Metastatic Urothelial Carcinoma: Optimizing Maintenance Therapy After Chemo


A comprehensive review of maintenance therapy strategies following chemotherapy in the context of optimizing patient outcomes.

Petros Grivas, MD, PhD:
Srikala, let’s say you go through 6 cycles of gemcitabine-cisplatin or gemcitabine-carboplatin in platinum-ineligible patients. How long do you wait until you start avelumab maintenance if you have a response or stable disease?

Srikala Sridhar, MD, MSc, FRCPC: That’s a great question. In the study, they looked at the treatment-free interval. They started avelumab between 4 weeks and 10 weeks to see if there was a big difference in that time frame. There really wasn’t a big difference. This becomes a discussion with the patient, individualizing when they want to start the avelumab within that time period. Sometimes they want to take a break after chemotherapy, so it allows you to do that, have a break, and come back and start it. It’s variable. On average, most of my patients start around 6 weeks out from the end of chemotherapy. They finish, they recover from their adverse effects, and then they’re ready to get started.

Petros Grivas, MD, PhD: That makes sense.Many patients are worried about progression. Median PFS [progression-free survival] was about 2 months on the control arm, so I agree. The data showed that as long as you’re waiting for 4 to 10 weeks, you’re fine. My tendency is to start sooner rather than later to avoid progression. But it’s important to think about it early on and discuss with the patient even before you start chemotherapy. That’s the sequential approach we take with maintenance therapy.

In that context, Tian, you mentioned before that the trial design was that you continue with avelumab until progression or toxicity. Do you follow that? Do you have a fixed duration? How do you approach it?

Tian Zhang, MD, MHS: I usually treat until progression or unacceptable toxicities. Some patients tend to do very well. They can go several years. At the 2- or 3-year mark, they’ll sometimes say, “What do you think? Could I come off?” We have a discussion. I don’t think there are good prospective discontinuation data. We do need that. But it’s reasonable if they’ve had an excellent response and, at 2 years, they’re motivated to stop. It’s a conversation with the patient.

Petros Grivas, MD, PhD: Iabsolutely agree. I always tell the patients that this is a data-free zone. When do you stop immunotherapy? The trial design, to your point, was until progression or unacceptable toxicity. There’s an ongoing trial in cooperative groups from the Alliance for Clinical Trials in Oncology led by Dr Xiao Wei from Dana-Farber Cancer Institute.

Guru P. Sonpavde, MD: That’s right. Dr Wei is leading this trial, called the IMAGINE trial. After 9 to 18 months, it allows an immune checkpoint inhibitor. Patients with a stable or responding disease are randomized to continue or discontinue. That’s how you might answer that question.

Petros Grivas, MD, PhD: And this is across immunotherapy and urothelial cancer, not only for maintenance?

Guru P. Sonpavde, MD: Correct. It’s an immune checkpoint inhibitor for urothelial carcinoma in any setting.

Petros Grivas, MD, PhD: That’s interesting. Srikala, we’ll go back to you. In terms of toxicity profile, immunotherapy is easier than chemotherapy. Do you have any comments on the data from the JAVELIN Bladder 100 trial about avelumab? Are there any adverse effects that you think about?

Srikala Sridhar, MD, MSc, FRCPC: It’s an immunotherapy. We’re getting better at dealing with the adverse effects of immunotherapy. Things you can watch for are colitis manifesting as diarrhea, fatigue, and pneumonitis. I keep an eye on the thyroid function because that can sometimes get missed along the way. If a patient comes in, they’re very fatigued. You might think it’s disease, but it might be their thyroid. At the same time, I also use dose delays or low-dose steroids, which I find very helpful in managing some of the adverse effects. Sometimes the adverse effects tend to settle down over time or they just get better at dealing with it. We have a poster this year at ESMO [European Society for Medical Oncology Congress] looking at the association between immune-related adverse events and outcome. Do patients who have more immune-related adverse events have better outcomes? Is there an association there? It might be interesting to see.

Petros Grivas, MD, PhD: That’s very interesting.

