Roundtable Discussion: Chemotherapy Followed by Switch Maintenance Has Favorable Possibility in Bladder Cancer

Vadim S. Koshkin, MD

During a Targeted Oncology Case-Based Roundtable event, Vadim S. Koshkin, MD, Genitourinary Oncologist, assistant professor at he University of California, San Francisco Health in San Francisco, CA, discussed switch maintenance for patients with bladder cancer.

SRINIVAS: To me, all of those seem really important. Platinum chemotherapy is important; can somebody get cisplatin or not? I think within the site of metastases, lymph node versus visceral is important, but I don’t know for frontline therapy whether you make a big choice between liver metastases versus bone metastases versus lung metastases.

SUPERFIN: I think renal function, comorbidities, something like PD-L1, and performance status would [all] be important to choose the treatment.

KOSHKIN: Yes, absolutely. Renal function and performance status are probably some of the main factors that shape eligibility for cisplatin-based therapy, for instance, but platinum-based therapy as a whole [is] definitely one of the first things I look at, as well. What about PD-L1 status? In what context [would you consider that], specifically?

AMBIKA: Yes, for cisplatin-ineligible patients, that does matter. According to the new FDA directive, you’re supposed to check for PD-L1 and not give the immunotherapy if they are negative.

KOSHKIN: Yes, but that would only really come into play if the patient were not cisplatin eligible. With a patient who’s eligible for cisplatin, it doesn’t really matter what their PD-L1 status is. If a patient were eligible for cisplatin, you’d probably start with platinum-based, or cisplatin-based, chemotherapy.

KOSHKIN: Then, if you’re proceeding with that treatment, how many cycles would you aim to use?

RAJABI: I would [use] up to 6 cycles, depending on a patient’s tolerance.

KOSHKIN: Would you just go for 6 cycles straight, or would you scan in the middle somewhere?

RAJABI: Definitely, after 2 or 3 cycles, I will do restaging if the patient is responsive. I go a maximum of 6 cycles.

KOSHKIN: Generally speaking, that’s what I would do as well. Do most of your patients whom you would pursue this approach with make it through 6 cycles, or do you end up usually having to stop earlier? Do you try to push for 6 cycles no matter what?

SHAHIDI: Mostly, in my experience, people end up getting 4 cycles.

VERMA: We aim for 6 cycles, but there are many factors that come into play. At times, the creatinine clearance deteriorates, or some of the adverse events [AEs] [become a problem]. So, depending on patients’ tolerance, we might have to stop earlier or switch to carboplatin if renal function is not going well. The restaging scans I try to do after 3 cycles.

KOSHKIN: Yes, I generally agree with that approach. What about if you have a patient who is cisplatin eligible, starts cisplatin-based chemotherapy, you scan after 2 cycles and they’re responding, then they make it for 4 cycles, and they run into trouble? Let’s say, with the fourth cycle, they have a lot of AEs. Do you try to push through to 6 cycles? Do you consider, at that point, going down to carboplatin or would you consider switch maintenance then?

VERMA: I think there’s a difference between cisplatin ineligible and platinum ineligible. First, we must [determine] whether the patient is cisplatin ineligible or platinum ineligible. In patients who are cisplatin ineligible and I can substitute with carboplatin, I would go for that. But if a patient becomes platinum ineligible, meaning [they] cannot even get carboplatin, those are the patients I then switch to maintenance.

KOSHKIN: It sounds like your approach would be to try to push through 6 cycles with platinum therapy, even if it means switching from cisplatin to carboplatin, as long as they can tolerate carboplatin.

VERMA: Yes, but if a patient becomes platinum ineligible, I’m not pushing through.

KOSHKIN: I think that makes a lot of sense.

SUPERFIN: If they get the best benefit with 2 cycles, and then for 3 and 4 it’s a plateau, you can feel better about stopping platinum and switching. For patients with PD-L1 positive disease, then you feel better about maintenance too.

KOSHKIN: So, potentially, [you are] also looking at what the scans look like after 4 cycles, or where you make the decision to go ahead with platinum, or switch to immunotherapy switch maintenance.

KOSHKIN: It looks like generally it’s under 20%. For most people, I guess it’s somewhere between 10% and 20%. Increasingly, these are patients who are probably older, [more frail], patients who have locally advanced unresectable disease someone who maybe, if they were better fit, you would consider radical cystectomy. A lot of times, if they’re completely platinum-ineligible, a checkpoint inhibitor is what you’re left with.

