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 here today by my colleagues, Dr. Sridhar and Dr. Tripathi. Dr. Sridhar and Tripathi, please introduce yourselves.
Dr. Srikala Sridhar:
Hi there. My name is Kala Sridhar. I'm a medical oncologist at the Princess Margaret Cancer Center and a professor at the University of Toronto. Thank you for having me.
Dr. Abhishek Tripathi:
Hi, everyone. I'm Abhishek Tripathi. I'm a GU medical oncologist and a clinical investigator, associate professor at the City of Hope Comprehensive Cancer Center. Happy to be here.
Dr. Matthew Galsky:
Thank you both for joining. So today we'll be discussing the role of immunotherapy and bladder cancer with three patient cases. Our second installment will focus on adjuvant therapy for a patient with pathological evidence of node-positive disease who is cisplatin ineligible.
This is an 82-year-old woman. She has a history of non–muscle-invasive bladder cancer. She's treated with prior BCG for carcinoma in situ, subsequently develops recurrence, receives intravesical docetaxel and gemcitabine, has high-grade clinical T1 disease, and then is found to have muscle-invasive disease when she undergoes a restaging cystoscopy plus TURBT. She has a CT of the chest, abdomen, and pelvis that shows bladder wall thickening, and her labs are notable for a creatinine clearance of 35. Otherwise, pretty unremarkable. And so she's referred to you as a medical oncologist. What are your initial thoughts, Dr. Tripathi, about how you're going to counsel this patient?
Dr. Abhishek Tripathi:
Absolutely. This is unfortunately a scenario that is not too uncommon in our clinic. Patients who are older, diagnosed, have a prior history of non–muscle-invasive bladder cancer and have a muscle-invasive recurrence despite intravesical therapy. And a lot of these patients end up having cumulative comorbidities that compromise the renal function at the time of diagnosis of muscle-invasive disease. Fortunately in this case, the patient does not seem to have any evidence of distant metastatic disease, so I would think about still treating this patient with a curative intent, assuming the patient has a good performance status and is otherwise a surgical candidate. But I would start thinking about what adjuvant therapy options we could consider to reduce her risk of recurrence for a patient who could not undergo upfront cisplatin-based neoadjuvant therapy.
Dr. Matthew Galsky:
Dr. Sridhar, how about you?
Dr. Srikala Sridhar:
Yeah, I would completely agree with that. There are a group of patients who are elderly, frail, have renal problems, and we're not able to give upfront neoadjuvant chemotherapy. I always try really hard, but sometimes we're just not able to get the patient there. So then we consider what treatment we do locally. And we are very lucky because we have a multidisciplinary clinic where they're evaluated by the urologist and the radiation oncologist together, they do the cystoscopy, and they come to the patient making a joint sort of recommendation in terms of what's the ideal local treatment.
We've done a lot of bladder sparing at our center over the last few years, and so I think that that's given us a lot of strength and hope that this is an approach for patients who are either not surgical candidates or those who are refusing cystectomy. And I think there's a growing population of these younger patients who really don't want to lose their bladder. Our institution has published a propensity analysis, quite a large assessment of patients who are equally eligible for radical cystectomy or bladder sparing, and the outcomes looked really similar. I think this allows us to start to consider more and more for patients a bladder-sparing approach if it's reasonable and appropriate. And by that I mean that they have solitary tumors tending to be less than 7 cm, no carcinoma in situ, no hydronephrosis. These are all considerations, not absolute contraindications. This is sort of what we think about when we see these patients in the clinic.
Of course, patient preference also comes into play as well. Some patients just want the bladder taken out and then other patients are more keen to preserve their bladder. And overall bladder function is important, because we say we don't want to retain a bladder that is not functioning very well. So we make these assessments upfront in a multidisciplinary fashion in the hopes of offering the patients the best options going forwards.
Dr. Matthew Galsky:
Thank you. And is part of that assessment, particularly for a patient like this, to do any formal frailty examinations?
Dr. Srikala Sridhar:
Yeah. That's a great question. I think we have a strong geriatrics team and we're starting to do that a little bit more, geriatric assessments. It's sometimes challenging to send the patient, get the referral. Having them coming and going can be difficult. But we're starting to look at those considerations in the clinic, their safety for receiving chemotherapy, other medications that they're receiving. All of these comes into our assessment, but really looking at this frailty index and geriatric assessment is really important, especially considering the average age of our patients is at least 70 or 72.
Dr. Matthew Galsky:
Thank you. So this patient is indeed referred to both a urologist and a radiation oncologist. A shared decision is made. She opts to proceed with radical cystectomy, she undergoes surgery, and she has pathological T3N0 disease, urothelial cancer of the bladder. She recovers from surgery, sees her urologist who sends ctDNA testing. That comes back by the time you see her and it shows detectable ctDNA. So pathological T3N0, detectable ctDNA in a patient with impaired renal function. Dr. Tripathi, what are you thinking about in terms of counseling her?