Cora Sternberg, MD, FACP: I tell my patients that anything that ends with –itis is a possibility. I’m not necessarily talking about avelumab. I’ve seen pneumonitis and adrenalitis. Adrenal insufficiency is something you should think about clearly when patients come in feeling really poorly, and the thyroid also as you said.

Petros Grivas, MD, PhD: Do you check cortisol levels, Cora?

Cora Sternberg, MD, FACP: I do. We do for those patients, yes.

Petros Grivas, MD, PhD: On immunotherapy in general?

Cora Sternberg, MD, FACP: Yes. But we did publish the SAUL study on atezolizumab, which we were able to give to patients who had immunologic diseases that were well controlled, like colitis, rheumatoid arthritis, and psoriasis. For many of the diseases, patients were left out of registration trials. They were able to tolerate immunotherapy. I give immunotherapy to patients with well-controlled immunologic diseases along with their treating physician. That’s important to know too.

Petros Grivas, MD, PhD: That’s very interesting. The SAUL trial is very interesting. I’m glad you did that trial because it answered questions for patients that aren’t usually enrolled in immunotherapy trials.

Cora Sternberg, MD, FACP: And with poor creatinine clearance too.

Petros Grivas, MD, PhD: Sure.

Tian Zhang, MD, MHS: That also forms the basis for the ongoing NCI [National Cancer Institute] trial evaluating nivolumab use in underlying autoimmune diseases, so those are really important data.

Petros Grivas, MD, PhD: For sure, and we should support those trials. It also depends on the type and grade of the autoimmune condition. That’s definitely a field for research and important for trials.

Srikala Sridhar, MD, MSc, FRCPC: It’s also important to look at real-world data. That speaks to this issue of patients who aren’t enrolled in trials. Some are fit and healthy, but what about the rest of the population? Even some real-world data with avelumab support that they’re seeing the same thing in the real world that they saw in the clinical trials, which is important.

Petros Grivas, MD, PhD: I totally agree with you, Srikala. Real-world data can complement this select patient population…in clinical trials. I know you’re working in that field, and it’s great collaborating in that regard. If you think about toxicity and patient-reported outcomes, JAVELIN Bladder 100 had a recent publication looking at patient-reported outcomes. It was published with Dr [Thomas] Powles, Srikala, and others, [and it showed] that patients have maintained their quality of life. Quality of life was not impacted negatively. The difference between patient supportive care and avelumab maintenance you saw no significant difference in quality of life. It’s a good thing that the quality of life was maintained in those patients. Quality of life can be a composite of toxicity and also progression, right? It’s interesting to look at that.

Cora Sternberg, MD, FACP: It’s easier than chemotherapy. They’re all happy.

Petros Grivas, MD, PhD: Absolutely. Especially after chemotherapy. Guru, we know there are a bunch of trials. We’ve talked about MAIN-CAV already. There’s another trial called PRESERVE3 that has a maintenance component. Can you briefly comment on it?

Guru P. Sonpavde, MD: PRESERVE3 is also a trial that builds on the JAVELIN Bladder 100 paradigm. It’s a randomized phase 2 trial. It has the JAVELIN Bladder 100 paradigm—platinum-based chemotherapy followed by avelumab maintenance—and is randomizing to plus or minus trilaciclib. It’s an intravenous CDK4/6 inhibitor. It’s approved for patients with small cell lung cancer getting platinum-etoposide chemotherapy to prevent myelosuppressive complications. But in a different study of triple-negative breast cancer, they saw an interesting survival signal. They wanted to examine this in urothelial carcinoma because in urothelial carcinoma, we also have the chance to improve the immune state with the avelumab that comes in. Data found that this drug can also enhance the immune state and protect the immune cells by putting the cells in a hematopoietic cell arrest after division. It protects the immune cells from chemotherapy and also protects the myeloid cells from chemotherapy myeloid toxicity. It might suggest both chemotherapy and immune checkpoint inhibitions. It’s an interesting paradigm to go with. We need to wait and see what the data show.

Petros Grivas, MD, PhD: We’re waiting for a follow-up at this point.

Guru P. Sonpavde, MD: Right.

Petros Grivas, MD, PhD: There are other trials, like the TROPHY trials, in which cohorts in maintenance therapy definitely show an interest in this maintenance paradigm.

Transcript edited for clarity.

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