrent chemoradiation in select patients, and properly selected patients, you know, with small select tumors, with not extensive multifocal CIS without significant hydronephrosis. And there is a very important clinical trial, but actually is launching hopefully in the next week or so-

Alicia Morgans: Yes.

Petros Grivas: -is the corporative group SWOG-NRG are leading and the ECOG-ACRIN alliance collaborate-

Alicia Morgans: Yes.

Petros Grivas: -the SN1806, and you are part of it yourself. You're leading the basic report outcomes and quality of life trials at work, which is very critical. And this trial is randomizing patients to concurrent chemoradiation plus/minus atezolizumab and ipilimumab in their bladder preservation setting. So, a very interesting trial and we'll provide biomarker work.

Alicia Morgans: Absolutely. And so you know, there are leaders and actually in all of these arenas from different cooperative groups, so I'm the lead from ECOG, but of course Ron Chan I think is sort of the overarching leader of the quality of life group. And then Parminder Singh, of course, is leading the whole thing, and you're leading a section yourself. I'm very excited about this trial because in terms of bladder sparing, it actually helps to consolidate the field's thoughts around some agreed-upon ways to deliver radiation, and to provide concurrent chemotherapy, that I think we've been lacking with all of these Phase II trials that are really using disparate methods. And then also, in the context of defining what's acceptable and what might be our standards, we're randomizing people to plus or minus atezolizumab to really get that understanding as well. And then we're also defining what is the quality of life of these people as they report it, not just by CTCAE complication rate, and not just by the assumption that, well keeping your bladder must be better. So I think that all of these together are going to give us a really robust picture of a treatment algorithm that may or may not include checkpoint.

I believe it probably will, but may or may not. But even if we're just studying bladder sparing as a modality or trial modality therapy as a modality, the largest trial of that type. And really, I think should help to push this methodology into community sites where many of these patients will be enrolled rather than keeping them solely in the ivory towers of our academic institutions.

Because if this is a safe modality for these people, and it looks from the data as if it's been for years, and I've adopted this method, and I'm sure that you have too. Really, we need to put it out in the community where patients can access it rather than keeping it in a place where it's so challenging for them to even access the care that could allow them to save their bladder. So, very exciting trial I think.

Petros Grivas: I fully agree with you. I think you hit so many important points and this is very critical to go out there as a message that we have to improve on the three "D's"; discovery, development, and delivery. And were suffering, you know, with delivery and access to care. And I think we'll have to make these modalities available to the broader community. And as you mentioned before yourself, this a huge effort from multiple cooperative groups and even in the translational, you know, the endpoint of the trial we have Joshua Meeks and Felix Feng and you know, work to work with me. The four of us, and Josh is actually the leader of the group to do translational research in the trial, similar to what you're doing, you know, in quality of life and PURE-01. So hugely important trial and you know, we all want to go behind it and support it for accrual.

And I think overall, you know, if anything, can give us some more information. The other relevant point is, you know, the role of patient advocates and advocacy, you know, from the patient side. And I think it's very exciting to have the Bladder Cancer Advocacy Network, the BCAN, we phrase it as BCAN, like a beacon of light and beacon of hope.

Alicia Morgans: Yes.

Petros Grivas: And now we have amazing efforts also in Canada and in Europe. And actually in this meeting in the EAU, in Barcelona, we have a fantastic collaboration between the European coalition for bladder cancer and the BCAN (Bladder Cancer Advocacy Network) for the world, you know, a global organization now advocating for bladder cancer. And there is a meeting here on Monday, on March 18, which is really exciting to have this synergistic collaboration between both sides of the Atlantic Ocean and try to advocate all together for more research and more funding and more support and more awareness for bladder cancer and upper tract urothelial cancer, urethra cancer. I think all of this, you know, is very, very important points and based on advocates can help us in those goals.

Alicia Morgans: Really a new era in bladder cancer, in bringing together researchers, clinicians, patients, their loved ones together around this topic and pushing the envelope in terms of therapy and awareness generally. So, wonderful to speak with you about all of these things today. I really appreciate you sharing your expertise and your perspectives.

Petros Grivas: Thank you so much for having me, Alicia. And every time I talk to you, I learn more myself. So thank you for having me here today.

Alicia Morgans: Thank you, Petros.