KOSHKIN: That’s how I describe those patients. What is the experience for others, specifically with this patient population?

SRINIVAS: I think frailty is a big factor in this. Unlike prostate cancer, patients with bladder cancer come in with such advanced disease that age [correlates] them to have so many comorbidities. So, I think frailty is a big factor that makes them completely platinum chemotherapy ineligible.

VERMA: A bunch of our patients have really advanced kidney disease, with poor creatinine clearance. That’s a big chunk of my patients who are platinum ineligible.

KOSHKIN: If their estimated glomerular filtration rate is under 30, or basically borderline dialysis, this is stage IV chronic kidney disease. Then yes, you wouldn’t give them even carboplatin.

AMBIKA: One of the caveats is, if there is obstructive uropathy, to fix that. That in itself does not make someone cisplatin ineligible if you can stent them and fix their kidneys. That’s one of the criteria.

KOSHKIN: Yes, absolutely. A lot of times putting a stent in, or a nephrostomy tube if the tumor is the cause of the renal dysfunction, leads to platinum ineligibility.

VERMA: That [is] a subset of the population, but there are quite a number of elderly [patients] who have hypertensive or diabetic nephropathy baseline, despite the tumor. So that also makes a big chunk in my population, patient population.

SUPERFIN: Sometimes patients just don’t want chemotherapy, absolutely don’t.

KOSHKIN: That’s another great point: that some patients come in with strong notions that chemotherapy is just not something they want, or they come in asking for immunotherapy. Patient preference also plays a large part in this.

VICUNA: I think there’s a big difference between cisplatin and carboplatin toxicity, and I rarely give cisplatin in the frontline setting because of toxicities. I think carboplatin/ gemcitabine is pretty well tolerated, so unless the patient really doesn’t want chemotherapy per se, I tend to use carboplatin/gemcitabine quite a bit.

KOSHKIN: But for patients who are eligible for cisplatin, would you use cisplatin?

VICUNA: [There are] risks associated with cisplatin, outside of the renal issues. Most of these patients are older and deconditioned from other comorbidities, so I still don’t think they would handle cisplatin very well.

KOSHKIN: That’s a very valid point; these are patients with metastatic disease, most of whom we will not cure. Although a minority can have long-term survival with cisplatin. But yes, you have to take into account what that chemotherapy will do to them.

YEH: I think I would put [a patient like this] on switch maintenance at this point.

KOSHKIN: It looks like most folks are in agreement with you. At least 1 person would consider clinical trial. And then, earlier, 1 of you would consider in this setting maybe switching to carboplatin. So that would be maybe under the “other” category.

KOSHKIN: It looks like most people chose switch maintenance therapy. The person who voted for clinical trial enrollment: Can you comment on what you would consider here?

SRINIVAS: I didn’t choose clinical trial, but I struggle with patients. If a patient had stable disease, which I think we have a need for what the next step would be—but if a patient had a complete response [CR], I’m not sure whether I would just jump into switch maintenance. For stable disease or partial response [PR], we have struggled with what the best option is, and maintenance seems to be a great option.

KOSHKIN: You don’t think that they may tolerate more platinum-based chemotherapy, they had a lot of AEs, so a more well-tolerated regimen like immunotherapy [is an option]. If we were to change up the question here, and say a patient had CR, or very deep PR, would that change anyone’s approach here? Would you consider doing what we would do before the switch maintenance trial results were read out and just observe the patient?

AMBIKA: The other question is, does the PD-L1 matter in that setting to make a decision? If they’re PD-L1 negative, you don’t do it if they already have CR?

KOSHKIN: In the beginning, if you know their PD-L1 status, though we don’t always for cisplatin-eligible patients, then would this sway your decision here whether to go with avelumab switch maintenance or not? That’s a good point.

SHAHIDI: I think the treatment is palliative anyway, whether it’s PR or [CR]. Even if it’s CR radiographically, there is residual disease so, if there is, as long as there is no progression after cisplatin-based chemotherapy, I would put [a patient such as this] on avelumab maintenance whether it’s CR, PR, or stable disease.

KRIJANOVSKI: I think patients can have contraindication to immunotherapy, so that’s the patient who might not get switch maintenance. They might choose not to be bound to the infusion center or didn’t like the AEs of the immunotherapy.

