Roundtable Discussion: Looking at the Use of Primary and Switch Maintenance Therapy for Advanced Bladder Cancer

Jeanny B. Aragon-Ching, MD

In treating patients with bladder cancer, criteria for treatment differ across practices. Ten oncologists from community practices and academia discussed how they would approach treatment of a 66-year old man with advanced bladder cancer.

Robert Dreicer, MD, MS, MACP

DREICER: Dr Aragon-Ching, do the Galsky criteria resonate with you? You’re an active clinical investigator. Is that something that you teach your trainees? What do you think about that?

ARAGON-CHING: Yes, I think it definitely aligns with our current clinical practice. Now, there’s going to be a difference between whenever we enroll patients in the clinical trial vs patients we see in our clinics. So, [with] the creatinine clearance in eGFR, we definitely may push the envelope a little bit, and not really adhere to the more than 60 mL/min every so often.

We know our population best. A lot of patients would have compromised renal function, so pushing it toward 50 mL/min and above would be, in general, my gauge for cisplatin eligibility.

DREICER: Dr Paul, let me ask you the second question: [What are the] gray areas with respect to cisplatin ineligibility. First thing, do you buy the criteria that we just talked about? What are your gray zones in terms of making decisions about giving cisplatin or carboplatin?

PAUL: Overall, we agree with the common criteria. But a few things come to mind. For example, some patients present with obstructive uropathy because of a big mass in the bladder, or vesicoureteric junction. They often go to the emergency department, get a nephrostomy tube, and sometimes the function borderline improves. But this is a younger patient, and she looks otherwise healthy. So I sometimes make compromises in those patients, if their function improves with this kind of nephrostomy tube, or over some time, even though that does not necessarily strictly follow these eGFR or creatinine criteria.

This is the 1 patient population in whom I sometimes make a compromise for, and closely follow, and do cisplatin with dose splitting, or a little bit of dose reduction. My preference always is to try to give cisplatin to [patients with] metastatic urothelial cancer. So, that is the one group of people. But for patients, if they have significant other comorbidities, particularly significant heart failure, or very poor functional status, I generally don’t go to cisplatin. But this is the 1 patient population [with] eGFR or creatinine clearance around 45 or 50 who can potentially improve over time.

DREICER: We’re going to drop down to that fourth question. Colleagues who use dose-dense MVAC [methotrexate, vinblastine, doxorubicin, cisplatin], or perhaps dose-dense gemcitabine/cisplatin as your go-to regimen: Does anybody in the audience have experience, and is that their regimen of choice?

MANCHANDANI: I used dose-dense during the training, but out of training, cisplatin and [gemcitabine] is the way to go. That’s easy, much more easily tolerable than dose-dense MVAC. But if I have a young patient with a good performance status and good renal function, I would try dose-dense.

My rationale—I might be wrong, I’m not an expert in the genitourinary [field]—but gemcitabine/cisplatin was compared with MVAC only, the regular MVAC, not with the dose-dense MVAC. So if there is some younger patient with good performance status, I probably would like to go to dose-dense MVAC other than gemcitabine/cisplatin.

DREICER: Do any other colleagues use dose-dense regimens as their go-to?

GAI: For metastatic disease, I probably use more gemcitabine/cisplatin. I very rarely use MVAC, especially dose-dense. I don’t see much benefit for palliative chemotherapy in terms of MVAC. I’ve used, for the T2; for neoadjuvant chemotherapy with MVAC I push a little bit more. But for stage IV disease, I generally don’t. That’s my advice.

MANCHANDANI: When I said that [I would use] dose-dense [therapy in a] young patient, that would be for early-stage resectable disease, not for metastatic disease.

BHANDARI: I have not used dose-dense. In metastatic disease, I use carboplatin/gemcitabine or immunotherapy.

DREICER: I hope this patient doesn’t have all those things, so let’s clarify a little bit. Let’s take the larger question to mean, for the group, to say in a patient in whom you’ve decided that you’re not able to give cisplatin to: How do you make a decision about whether or not you can give carboplatin at all?

BAHRAIN: If the patient had adequate performance status, I would proceed with carboplatin without hesitation. I generally don’t look at the age. I put more of my bias on the performance status, so that would be my biggest factor. I don’t look at peripheral neuropathy, hearing loss, sites of metastasis, or comorbidities as much as the overall performance status.

DREICER: In the population of patients where it’s marginal, so let’s say the patient has an ECOG of 1, has eGFR of 60.5 mL/min, a little bit of well-controlled hypertension, etc, grade 1 peripheral neuropathy. What’s the decider for any of us about whether you use cisplatin and carboplatin? What are the key criteria that drive your decision?

BAHRAIN: For me, it’s performance status and renal function.

DREICER: Is the patient I presented to you just now a cisplatin candidate for you?

BAHRAIN: Yes, I think so. The renal function seems adequate, the performance status of 1. Yes, I think I would proceed with cisplatin over carboplatin in that situation.

DREICER: When your patient says to you, “I’ve been reading about this other kind of chemotherapy, carboplatin. It seems to be safer. Why aren’t you giving me that?” How do you handle that for them?

BAHRAIN: I generally tell them that the cisplatin has a better overall response compared with the carboplatin. If they are truly against dealing with the potential adverse effects of cisplatin, I won’t overly push it, especially in the metastatic setting. I’m open to making a decision together with the patient.

