Recap: Selecting Frontline Therapy for Metastatic Urothelial Carcinoma

The treatment landscape for urothelial carcinoma has seen many advancements in the last few years, with frontline maintenance regimens leading the way. At an Around the Practice presentation hosted by CancerNetwork®, experts discussed the improving outcomes for this population by using a patient case and audience polling questions. The panel was led by Peter H. O’Donnell, MD, associate professor of medical oncology at The University of Chicago Medicine in Illinois, who started the conversation by reflecting on the recent changes he’s seen in the field.

“As we all know, a lot of changes [have occurred] in this area recently. It’s an exciting time to be treating bladder cancer. We’re going to focus on the first-line setting and the idea of maintenance, which clearly has been one of the major paradigm changes over the past year or so,” O’Donnell said.

Joining the moderator were Matthew T. Campbell, MD, MS, assistant professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at the University of Texas MD Anderson Cancer Center in Houston; Shilpa Gupta, MD, director of Genitourinary Medical Oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at Cleveland Clinic in Ohio; and Cora N. Sternberg, MD, professor of medicine and clinical director of the Englander Institute for Precision Medicine at Weill Cornell Medicine, NewYork-Presbyterian, in New York City. They kicked off their review of the topic by looking at the case of a patient with PD-L1–positive metastatic urothelial cancer being treated in the frontline setting.

In a polling question to the audience (Poll question 1), participants indicated that for a patient such as this, the most favorable regimen was gemcitabine plus carboplatin, followed by the PD-1 inhibitor pembrolizumab (Keytruda).

Poll Question 1

Gupta said that she agreed with the audience choice, adding that she would follow gemcitabine plus carboplatin with avelumab (Bavencio) maintenance based on data from the pivotal phase 3 JAVELIN Bladder 100 trial (NCT02603432).¹

When choosing a chemotherapy regimen, Sternberg said her preference is to treat with cisplatin if the patient’s condition will allow.

“I would feel much better giving him something like gemcitabine and cisplatin, perhaps on a split dose, then followed with avelumab maintenance. I would have to understand why this patient has a performance score of 2,” Sternberg said. “Cisplatin has a huge advantage in bladder cancer, and I’ve never seen anybody cured with carboplatin. I barely use it in the adjuvant setting.”

Looking at immunotherapy, Campbell said the high PD-L1 expression does make the use of pembrolizumab alone a possibility in this patient. “The argument is that if you do get a patient who is in that lucky group of about 25% to 40% of patients with high PD-L1, you can achieve a response,” he noted. “I’d be much more concerned if this patient had liver or bone metastases [whereas with] lymph node and lung [metastases], unless the patient had declined very quickly, you have a bit of room to give immunotherapy a chance.”

Choosing Maintenance Therapy

O’Donnell then queried the panel regarding their rationale for maintenance therapy choice in this setting.

“I’m definitely using avelumab and that’s what the [National Comprehensive Cancer Network] guidelines, the [European Society for Medical Oncology] guidelines, the [American Urological Association] guidelines, and the [European Association of Urology] guidelines suggest with level 1 evidence,” said Sternberg. “The only other trial we have is a very small, phase 2 randomized trial [NCT02500121] with 100 patients using pembrolizumab, and there was a crossover.² [It did not evaluate for] overall survival. They saw an improvement in progression-free survival with 50 patients in each arm.”

CASE

In another question to the audience, there was unanimous agreement that a patient such as this would certainly receive some maintenance therapy (poll question 2). In a follow-up question, the audience was again united in their decision to treat with avelumab maintenance (Poll question 3).

Poll Questions 2 and 3

“Avelumab is very well tolerated. You do have risk of infusion reactions, which you’ll typically see within the first 2 or 3 doses,” Campbell said. “But at this time, once you get past those potential infusion reactions, it has an excellent safety profile similar to that of most other [anti–]PD-L1 agents. As the general rule, the adverse effect profile is a bit more favorable with the PD-L1 agents as compared with the PD-1 [inhibitors], in composite.”

However, Gupta said she sometimes favors giving pembrolizumab in this population based on the dosing schedule. “The [every-] 2-week dosing is quite burdensome, which is a problem for a lot of patients. They end up missing so many doses because of bad weather or just the burden on [with] work. Based on the phase 2 trial of pembrolizumab, I do consider that as a choice in patients who I feel won’t be able to come every 2 weeks.”

Sternberg pointed out that the 6-week dosing schedule for pembrolizumab does appear more palatable, but she argued that the clinical evidence to support this schedule is shaky. “Pembrolizumab every 6 weeks is attractive, but we have only a small phase 2 study that [administered treatment] every 3 weeks. I don’t know where they came [up] with the 6-week [dosing schedule]. It’s a bit strange to me,” she said.

For patients with a complete response (CR) to platinum-based chemotherapy, Gupta said she would still consider administering avelumab. “Patients who achieve CR with cisplatin are a minority and those patients do well [over the] long term,” she explained. “Offering them maintenance avelumab should still be the practice, although I will not continue it indefinitely if their scans continue to show complete response.”

