Dr. Matthew Galsky:
Welcome to The ASCO Post Roundtable Series on Immunotherapy Approaches in Muscle-Invasive Bladder Cancer. I'm Dr. Matthew Galsky from the Icahn School of Medicine at Mount Sinai. And I'm joined today by my two colleagues, Dr. Sridhar and Dr. Tripathi. Please both introduce yourselves.
Dr. Srikala Sridhar:
Hi, there. I'm Dr. Srikala Sridhar. I'm a medical oncologist at the Princess Margaret Cancer Centre and a professor at the University of Toronto.
Dr. Abhishek Tripathi:
Good morning, everyone. My name is Abhishek Tripathi. I'm an associate professor at City of Hope Comprehensive Cancer Center, GU medical oncologist and clinical investigator. Happy to be here.
Dr. Matthew Galsky:
Thank you for joining today. So today, we'll be discussing the role of immunotherapy in bladder cancer with three patient cases. Our final installment will focus on perioperative strategies for a patient with muscle-invasive bladder cancer with borderline renal function.
So this is a 74-year-old man. He has a history of hypertension. He's seen in the emergency room for lower abdominal discomfort and gets a CT scan, and the CT scan shows a bladder mass. His labs are notable for a creatinine clearance of 43, but they're otherwise unremarkable. Dr. Sridhar, what do you recommend doing next for this patient?
Dr. Srikala Sridhar:
Yeah. I think in this 74-year-old man, this is a fairly common presentation in our clinic. He has a bladder mass locally. He does have some compromise in his renal function, his creatinine clearance of 43. He immediately makes me a little bit worried about being able to give neoadjuvant chemotherapy. Much of our chemo, of course, cisplatin based and this can have an impact on the kidneys. I start by trying to optimize the renal function as much as possible, make sure he's well hydrated. I may get a nephrologist or an onconephrologist involved in order to, again, see if we can do anything better with the renal function. And as well as some of these patients do have obstruction, and so having a tube placed in might actually improve the renal function. So that's what I'm thinking about from a renal function standpoint. And then I'm also starting to think about the ideal treatment approach in the context of a compromised renal function.
Dr. Matthew Galsky:
Thank you. So he's referred to a urologist, has an office cystoscopy and that shows a bladder tumor and so he's taken to the operating room and has a transurethral resection of bladder tumor. And Dr. Tripathi, he's referred to you. Pathology report isn't back at the time of the referral. He comes in to see you. You get the pathology report and it says, "High-grade urothelial cancer invasive into the lamina propria. No muscularis propria present." What are you thinking? What are you talking to the patient about in that setting?
Dr. Abhishek Tripathi:
Absolutely. So this is a situation where we really need to find out the presence or absence of muscle invasion. And this is something we even talked to our fellows during our clinic rotations that always look for the presence of muscle in the pathology specimen to make sure that it was an adequate TURBT. The presence of muscle has a significant impact, whether we use neoadjuvant or perioperative therapy. It has implications on other aspects of the treatment. So I would definitely try to get a better TURBT specimen, perhaps refer back to a urologist and do a maximal TURBT, which may have some benefits in terms of bladder preservation down the road as well and at least get us a more accurate diagnostic assessment of presence or absence of muscle invasion. If there are additional issues identified on the imaging such as hydronephrosis, basal bladder involvement, that also increases my clinical staging for high-risk disease or T3 disease. So other things I'd review carefully on the imaging.
Dr. Matthew Galsky:
Thank you. So he's taken back to the operating room by the urologist, has a repeat TURBT, comes back to see you. The pathology report says, "High-grade urothelial cancer invading into the muscularis propria." So now we have a patient with confirmed muscle-invasive bladder cancer, creatinine clearance of 43, otherwise, no major comorbidities. Nothing really apparent on imaging in terms of intervention to relieve ureteral obstruction that would result in a near-term improvement in creatinine clearance. So how do you counsel this patient regarding next steps?
