Roundtable Discussion: Looking at the Role of Avelumab Maintenance in Metastatic Bladder Cancer

Daniel Petrylak, MD (Moderator)

Professor of Medicine (Medical Oncology) and Urology

Chief, Genitourinary Oncology

Yale School of Medicine

New Haven, CT

SUH: For me, [the most important factor] is ECOG performance status. One just can’t beat that. How the patient looks, how they’re doing [in terms of] performance status trumps all. And then one of the things that weighs heavily in terms of decision-making and treatment is [the] sort of social support system they have.

PETRYLAK: If they don’t have a support system, would you tend to go with an immune checkpoint inhibitor [ICI] that may be a little less toxic?

SUH: Right.

PETRYLAK: Do you use PD-L1 expression status in these patients to select ICI vs chemotherapy, or is that not a heavy factor for you?

SUH: That is not a factor in our practice.

LAMBA: I agree with Dr Suh. You look at the whole patient, and the performance status is obviously important, and then all the comorbid conditions. Look at renal function, cardiac function, neuropathy—all of those are comorbidities—and then decide whether you’re going to give cisplatin or carboplatin or go directly to immunotherapy. PD-L1 expression, again, is less of a [factor].

BHARDWAJ: I think that it’s more about the performance status. It gives me a sense as to what this patient can handle. I’m not looking at the PD-L1 status to decide that I’m going to give an ICI instead of chemotherapy.

PETRYLAK: That’s interesting. I generally look at the PD-L1 status, but if I’m trying to decide between an ICI and chemotherapy, I look at visceral vs nodal disease more than anything. I’m more inclined to give a PD-L1 agent in a nodal patient than somebody who has liver metastases.

BHARDWAJ: That’s interesting. Are there data that suggest that?

PETRYLAK: I published that in the original atezolizumab [Tecentriq] phase 1 study data.¹ Patients who did best with second-line, single-agent checkpoint inhibitors had nodal disease and good performance status. Patients with visceral disease don’t tend to respond well in my experience. We do see responses, but my feeling is we should get the disease under control first, and the fastest way to do that would be chemotherapy. ICIs take some time. In that whole assessment, the rapidity of how the disease is progressing [should be considered].

There is this phenotype that I’ve seen, which I’m sure everybody here has experienced, where you simply can’t get good control of a patient up front, and they’re going to blow through every treatment, and would be dead within 6 months. That’s a patient for whom I think if you’re going to make a difference, you’re going to have to get the cytotoxic therapy early because they’re just not going to have enough time to respond to immunotherapy.

ALTER: I still believe chemotherapy up front is going to do better if they’re [healthier]. I do not know the data on nodal vs visceral disease. Again, to me, disease downtime to primary [therapy] just needs to be treated as aggressively as possible, just because I think we’ve all tried using atezolizumab and other immunotherapies as first-line therapies, and I don’t think we’ve seen a great first scan or second scan response. I’m trying to think about using chemotherapy as a second-line therapy, and I think the reverse order is probably better. Physically and mentally, patients would rather come in for mild therapy to push against their disease, so I’m cruising in with a little less toxicity and quicker visits without having complications, so I think all these factors are important. If the patient is in front of you, age is [less relevant], and I obviously check for comorbidities, but PD-L1 status is something I do not even look at. I’m getting next-generation sequencing [NGS] upon the first visit because I need to know whether they’re FGFR positive.

PETRYLAK: Exactly. I think that we all should be doing that, because I think, again, [FGFR inhibition with erdafitinib (Balversa)] is going to become a potential second-line or third-line therapy for these patients.

ALTER: I would do a maximum of 6 cycles, but it depends on how the patient tolerates 4 cycles. I scan them after, so it depends on the regimen. I’d probably scan them after 3 or 4 cycles, but it depends on how they’re holding up on the [blood cell] counts. If I see that they’re crumbling early, I will stop at 4, even sometimes 3. My conversation [with the patient] first is 6 cycles, but I am anticipating 4 cycles. If they’re doing quite well and they’re having a dramatic response, I have no more of a problem pushing to 6 cycles and stopping, and then just not even thinking about going beyond it because I can always use platinum-based chemotherapy later if I need to.

BHARDWAJ: I would echo what Dr Alter just said. That’s how I approach it. I’ll talk about 6 cycles, but I’d settle for 4 cycles.

WU: Yes. I usually do 4 cycles because [although] I still believe [administering] 6 cycles gives patients better benefit, it makes patients more wiped out. In practice, patients go on to PD-L1 maintenance, so I tend to do 4 cycles in general.

PETRYLAK: I [would] look at the patient, see how they’re doing, and if you can get 6 cycles in, try to do it, but generally, one can’t.

KHOT: I usually do 4 cycles, but also, if the PD-L1 status is positive and the scans are good after 3 or 4 cycles, I might switch them quickly to immunotherapy. That’s what I usually end up doing, but if it’s a low PD-L1 status and they have a good response to 4 cycles of a platinum treatment, then I would push for 2 more to finish the 6 cycles.

PETRYLAK: Yes, we don’t want to [avoid] giving them the maximum treatment.