PD-L1 Testing

In discussing the JAVELIN trial data, Sternberg pointed out that the outcome in patients with PD-L1–negative tumors was not a prespecified end point and, therefore, there are no data to compared maintenance with or without avelumab.

“It is interesting that we haven’t seen the [Kaplan-Meier curve for overall survival in] the PD-L1–negative group from JAVELIN,” said O’Donnell. “It makes you wonder what that curve looks like.”

When the panel was asked about their testing practices, responses varied. “I am not testing PD-L1 in all patients because it is not as robust of a biomarker as we [once] thought it [was],” Gupta said. “I’m not testing [for] it because there are no decisions that I make [with the results], unless it’s a patient for whom I offer gemcitabine plus carboplatin and is hesitant to get it. [If they have] high PD-L1, we could make a case for using single-agent immunotherapy.”

“I [test PD-L1 in] everyone,” said Campbell. “I agree that it is not a big decision maker for me, but I [do] it more so out of curiosity. [Additionally], I do like genomic profiling—PD-L1 and HER2 testing—for every patient with metastatic urothelial cancer.

“It’s not the most reliable [biomarker] and all universities probably test for it in different ways, as well,” Campbell pointed out. “But we do test for PD-L1, we test for FGFR, and we test for as many things as we can to know how to treat our patients better.”

Discussing Treatment Choice With Patients

O’Donnell turned to the panel to determine the best time to discuss the possibility of maintenance treatment with patients who are receiving platinum-based chemotherapy in the frontline setting.

“I broach the subject when I’m discussing the frontline therapy. Patients love to hear about immunotherapy and in urothelial cancer, if they respond, they go on maintenance, which is a concept most patients really like,” Gupta said. “If they don’t respond, then we also do immunotherapy. I do bring that up, but I don’t go into the details until we know from first scans what we’re going to do.”

“I absolutely agree,” Sternberg said. “I discuss it earlier and earlier. When we were doing the trial, we weren’t discussing it as much. Now, though, I discuss it earlier and earlier with patients for whom we plan to give certain chemotherapies and then do maintenance. People really do like to hear about immunotherapy.”

Immunotherapy Maintenance in the Presence of FGFR

Given the approval of the FGFR inhibitor erdafitinib (Balversa) for the treatment of patients with FGFR2- or FGFR3-altered metastatic urothelial cancer that has progressed following platinum-based chemotherapy, O’Donnell asked the panelists if they were still offering immunotherapy maintenance for this patient subset.

“Unfortunately, we don’t know the FGFR status of patients [in the JAVELIN trial],” said Gupta. “But the way I see this is that if they have FGFR-mutated tumors, it just gives us an additional option down the line. Being that avelumab maintenance timing is crucial, I would rather do that first and reserve an FGFR inhibitor for later, as opposed to not utilizing maintenance at all.”

Duration of Maintenance Therapy

When considering fixed-duration therapy vs treating until disease progression, O’Donnell pointed out that the field is split. As such, he turned to the panelists to see what their preferred treatment strategy is with immunotherapy maintenance.

“The way the [JAVELIN] study was designed was to continue until patients progressed,” Sternberg said. “Having said that, if you have a patient who has been on management for 2 years in CR and they’re sick and tired of coming in every 2 weeks, I don’t think there’s anything wrong with stopping and seeing what happens. We don’t know that from the study—that’s just clinical practice and what we’ll decide to do.”

“The patients driving these conversations about stopping tend to be the patients who are doing extremely well,” said Campbell. “A 2-year mark is reasonable to consider stopping patients.”

Looking Forward

When asked about new combination therapies on the horizon in metastatic urothelial cancer, Gupta quickly jumped in with data regarding the nectin-4–directed antibody-drug conjugate enfortumab vedotin (Padcev). She cited the phase 1/2 EV-103 trial (NCT03288545) of enfortumab as monotherapy or in combination with other agents across treatment settings, as well as the phase 3 EV-302 trial (NCT04223856) of enfortumab plus pembrolizumab vs chemotherapy in untreated urothelial cancer.

“I see the possibility that it might become the next frontline regimen if the data are reproduced, and it may replace platinum in this setting,” Gupta said.

Sternberg agreed, but she said she foresaw some issues with adverse events of this regimen. “The only problem is the neuropathy, so it would depend how many cycles we give and how we give it,” she noted. Sternberg also mentioned sacituzumab govitecan (Trodelvy) as a potential option in this space, “but I think [enfortumab vedotin] is the most promising at the moment.”

Regarding unmet needs in the space, Campbell said health disparities are still a major issue. “We have a good number of patients who are not eligible [for clinical trials]. I would say at least half of the patients who come in are not represented well by the studies,” he stated. “So, we still need to figure out our best options for patients who have the most aggressive disease [and how to] have those results translate to the community setting.”

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. 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