KOSHKIN: Fair enough. Certain patients who have significant autoimmune disease would have a serious contraindication. For patients who are, let’s say, organ transplant patients, you probably wouldn’t use immunotherapy.

KESHAVA-PRASAD: I think we should also keep in mind that cisplatin eligible versus cisplatin ineligible, the survival [curves]….I think since we have a tool to improve on that, we need to consider the maintenance in all patients who do not have a definite contraindication to immunotherapy.

KOSHKIN: Yes, absolutely. Patients who will respond to platinum-based therapy we don’t know who those long-term responders will be. We have a sense that certain patients with lower burden of disease [will be long-term responders] probably mostly patients with lymph node involvement rather than liver metastases, for instance. But ultimately, we don’t know. Aiming for a deeper response with subsequent therapy, with switch maintenance, I think is very reasonable.

KOSHKIN: Are there certain characteristics, like having a CR, for instance, that would make you less likely to treat with avelumab? Or, if the patient tolerated more or less chemotherapy, would that make you more or less likely to give them switch maintenance?

SHAHIDI: I think at the end of the fourth cycle of gemcitabine/cisplatin, if the patient is motivated enough to go ahead with maintenance immunotherapy, I would recommend maintenance immunotherapy. If they had a very good response and they want to take a break from treatment, then I will observe them.

KOSHKIN: I generally agree with that approach.

AMBIKA: Were there any data from the molecular classification for this? Just curious as to other subsets of populations that are going to benefit.

KOSHKIN: As far as I know, molecular classification was not reported, not in the New England Journal of Medicine paper and not in subsequent presentations. I wonder if this is something that they’re planning to present later, because this was a very biomarker-rich trial that had a lot of important correlates. I think that certainly that’s a very important question, whether, for instance, basal- versus luminal-type tumors would benefit more or less from this approach. But at this point, I don’t think we know that yet.

VICUNA: For me, it looks like the data show that the 4 versus 6 cycles looks similar enough that I’ll probably start changing over to maintenance after 4 cycles.2 The last few patients I’ve had, I waited until 6, and it looks like I don’t have to do that. It’s interesting, though, I saw that the 5-cycle graph overlapped the [survival] curves—is that because there was only a small number of patients in that 5-cycle subset analysis?

KOSHKIN: I think it was the numbers. They were much smaller, whereas most patients had 4 or 6 cycles only. I think it was in the [50s], the number of patients who had 5 cycles total. It was a weaker signal, basically, because of the smaller sample size. I wouldn’t think that there’s something different about 5 cycles versus 4 or 6 if they benefit after both 4 and 6 cycles.

KRIJANOVSKI: I always offer immunotherapy and had some patients who continued maintenance 2 years after the initial chemotherapy. Some of them discontinued and remain cancer free for 2 or 3 years. There is sometimes interesting and prolonged responses to immunotherapies. I think it’s worthwhile to try and do as a maintenance after the chemotherapy.

KOSHKIN: That’s a great point. Not only does immunotherapy switch maintenance produce sometimes deeper responses, as we saw in the JAVELIN Bladder 100 trial, some patients had responses on immunotherapy after already having had a prior response or stable disease to chemotherapy. But also, when patients do respond to immunotherapy, these are usually durable responses, much more so than what we usually see. That is one of the motivating factors to treat patients with a checkpoint inhibitor.

KOSHKIN: In terms of discussing the pros and cons of using avelumab maintenance therapy, I think one of the questions that comes up for me is when do you stop it, exactly? If you have a patient with a CR or very deep partial response, you start them on avelumab maintenance, and now they have a CR. They’re disease free after a year. The patient starts asking you how long they have to come in every 2 weeks, because this drug you do have to give every 2 weeks to space it out. Would you stop eventually, would you keep a patient going indefinitely? The trial doesn’t really tell us what to do in this situation.

RAJABI: I continue until the disease progresses or severe toxicity happens. [Otherwise] I will give for 2 years, at least.

KOSHKIN: I think that’s a fair point because it’s often hard to stop a therapy that is working.

_REFERENCES

_{1. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788}

_{2. Loriot Y, Powles T, Dur n MAC, et al. Avelumab (Ave) first-line (1L) maintenance plus best supportive care (BSC) versus BSC alone for advanced urothelial carcinoma (UC): JAVELIN Bladder 100 subgroup analysis based on duration and cycles of 1L chemo}