PETRYLAK: So 92% of you considered avelumab [Bavencio] maintenance. For the person who answered clinical trial enrollment, which trial would you be enrolling [the patient] in?

PREET: Depends on whether we have [any] clinical trials available that they will benefit from, but if there is no clinical trial available, avelumab maintenance is the best [choice].

PETRYLAK: It sounds like [the participants] don’t use PD-L1 staining for first-line therapy. Does anybody use it in selecting a patient for maintenance therapy?

BHARDWAJ: I don’t. If I decided to do it, I’d do it regardless of PD-L1 status.

PETRYLAK: As we see from the data, patients who are PD-L1 positive do better, but there’s a survival benefit for the PD-L1–negative patients [From the Data²].

BHARDWAJ: I know avelumab has the FDA approval, but those of us who treat other tumors tend to use a different ICI made by another pharmaceutical company. Does it make a difference?

PETRYLAK: You bring up a very good point because there is a trial that was done with pembrolizumab [Keytruda]. It was a study by Matthew Galsky, MD, [of Tisch Cancer Institute].³ He looked at radiographic progression-free survival [rPFS], and [results] showed a positive difference for rPFS, but there was crossover in the study, and there was no overall survival [OS] benefit. Right now, we’re still looking at nivolumab [Opdivo] in the adjuvant setting, and then there’s a larger pembrolizumab trial, but atezolizumab failed in that situation.⁴ It didn’t show a rPFS difference, whereas pembrolizumab did, so we don’t know whether these drugs are truly 100% different. My own feeling is to go with the FDA indication even though it may be more convenient to give other drugs in the situation.

BHARDWAJ: Are the toxicities different?

PETRYLAK: I haven’t observed different toxicities, but perhaps others have. I’ve noted the toxicities are about the same. There is an interesting scenario in our case. Say the patient developed their toxicity after 2 cycles of chemotherapy, and they had stable disease. What would you do?

WIEDER: I would still consider switching them to immunotherapy. One can look at it as a maintenance therapy or could even consider it as a second-line therapy.

PETRYLAK: Yes, if you use it as a second-line therapy, that would open up what you use because technically, you could then use anything. There are 3 approved ICIs in the second-line setting, so it would depend on your interpretation of the definition of second-line therapy, which would be if first-line therapy is intolerable and they can’t go on, but they haven’t achieved that stable disease response after 4 cycles.

CHEUNG: After 2 cycles, if the patient develops mostly nephrotoxicity, can you drop the cisplatin then continue gemcitabine and continue maintenance?

PETRYLAK: Yes. The other thing you could do is switch from cisplatin to carboplatin after 2 cycles, especially if they’re responding to the primary treatment. You want to get their maximum response first, so I think that that would be reasonable.

ALTER: Tolerability and durability [are most important]. You never know when to stop. It’s not like you have patients with CR [complete response] here. These patients have metastatic disease and active disease, so I think as long as they sign up for it, and they’re OK coming in, [I will continue]. I have not switched to giving avelumab every 4 weeks. I know physicians have, but I am still doing it every 2 weeks. I probably will make that switch soon enough, but patients are motivated, so I have no problem continuing with the therapy if it’s well tolerated.

PETRYLAK: A meaningful end point is progression and then of course, tolerability. So if a patient does develop a severe immune reaction, that’s somebody you’re going to pull off at some point. Geographic considerations come into play as well. If the patient lives far away, that’s also an issue, and they’ve got to come every other week, but most patients are willing to do that.

WU: It’s important to me that patients who are taking therapy live so much longer; before chemotherapy, it was 14 months or 15 months, right? Now we go way beyond 20 months, so I think that’s a major benefit of pretreatment, so I would probably not do immunotherapy unless patients cannot tolerate chemotherapy at all and they are PD-L1 positive. So I’d try avelumab if at all possible, for maintenance.

PETRYLAK: That’s a good point. We’re seeing the survival extending longer than we had seen in the past, and then remember that trial was done before enfortumab vedotin [Padcev] was approved, so that also is improving survival, so at least this group of patients are living longer, and they’re living better.⁵ Their quality of life, I think, is better than [it was] previously.

PETRYLAK: The pros are obvious, [most of all] the survival benefit, but what are some of the cons?

CHEUNG: It [must be given intravenously] every 2 weeks.

KHOT: I agree with that [point] on every 2 weeks, and I’ve seen quite a bit of cytopenia compared with using the other ICIs.

PETRYLAK: Which cytopenia predominantly?

KHOT: Anemia.

PETRYLAK: That could be a long-term effect from the platinum. That could be a delayed effect; especially with carboplatin, you sometimes get delayed anemia. Or it could be presensitized by the chemotherapy, and then this may be the cause of it.

To me, the biggest drawback [of avelumab maintenance] is that the patients don’t have a finite time on treatment. It’s not like you’re giving it for 2 or 3 years. Then how do you [know when to] stop?

KHOT: If they get a CR, what are your criteria for stopping the avelumab?