ARAGON-CHING: I’m just curious for the group. Let’s say the same case that Dr Dreicer presented, but it’s an 80-something-year-old patient. Would people still consider cisplatin, or just based on that age alone, would people lean more toward carboplatin?

BHANDARI: In stage IV disease—you mentioned 80, so definitely carboplatin. Carboplatin/gemcitabine, maybe. In the case that was presented, she was 66 years old and had stage IV metastatic disease; I would still probably consider carboplatin/gemcitabine, because we will have peripheral neuropathy and some of the adverse effects that can be quite impairing to their quality of life. Older than 75 to 80 years, I will be very careful when I use cisplatin. I will tend to use carboplatin, but again, be very cautious.

DREICER: What affects your decision to think about giving avelumab maintenance?

YU: I think it should be offered to all patients with stable disease, or improvement of their disease with initial chemotherapy, regardless of PD-L1 status. In terms of renal function, too, [if the patient has] significant pre-existing renal disease, I would say less than 30, I probably would hold off. But I think anything greater than 30 to 40, I [would use] avelumab.

ZAMAN: I use avelumab in as maintenance in these patients if there is no contraindication to using immunotherapy because of the data. It’s irrespective of whether they are PD-L1 positive or negative.

DREICER: We have 2 frontline randomized studies that tell us that if you give chemotherapy plus an immune checkpoint inhibitor, it doesn’t really do any better than sequential therapy. So, what is the rationale that you would give chemotherapy, achieve some degree of anti-tumor kill, and then get a response to immune intervention? Mechanistically, this is different, and the world is chasing the concept of neoantigen creation making the immune milieu better for an immune checkpoint.

What we have, although it doesn’t explain it, is two 1000 patient trials that tell us that giving it together isn’t better than giving chemotherapy alone. You have a well-done, large, randomized study that tells us that if you give chemotherapy and get a response, that if you follow it by giving immune checkpoint therapy, you change the natural history of the disease. I think the underlying science remains a little bit challenging to understand, mechanistically, what’s going on.

BAHRAIN: What are your thoughts on why giving chemotherapy works better when you subsequently give immune checkpoint inhibitors?

DREICER: What I know is that when you give immune checkpoints after patients get platinum-based chemotherapy, you can make people live longer. We have a phase 3 trial that took all-comers, those who progressed on platinum ultimately, and gave them an immune checkpoint inhibitor, and it made them live longer compared with doing something else. So, the issue isn’t so much what the rationale is. I think the rationale is that this is a disease that has a milieu that allows a subset of patients, probably 1 out of 5, to have a significant anti-tumor response to that therapy.

So if you then say, “We know that it works in patients who progressed on platinum, would it be a surprise to say that if you took a group of patients enriched for response, and you add that drug, in a sense, earlier, that you might also heighten that response?” I’m not sure that we know what those 2 different milieus look like. There’s likely to be a fair amount of overlap. It’s a really great question. I think if we understood that, we’d be able to pick our patients better, but I don’t think we understand all the things that are working right now.

DREICER: Do any of the subsequent data change how all of you wanted to use avelumab switch maintenance in the patient? What’s the driver? Is it really just the frontline overall survival data, or are there other factors that impact on how you think?

BHANDARI: I think, based on the JAVELIN trial, it reassures me to use maintenance immunotherapy. I think this is one of the treatment paradigm–changing trials in bladder cancer, because we don’t have many options in this disease.

DREICER: For a patient like this, would you ever consider a single-agent immune checkpoint inhibitor over gemcitabine/carboplatin and avelumab? So, the cisplatin-ineligible patient, who you could theoretically give carboplatin/gemcitabine, who has PD-L1–positive disease, then you can use an immune checkpoint. So, does anybody find settings where they might use an immune checkpoint in lieu of giving gemcitabine/carboplatin with the anticipation of avelumab? The patient can’t get cisplatin, this is a carboplatin-eligible only patient, and your decision is: Do you give gemcitabine/carboplatin and avelumab, or an immune checkpoint as monotherapy. Would you ever see yourself doing the latter, as opposed to the former?

RAJAGOPAL: If the patient is really frail, yes, they could get chemotherapy, but if you’re going to wind up worsening their performance status, why do that?

BHANDARI: [I’d probably use] gemcitabine/cisplatin followed by maintenance avelumab.

DREICER: So you get through 4 to 6 cycles of gemcitabine/ carboplatin. You have a patient with a partial response. You present your patient with data. We say, “We know that if we give you an agent, this immune checkpoint, we can potentially make you live longer.” So, is this a shared decision, per se, like, “Do you want this or not”? Or is it, “I’m recommending that you get this, based on best evidence”?

BHANDARI: I think shared decision with the patient with presenting data would be helpful to them. What we are seeing is there is evidence behind that. At the most, our patients are looking after the physician to give them the right advice, with assurances.

DREICER: Has anybody to date—granted the approval is only a year, so there may not be huge numbers—had a patient who would otherwise have been a candidate for switch maintenance, where the patient said, “I don’t want to do that.”

ZAMAN: Patients are looking for immunotherapy. Even when we are starting the chemotherapy, they say, “How about immunotherapy?” That’s an easier sell, because of the toxicity also.

_REFERENCE

1. _{Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. doi: 10.1056/NEJMoa2002788. Epub 2020 Sep 18.}