Expanding Armamentarium Underscores the Importance of Close Monitoring in Urothelial Cancer

Evan Y. Yu, MD

With new therapeutic options, such as enfortumab vedotin-ejfv (Padcev) and erdafitinib (Balversa), available to treat patients with locally advanced or metastatic urothelial cancer who require second- or third-line therapy, early detection of disease progression is critical, said Evan Y. Yu, MD, who added that this patient population can progress quickly, so frequent imaging and close disease monitoring are crucial.

“We should keep closer watch on our patients, see them more often, understand their symptomatology, and take a close look at the frequency of imaging,” said Yu, clinical research director of Genitourinary Medical Oncology at Seattle Cancer Care Alliance, and a professor of medical oncology at the University of Washington (UW) School of Medicine, in an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on genitourinary cancers.

“Perhaps, [we want to] image more often to catch the patient when they are just starting to progress rather than waiting until they progress to the point where their performance status has declined. Then we miss the opportunity to switch to something else that is active,” Yu added.

The virtual meeting covered first- and later-line treatment options in metastatic urothelial carcinoma as well as in renal cell carcinoma (RCC).

During the interview, Yu, co-chair of the meeting and assistant fellowship director at UW Medicine, a professor in the clinical research division at the Fred Hutchinson Cancer Research Center, and medical director of clinical research support at the Fred Hutchinson Cancer Research Consortium, provided insight into treatment sequencing for patients with metastatic urothelial carcinoma, considerations for treatment decisions, and emerging therapies in the paradigm. 

OncLive^®: What considerations are required to optimize second-line treatment for patients with metastatic urothelial carcinoma?

Yu: When I think about patients [in need of] second-line treatment for metastatic urothelial carcinoma, the most important factors [include] what they received in the first-line setting and their overall fitness and comorbidities [to determine] their eligibility to receive certain treatments. The first thing I look at is whether they received platinum-based chemotherapy in the first-line setting. If so, generally, the second-line agent would be an immuno-oncology agent, such as a PD-1/PD-L1 antibody.

Of course, some patients might have received platinum-based chemotherapy with maintenance avelumab [Bavencio], in which case we are taking about third-line [treatment]. If, however, the patient was ineligible to receive cisplatin in the first-line setting because of comorbidities, such as renal dysfunction or performance status, that is a different situation. In the second-line setting, we have a new approval for enfortumab vedotin, an antibody-drug conjugate [ADC] against nectin-4.

The data [that supported the approval came from] patients who received immunotherapy in the first-line setting, but the FDA granted a broad approval, recognizing that there may be patients progressing quickly on first-line therapy who might have received immunotherapy in the first-line setting. [They also could have received] something like [frontline] gemcitabine/carboplatin, which is platinum-based chemotherapy, just not cisplatin. Those patients really needed something that could produce a rapid response. In that instance, the FDA gave a broad label that extended beyond the actual data, and enfortumab vedotin would be a very reasonable option for patients.

The third situation is for patients who uniquely have an FGFR alteration, either an FGFR3 mutation or an FGFR2/FGFR3 fusion. Those patients are eligible to receive erdafitinib in the second-line setting. 

Those are my key considerations for patients in [need of] second-line therapy based on prior treatment, their overall fitness, and whether they have an FGFR alteration [identified] by next-generation sequencing. 

How does the utilization of maintenance avelumab affect subsequent treatment decisions?

[In those cases], essentially that patient [requires] third-line treatment. If we are going to the third-line setting, the one agent that has survival data is enfortumab vedotin. The recently published manuscript in the New England Journal of Medicine, in which third-line patients received enfortumab vedotin vs taxane chemotherapy. We saw a significant overall survival [OS] benefit in that situation. As such, that is my default agent in the third-line setting.

Of course, if a patient has an FGFR alteration and hasn’t received erdafitinib yet, they can receive that agent as well. Generally, in my practice, I tend to default more toward level 1 evidence and OS benefit if it exists, which it does with enfortumab vedotin. 

What emerging agents are you keeping a close eye on for metastatic urothelial carcinoma?

Sacituzumab govitecan-hziy [Trodelvy] is an agent that is an ADC against TROP2. It has a payload of SN-38, which is the active metabolite of irinotecan. It is approved in breast cancer, but it also has an accelerated approval in bladder cancer for patients who have received prior platinum-based chemotherapy and an immuno-oncology agent. Interestingly, one could even use [sacituzumab govitecan] in the third-line setting, although the survival data for enfortumab vedotin warrants usage there.

I tend to use sacituzumab govitecan in the fourth-line setting or beyond. It was granted an accelerated approval, but there is an ongoing randomized study that is in the third-line and beyond settings of sacituzumab govitecan vs taxane-based chemotherapy. That is a trial of interest for the field.

Something that hasn’t been talked a lot about is that there are a lot of new HER2-targeted agents. HER2 is amplified in 15% to 30% of metastatic bladder cancers. Both [fam-]trastuzumab deruxtecan[-nxki; Enhertu], which is an ADC against HER2, and tucatinib [Tukysa], which is a small molecule targeted against HER2, are being studied in patients with urothelial bladder cancer that harbors a HER2 amplification or HER2 activating mutation, in some cases. 

What message should community oncologists take away regarding the treatment of patients with metastatic urothelial carcinoma?

Overall, we have a lot of new treatment options in bladder cancer now. Patients are living longer and doing better. The fact that we are even talking about third- and fourth-line therapy is outstanding. The message is clear.

Something that I would take to heart is that these patients progress quickly, and if one looks at the data that exist, it is not uncommon for patients to drop off after first-line therapy and not make it to second- or third-line therapy. The numbers keep getting smaller [as the lines of therapy progress].