PETRYLAK: I think that would be 1 situation where I’m considering it. It’s very interesting how patients react to this. Many have said to me right from the beginning, “I don’t want to stop it if it’s working. I’m afraid that if I do stop, it’s not going to work anymore, and then if I must restart again, it’s not going to work.”

LAMPERT: I would think that a CR makes it harder to stop, because you have proof of activity, and why would you go and stop a relatively low-toxicity therapy when it’s clearly working?

LAMBA: Does anyone [act like we do with immunotherapy in] lung cancer, where we stop after 2 years?

CHEUNG: Or is there a biomarker that can measure the tumor load, and as soon as there is MRD [minimal residual disease], you can stop and wait?

PETRYLAK: I don’t think anybody has done that. The situations where I see MRD being used are more in the adjuvant setting, post cystectomy. Here it may be a bit more difficult to have clear-cut masses that may be present, but it’s a very good thought. It may help you if the burden of disease goes down [according to] these molecular techniques, but clearly, it needs some prospective confirmation of that. I think the real cons here are the schedule and the indefinite treatment.

WIEDER: We always want to discuss potential toxicities and make patients aware if they experience certain things that they want to get your attention, not ignore it. Fortunately, these are relatively well-tolerated medications compared with some of the cytotoxic chemotherapies that we use, but there are certain potential toxicities, whether it’s pneumonitis or diarrhea, where if a patient is unfortunate enough to get some of them, they can get sick very quickly. So education in terms of potential adverse events [AEs] that patients just need to be aware is very critical for these patients. Hopefully, its never needed, but obviously, they need to be aware of it.

FRIEDLANDER: We should also mention permanent potential toxicities like vitiligo and endocrine toxicities.

PETRYLAK: Right. Those are always things that came to mind, and of course, the logistics, which are difficult, especially if [the patients are older], and they may not have transportation.

Those are the key points, but identifying immune-related toxicities early is key. Then you can start steroids because they may not be able to receive treatment if they get to grade 3 or grade 4 toxicities.

FRIEDLANDER: Are there any data on the effectiveness of avelumab maintenance if the patient got 4 cycles vs 6 cycles of cisplatin plus gemcitabine?

PETRYLAK: There’s no difference.⁶ Again, it’s just getting to that CR, partial response, or stable disease state.

WIEDER: The patients are living longer, and obviously, with more options, hopefully, we can delay progression and keep patients alive for longer, and hopefully, in doing so, we don’t necessarily jeopardize their quality of life.

PETRYLAK: I like to call it line 1.5. It’s not second-line treatment, but it’s somewhere between second- and first-line therapy. What it's doing is moving all your other treatments up earlier, so we know that enfortumab vedotin is approved for third-line therapy, sacituzumab govitecan [Trodelvy] is approved for fourth-line therapy, and then there are FGFR inhibitors, so it’s moving these treatments into the earlier state of disease.^7,8

Of course, as time goes on, what’s going to happen when a patient has been on nivolumab, then develops metastatic disease, and you give them chemotherapy and they respond, you give them an ICI, and you give them avelumab maintenance therapy? Technically, you do because that’s what the indication is, but we’ve never seen what the effect of giving 1-year nivolumab is going to be on subsequent response to immunotherapy. There have to be a lot of changes in thinking based on how the approval process is going to go in the future.

ALTER: Especially if the patient progresses while on maintenance adjuvant therapy.

PETRYLAK: You’re making a great point. The criteria for second-line therapy are [based on a group of oncologists] deciding what they thought it was, so that’s where this 1-year [schedule] came about, but is relapse at 1 year different from 14 months? So if you relapse early, you’re not going to respond again to [the next treatment].

What are we going to do if enfortumab [alone or with] pembrolizumab [in the first line] turns out to be positive in trials? What is that going to do to switch maintenance, because we’ve already got an ICI involved? That is going to be an interesting question.

KHOT: That would be in cisplatin-ineligible patients, though, right?

PETRYLAK: No, the phase 3 trial of enfortumab [plus pembrolizumab] is for both cisplatin-eligible and -ineligible patients. There are 2 studies that are going on right now. The EV-103 trial [NCT03288545], which we’re waiting for the results for, that is part of a large phase 1 trial, and there is the phase 3 EV-302 trial [NCT04223856], which is for both cisplatin-eligible and -ineligible patients.

_REFERENCES

_{1. Petrylak DP, Powles T, Bellmunt J, et al. Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer: long-term outcomes from a phase 1 study. JAMA Oncol. 2018;4(4):537-544. doi:10.1001/ jamaoncol.2017.5440}

_{2. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2022;40(suppl 6):487. doi:10.1200/ JCO.2022.40.6_suppl.487}

_{3. Galsky MD, Mortazavi A, Milowsky MI, et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol. 2020;38(16):1797- 1806. doi:10.1200/JCO.19.03091}

_{4. Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(4):525-537. doi:10.1016/S1470-2045(21)00004-8}

_{5. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807}

_{6. 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}

_{7. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed October 31, 2022. https://bit.ly/3Dlu4Pn}

_{8. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA. April 13, 2021. Accessed October 31, 2022. https:// bit.ly/3zwprRh}