Dr. Abhishek Tripathi:
Yeah, definitely a high-risk case, so I would have a discussion with the patient regarding the pathologic stage and time of cystectomy, which is an important prognostic factor. And then since we have the results of ctDNA, I would explain the significance of those results. ctDNA, by context, is a really emerging promising tool that has brought about a paradigm of MRD assessments in localized bladder cancer. That's new for bladder cancer field in general. We know from the IMvigor010 trial that patients who have detectable ctDNA after surgery have micrometastatic disease and do significantly worse in terms of their recurrence-free survival and overall survival after cystectomy. So my goal would be to discuss potential adjuvant therapy options with her based on these two high-risk characteristics, obviously allowing for performance status post-cystectomy and allowing for recovery from the actual surgery itself.
Dr. Matthew Galsky:
Thank you. Dr. Sridhar, adjuvant therapy options for her?
Dr. Srikala Sridhar:
Yeah, I think the adjuvant space has been a really interesting space over the last few years. Lots of development in this area, recognizing that patients post-surgery can often have high-risk disease. So post-neoadjuvant chemo, if they have T2 to T4 node-positive disease, or without neoadjuvant chemotherapy, T3, T4 disease node positive, this group of patients is at significantly high risk for recurrence. And so there've been really three adjuvant studies that have tried to explore this question.
The IMvigor010 study was the first study, and of course, interestingly this was a negative study, but they had really elegant biomarker ctDNA analysis, as Dr. Tripathi mentioned, and in that they found that in patients who are ctDNA positive, like this patient postoperatively were at not only higher risk, but also seemed to benefit from the adjuvant atezolizumab, although overall in the study, it was a negative study. So it was really interesting to pull out this patient population.
And then the other two studies, there was the CheckMate 274 and the AMBASSADOR studies both looking at a PD-1 inhibitor. The CheckMate 274 study was particularly interesting because it compared against placebo and it gives us a bit of strength in this context where we use a placebo control. This, of course, was a positive study for DFS. And interestingly in this study, patients who were PD-L1 positive had an even better hazard ratio at around 0.5 compared to patients who were PD-L1 negative. And indeed, in some places, the recommendation for adjuvant nivolumab is based on PD-L1 status. For us, we don't test for PD-L1 and we have it approved for all patients, fortunately who are considered high risk. And then more recently we've seen the AMBASSADOR study as well, which is sort of in line, somewhat similar in terms of DFS improvement. So taken together, all of these adjuvant studies are supporting the role of an adjuvant immunotherapy approach in patients who have high-risk disease, and certainly for us, this has become the standard of care over the last few years.
Dr. Matthew Galsky:
Thank you. Are you both checking ctDNA routinely in this context?
Dr. Srikala Sridhar:
Yeah, I wish I could say I am. I'm not. I would love to have this data just because it informs us a little bit about risk. But I think it's not only a point in time type test, I think it's something we can use longitudinally to better understand what's happening with this disease over time. So I'm hoping that we'll be able to get this test over the next few years. I'm also interested in exploring things like urine ctDNA because it's such a non-invasive test and it'll be great if we can incorporate that into this setting as well.
Dr. Matthew Galsky:
Dr. Tripathi, how about you?
Dr. Abhishek Tripathi:
Yeah, we are using some ctDNA in the perioperative setting. Upfront, we try to think about it in the bladder-sparing space a little bit. There's great exciting data coming out for patients who cleared the ctDNA. They tend to be much better candidates for bladder sparing. Lots to be investigated over there. And in the adjuvant setting as standard of care across the board, I don't, and that's predominantly because the approval and the benefit seen with nivolumab was across the board in the intention-to-treat population.
But going forward, as the data from IMvigor011 comes about, that is specifically looking at adjuvant therapy and intensification in the ctDNA-positive population, we might be looking at it. Obviously we have the Alliance MODERN trial that is looking at treatment intensification and de-intensification in the adjuvant setting based on ctDNA clearance, so we are going to have more and more reasons to test these patients for ctDNA going forward.
And lastly, I just wanted to talk about the borderline cases where the patient is declining adjuvant therapy, but you would really want to make an informed choice, and that is a situation that I would perhaps use ctDNA to give us more tools to discuss. If in that situation the patient is on the fence for adjuvant therapy and the ctDNA comes back negative or positive, that may also sway your decision just based on the historical data we have seen in this setting. So a mixed bag of utilization of ctDNA currently, but I foresee it being used more and more in the clinic in the future.
Dr. Matthew Galsky:
Thank you. Those are great points. So we have pretty good data on clinical validity of ctDNA testing in the adjuvant setting or in the post-surgical setting, rather, but clinical utility data from prospective randomized studies, we're awaiting.
So key takeaways from this case. Checkmate 274 demonstrated a significant improvement in disease-free survival with adjuvant nivolumab vs placebo in cisplatin-ineligible patients, like our patient, with pathological T3 or higher disease or pathological node-positive disease. The AMBASSADOR study done within the US cooperative system, the Alliance, also demonstrated an improvement in disease-free survival in a similar patient population with adjuvant pembrolizumab. IMvigor010, as we discussed, did not meet its primary endpoint, but it established very important data on the prognostic information obtained from ctDNA testing in the post cystectomy setting, and prospective clinical trials are seeking to establish clinical utility for such testing.
This brings us to the end of this case. Please see the other segments for further discussion on the latest research in bladder cancer or visit ascopost.com. Thank you.
