Treatment Strategies in Advanced Urothelial Carcinoma - Stephen Boorjian
March 29, 2022
Stephen Boorjian, MD, Carl Rosen Professor of Urology, Chair, Department of Urology, Director, Urologic Oncology Fellowship, Mayo Clinic, Rochester, MN
Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center
ASCO GU 2022: First Line Avelumab in PD-L1+ve Metastatic or Locally Advanced Urothelial Cancer Patients Unfit for Cisplatin: The ARIES Trial
ASCO GU 2022: Final Results of a Multicenter Prospective Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy in Patients with High-Grade Upper Tract Urothelial Carcinoma
ASCO GU 2022: Meet-URO12 Phase II Study of Niraparib Plus Best Supportive Care vs BSC Alone As Maintenance Treatment in Advanced Urothelial Carcinoma Patients Whose Disease Did Not Progress After First-Line Platinum-Based Chemotherapy
Sam Chang: Hello, everyone. We are quite fortunate to have Dr. Steve Boorjian join us today. Steve is the Chair of Urology at Mayo Clinic in Rochester and is actually the Past President of last year's ASCO GU meeting. This year, he is actually the moderator for the Rapid Abstract Session, focusing on urothelial carcinoma. So, we are quite fortunate to have him here today. My name is Sam Chang. I'm a urologist at Vanderbilt in Nashville, Tennessee. Again, Steve, thank you for spending some time with us today. It's always a pleasure to be in the company of greatness when I'm here with you. So, tell us a little bit about what these rapid abstracts are generally about, and perhaps we can focus on some of the highlights of them.
Stephen Boorjian: Sure. So, Sam, thanks for having me. It's a pleasure to be here, and it's quite fun to be back in person and be able to enjoy the meeting together. So, the rapid abstract session in urothelial cancer covers what I would say are three broad topics in advanced urothelial cancer. One abstract covers the role of neoadjuvant chemotherapy with gemcitabine and cisplatin, for patients with upper tract urothelial carcinoma. One abstract covers maintenance therapy with a checkpoint inhibitor, for patients who've not experienced disease progression after chemotherapy for metastatic urothelial carcinoma. Then three abstracts deal with post-chemotherapy, systemic therapies for patients with metastatic disease.
Sam Chang: Okay, well, let's talk about the first one. What were some of the key highlights you think of the first abstract?
Stephen Boorjian: Yeah, so the role of neoadjuvant chemotherapy in upper tract urothelial carcinoma, I think adds to what is becoming an increasingly complex story. So, this study looked at, in a Phase two, single-arm design, four cycles of gemcitabine and cisplatin for patients with high-grade or radiographic evidence of invasion. The primary endpoint of the study was looking at pathologic response rates, and then they did also look at progression-free and survival rates. What they found was a substantial pathologic response rate of 63% of patients achieving sort of non-muscle invasive disease, and they found a 19% complete response rate. So, it's interesting data. I think because many of us who treat urothelial carcinoma have, for a long time, extrapolated the benefit of neoadjuvant chemotherapy from muscle-invasive bladder cancer to the upper tract. I think what makes it really interesting is that in the last couple of years, we've had adjuvant trials now, which have been randomized trials, come out, which may confuse the story a little bit.
We have the POUT trial, which showed that adjuvant chemotherapy with gemcitabine and cisplatin or gemcitabine and carboplatin, significantly improved disease-free survival. Then we have the adjuvant nivolumab data that recently came out, and 20% of those patients actually had upper tract urothelial carcinoma. So, I think it has re-raised the debate about neoadjuvant chemotherapy, and do we need to be doing the same paradigm that we are doing in the bladder in the upper tract, if we have adjuvant options, even with IOs in patients with renal insufficiency? So, I think this study was important because it did show a significant response rate, as I mentioned. It also showed that those patients who had that pathologic response had better progression-free survival and other kinds of clinical outcomes.
Sam Chang: Really an exciting time, especially as we struggle with a lot of these upper tract patients in terms of, clearly there seems to be some benefit to combination therapy of some type. Just as you stated, neoadjuvant versus adjuvant, do we have markers? Do we have anything predictive of who would benefit, in what setting? We don't know. Which is the best combination? We really don't know. And how they stack up against each other, we really don't know. But I think it has been a big change in terms of, we understand that there is some possible benefit to the combination of the therapies. What about the second abstract then, Steve?