Dr. Srikala Sridhar:
Yeah. So I mean, this is a patient with muscle-invasive bladder cancer. We know that they're at high risk for recurrence. We also know from all of our data for years that just doing surgery alone is likely not going to be enough to keep this patient from having a recurrence. So the first thing I'd start to think about is neoadjuvant chemotherapy. Of course, we have to keep in mind the creatinine clearance at 43, so we're a little bit cautious in this setting. I tend to use a lot of split-dose gemcitabine/cisplatin where the cisplatin dose is split over day 1 and day 8, so gemcitabine/cisplatin on day 1, gemcitabine/cisplatin on day 8, about 35 mg/m2/day.
The anti-emetic regimens are the same, which actually makes it a lot easier for patients. We don't have them calling, being not sure about what to do from an anti-emetic standpoint. And I think it really helps us to maintain the dose intensity, continuing to give patients the treatment that they need. The other thing that we started doing, actually, in and around the pandemic, we were actually told to try to not give chemo, which is really hard as an oncologist. And so we started using a lot of G-CSF. So on day 9, we would give our patients all G-CSF. And we're just putting that data together, but we have seen significant, significant reductions in hospitalizations, febrile neutropenia and the like on the basis of that practice. And we're continuing to do it for that reason, especially when we consider this patient population who tend to be elderly, they have comorbidities, they have various tubes and catheters. So I think their baseline risk of neutropenia is really quite high. So that's the regimen that we have really used and have evolved to be using over the last few years, split-dose with some G-CSF to help support.
I think currently with the data from the NIAGARA study where you have patients who are getting a split-dose cisplatin with durvalumab, of course, and they allowed patients down to a creatinine clearance of 40, I think this patient would fall very nicely into that regimen. They would get the upfront durvalumab with the chemotherapy, have surgery and then have adjuvant treatment. And I know one of the issues in the adjuvant setting is getting these patients the adjuvant treatment after a major surgery. We found this with adjuvant chemotherapy. I think it's very much the same with any adjuvant treatment including adjuvant immunotherapy. And so I think a regimen like NIAGARA might work particularly well because you're getting both treatments in upfront and early.
Dr. Matthew Galsky:
And to my knowledge, one of the first, if not the first, large-scale randomized phase III studies to allow split-dose cisplatin and really generate that data, even on the control arm in a large population of patients getting neoadjuvant split-dose gemcitabine/cisplatin.
Dr. Srikala Sridhar:
Yeah. Absolutely. And I think we've done some work looking at the use of split-dose across 10 countries. The use is growing and the use is there. I think it speaks to the fact that this is such a well-tolerated regimen. And I think the fact that it was incorporated into NIAGARA I think was really very forward-thinking, and I was really happy to see that.
Dr. Matthew Galsky:
Dr. Tripathi, any role for dose-dense MVAC in this patient?
Dr. Abhishek Tripathi:
Absolutely. So dose-dense MVAC, as we know, has been studied in two single arm studies previously and was developed after the development of growth factor support and a tack on to conventional MVAC. So there was improved tolerability, but we have looked at larger studies recently, more specifically the VESPER study, and it did show improved outcomes compared to gemcitabine-cisplatin, but a significant subset of patients were not able to complete the full six cycles of dose-dense MVAC in that setting and there were also imbalances in terms of number of cycles of cisplatin, the amount of chemotherapy that is given. It can be a reasonable option for young, fit patients who are eligible to get split-doses cisplatin again, because splitting the dose of cisplatin as MVAC as well. So that remains an option. But the challenge remains that how do we integrate the NIAGARA data in the context of dose-dense MVAC, which now brings an immune checkpoint inhibition? I think in the grand scheme of things, in the totality of data, I would probably still favor the NIAGARA dataset because it brings in cisplatin and combines it with the checkpoint inhibitor for this specific patient population.