Stephen Boorjian: The other one, the second abstract looked at avelumab, which has been demonstrated to have a benefit for maintenance therapy in patients with cisplatin-ineligible, metastatic urothelial carcinoma. So, it tested this checkpoint inhibitor for patients with cisplatin-ineligible metastatic disease. Again, this, I think is interesting because we have several NCHCN and FDA- approved agents for cisplatin-ineligible disease. This trial restricted it to PD-L1 expressing patients, so it's a little bit different than what has been done before. I think the question will be, how this fits in the landscape of the agents that we already have with atezolizumab and pembrolizumab. So, I feel like we have an expanding number of areas in urologic cancers with metastatic kidney cancer, with M0 CRPC, where we have a group of agents in the same disease class, and choosing between them is going to become increasingly complex, pending additional data from avelumab in the cisplatin-ineligible, metastatic setting. We may have the same issue here.
Sam Chang: Yeah, I think in terms of balancing out and parsing out who would get a benefit, understandably there was an attempt to enrich the population with the expression. Understanding that there is a huge amount of variability in terms of what that expression may actually truly be within an individual, within one sample, within an individual. It does, at least, again, give us the opportunity to examine other possible agents within the same category of medications. How we'll choose which one will be I think increasingly difficult.
Stephen Boorjian: I'm looking forward to hearing the authors talk about that a little bit. Where is its place going to be in the disease space and a little talk about the biomarker issue and was [PO1 00:05:44] the correct one? Are there going to be others? How are we going to make that choice happen?
Sam Chang: I think that's again, almost not quite an embarrassment of riches, but at least we have options where we didn't have options before. Choosing which may be the correct option I think is going to be increasingly difficult. And then you mentioned a group of abstracts looking at maintenance therapy. Is that correct?
Stephen Boorjian: Well, one was maintenance therapy, so it's post platinum ...
Sam Chang: Options.
Stephen Boorjian: Options. One abstract looked at maintenance therapy with a PARP inhibitor and two abstracts looked at patients with disease progression on chemotherapy with different second line options. One was nivolumab plus a HER2 inhibitor. One was a very clever I think, trial design, a Titan trial, looking at nivolumab with a boost of Ipi/Nivo in patients who had disease progression. And so both the HER2 nivo and the Nivo/Ipi sort of moved the response rate from around 20%, which is what's consistent with monotherapy, to mid 30s.
Sam Chang: In a salvage setting.
Stephen Boorjian: In a salvage setting.
Sam Chang: Got it.
Stephen Boorjian: Both of them had a response rate between 32 and 36 percent by adding something on to nivolumab.
Sam Chang: So in considering that trial, the combination of Ipi/Nivo, it just reminds us of the combination of therapies when we're dealing with other advanced cancers. In looking at that, do you think based upon the abstracts that looked at these salvage therapies that it's probably going to be a combination of agents? I guess then the trade off is what was the toxicity profile? And that's probably questions you're going to raise to the authors at that point as well.
Stephen Boorjian: Both. Absolutely correct. The HER2 has with the nivo an interstitial lung toxicity. I'm looking forward to talking about in a population of patients where smoking is quite prevalent with bladder cancer patients and upper tract urothelial cancer patients in general, how is that toxicity play in? I think the other thing to your question about combination versus, for example sequential therapies, will be now that nivo moves into the potentially adjuvant space, what's going to be the place of it in combination therapy later on and I don't think we know. I think the second line landscape continues to expand now with enfortumab, with erdafitinib, FGFR. The other question, which I think will be really interesting to bring out during the panel discussion, is personalized medicine. Are there biomarker panels that we should be obtaining to help guide us? Should it be toxicity driven? Should it be biomarker driven? I think there's a lot of fertile ground here for future direction.
Sam Chang: Right. Especially in that salvage setting where perhaps there isn't at this point a marker that we know for instance, the FGFR3. Then may default currently to enfortumab but these now, other medications, combination, where to they fit in, in comparison. We already have an FDA-approved agent in a salvage setting. How do you apply? What do you do? I don't know enough to know if will they get approved without going head-to-head against one of these salvage agents. Looking at the landscape of these rapid abstracts that you will be helping to run the session at GU ASCO, what excites you the most for the next steps? Is it getting better with predictive biomarkers? Is it improving success with decreasing toxicity? I'm sure it's a combination of all those things.