Dr. Matthew Galsky:
Thank you. Dr. Sridhar, any further testing that you're doing in this patient? Next-generation sequencing? ctDNA? Anything?
Dr. Srikala Sridhar:
There's a lot I would like to be doing. We're not currently doing that right now, but I think the field of urothelial cancer's really expanding a little bit more in terms of targeted therapies. We’ve had FGFR targeted therapies. We're now starting to have HER2-targeted therapies. So this is what I want to look at in the tumors itself. Certainly, things like circulating tumor DNA are going to be really important, again, not just at one point in time, but I think longitudinally to follow these patients, even the thinking that ctDNA may alert us to a recurrence before we see it radiologically. I think this will be really important as well, especially if intervening sooner really makes a difference in overall outcomes.
We're also starting to see another group of treatments under the category of antibody-drug conjugates that over the last few years have really shown significant improvements in the metastatic setting and are being actively evaluated in the earlier setting, in the MIBC setting. And I think as all of these treatments drive pathological complete response rates higher, the question will really be what do we do with the bladder? And can we institute bladder-sparing more commonly, more regularly? Are our outcomes going to improve even more? And do patients maybe get to keep their bladder? Because I think that's something that they're really thinking about.
Dr. Matthew Galsky:
Thank you. We spoke a lot about surgical therapy for this patient in terms of the definitive local therapy, but how about trimodality therapy, chemoradiation? And Dr. Tripathi, do we have randomized data with cystectomy vs radiation-based approaches?
Dr. Abhishek Tripathi:
Yeah. Cystectomy vs radiation approaches in the randomized setting have been... Those trials have been difficult to do just because of patient preferences and difficulties in randomization in this setting. But we have now really high-quality data that adjusts for the baseline risk factor status and has long-term follow-up that shows that you can actually have equivalent outcomes when appropriately selected patients are offered bladder-sparing trimodality therapy. It includes concurrent chemotherapy, TURBT and concurrent radiation therapy. And the role of systemic therapy there is mostly radio-sensitization. And the duration of systemic therapy there can be a little bit shorter as well.
We're building on top of that with an immune checkpoint inhibitor. So we have this S/N1806 trial that is adding atezolizumab to the combination of concurrent chemotherapy and radiation, and that trial should be reading out in the next year or so. Then we have other trials in development. To Dr. Sridhar's point, for patients who have neoadjuvant therapy and have a great response, can those then get to save their bladder and have a bladder-sparing approach? So we have a trial in development through SWOG where patients are evaluated post-neoadjuvant therapy and if they have a good clinical response, then they get to have just definitive local therapy with radiation and immune therapy. And obviously Matthew, you've led a lot of work in this setting with the Hoosier studies where systemic therapy alone was used for bladder-sparing after stringent assessment of clinical CR.
So as systemic therapy approaches become more and more effective, specifically looking at the horizon with EV-pembro and other novel class of agents, there is increasing possibility that a lot of these patients with what we think will have a pathologic complete response would be able to keep their bladders and we'll have to just use multimodal surveillance and observation for these patients to monitor these patients in the bladder-sparing setting.
Dr. Matthew Galsky:
Thank you. Certainly a major goal of ours. So let's talk about key takeaways.
Patients with high-grade urothelial cancer that's invading into the lamina propria with no muscularis propria on a pathology specimen really need to have a repeat TURBT to determine whether or not there's muscle-invasive disease. Eligibility for the NIAGARA study did include patients with a creatinine clearance of 40 to 60 and those patients could receive split-dose gemcitabine/cisplatin with durvalumab. And chemoradiation vs radical cystectomy for the treatment of muscle-invasive bladder cancer has not been definitively compared in a randomized trial because the one randomized trial seeking to address that failed to accrue sufficient patients. However, we do have good observational data to suggest pretty similar outcomes with these approaches.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in bladder cancer or visit ascopost.com. Thank you.