Stephen Boorjian: Yeah.
Sam Chang: But what do you think is the most exciting next steps?
Stephen Boorjian: I think the most exciting next step is going to be personalizing this. Because for me, that's a big question, just as you used that embarrassment of riches. It's happening in multiple disease states. I think that in order for us to best achieve individualized patient outcomes, there has to be a strategy moving forward. Whether it's a biomarker strategy, whether it's a head-to-head comparison strategy, whether it's relative toxicity strategy. I think the most exciting thing is that we show activity. Now let's be thoughtful about which one for who?
Sam Chang: Yeah. Along those lines in that something we've mentioned in our discussions is that clearly we need to be more aggressive with certain patients. But we definitely can also de-escalate some of our treatments, our regimens, our maintenance and determining who those individuals are I think is probably just as important.
Stephen Boorjian: I think absolutely. I think the upper tract is a great example of that. One of the, I would say historic criticisms of neoadjuvant chemotherapy and upper tract disease, has been our poor staging. So we use grade as a surrogate primarily. But the question is for those who advocate adjuvant therapy, that they would put forth that you are getting after pathologic stage and you are avoiding the toxicities, which are not insignificant, of systemic therapy with pathology-driven treatment, which now has level one evidence to support it. I do think that de-escalating is just as important a consideration as the other ones in the advanced stage are of escalating.
Sam Chang: I'm going to take one tangent here before we finish, because what you've stated I think is really important with the upper tract disease individuals. Prior to any neoadjuvant trial, we probably need to do a better job of attempting to really study apples to apples and oranges to oranges. Do you think it will require better pathologic sampling, will be better imaging, to kind of categorize. There's a big difference between a small 1 cm, 1.5 cm high grade lesion that is papillary on a thin stalk versus that infiltrative mass and it's just like any kind of bucketing or risk stratification table. You're going to have those outliers on each end.
What do you think we're going to need to do better in terms of pre-treatment staging for upper tract? Are we going to need to come up with a classification system? There's a lot of data at Mayo. You guys need to get working on that. That's what I'm thinking about already. Do you envision kind of like a nephrometry score or something that comes up that allows us better attempted in individualized medicine without actually tissue at this point?
Stephen Boorjian: There have been some attempts at that made. There's one risk model called the triple screen, which is grade cytology and hydro.
Sam Chang: Okay.
Stephen Boorjian: That combining those three has been found to predict the presence of muscle invasive and extraluminal disease. I think that really though, what needs to be investigated further are molecular biomarkers. It's being done in FGFR studies for upper tract in a prospective fashion. That's what I would say from a staging standpoint, adding to risk models like the triple screen with molecular stratification will help us. I also think though, that in order to demonstrate efficacy upfront because of the acknowledged staging limitations, we have to go beyond pathologic endpoints.
Sam Chang: Yeah.
Stephen Boorjian: And that's really one of the things I'm looking forward to bring out in the discussion tomorrow, which is, it's important to show pathologic complete response and pathologic down staging to non muscle-invasive disease, but we don't really know whether it existed beforehand at the outset. So showing progression free and overall survival benefits in a randomized fashion against, is going to be what's really important to me in that disease.
Sam Chang: I agree totally and unfortunately it also then gets muddied about what ultimately happens in the bladder.
Stephen Boorjian: Correct.
Sam Chang: Is that in some way linked to that upper tract disease? Is it a separate issue situation and all those things. To me there are different oncologic disease scenarios that I struggle with and those who know me say I struggle with almost all the ecologic scenarios. But the one that I really do are these upper tract individuals that have a degree of renal insufficiency, that have "high risk" disease, who probably don't need a [nephrectomy 00:14:08], but maybe they do and they don't. I love your thoughts in terms of, being additive to gain more information with molecular staging, understanding the impact of that in light of everything else. Steve, as always, I learn much more from conversations with you than in terms of me trying to ever tell you anything. I really appreciate the time that you spent.
Stephen Boorjian: Thanks.
Sam Chang: I look forward to the session at this year's GU ASCO.
Stephen Boorjian: Great. Thanks for having me again, Sam. Appreciate it.