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Chief, Division of Genitourinary Medical Oncology
Director, Genitourinary Clinical Research
Professor, Department of Hematology/Oncology
Fox Chase Cancer Center
Elizabeth R. Plimack, MD, MS has disclosed that she has received funds for research support from Astellas, Bristol-Myers Squibb, Genentech, and Merck, and consulting fees from AstraZeneca, Bristol-Myers Squibb, Flatiron, Genentech, Janssen, Merck, Pfizer, and Seattle Genetics.
Over the past 5 years, the treatment options for patients with urothelial carcinoma (UC) have continued to expand through multiple new FDA approvals. In 2019, we were fortunate to have 2 additional new agents approved for the treatment of metastatic UC—erdafitinib and enfortumab vedotin—both of which performed very well in early clinical trials and consequently received accelerated FDA approval, meaning that while there was not a randomized trial performed, the data from the phase II trials were compelling enough to receive approval. In addition, avelumab was also approved by the FDA as a maintenance therapy in June 2020. I will talk about each of these new approvals in this commentary.
Erdafitinib is an oral, small molecule tyrosine kinase inhibitor of FGFR and is only approved by the FDA for patients who harbor a certain alteration in FGFR2 or FGFR3 in their tumors and who have UC that is progressing on or after treatment with platinum-containing chemotherapy. Erdafitinib is only effective in the subgroup of patients with these FGFR2 or FGFR3 alterations, but is a nice option for these patients because it can be taken once daily as an oral drug and was shown to be quite effective in the pivotal phase II trial.
There are some unique challenges with the use of erdafitinib that clinicians typically do not encounter when treating bladder cancer with chemotherapy or immune checkpoint inhibitors. This is an oral tyrosine kinase inhibitor, and there can be some chronic side effects that make it hard for some patients to tolerate. The key things to watch for that may be more uncommon are hyperphosphatemia, central serous retinopathy, and skin and nail bed changes. Other side effects that also occur with erdafitinib are the more typical ones: Nausea, fatigue, and lower blood counts; all of these we know how to watch for and are comfortable managing. Careful assessment for such side effects, and mitigation with supportive measures and dose adjustment is important.
For hyperphosphatemia, patients should be routinely monitored for potential increase in phosphate levels: Serum phosphate levels should be assessed 14 to 21 days after initiating treatment and monthly thereafter. Serum phosphate levels ≥ 7.0 mg/dL require dose hold and/or dose reductions, depending on severity and overall duration of hyperphosphatemia.
The other thing that we monitor closely for is central serous retinopathy, which requires eye exams monthly during the first 4 months of therapy, then every 3 months thereafter, to diagnose any eye disorders. An eye exam should also be performed if any symptoms occur, including dry eye or any change in vision. This AE can be mitigated in most cases by holding erdafitinib until resolution of central serous retinopathy, then restarting at a reduced dose if symptoms resolve within 4 weeks. If grade 4 ocular toxicity occurs, erdafitinib should be permanently discontinued.
Finally, we also watch carefully for any skin and/or nailbed changes. For example, some patients can have pain around their nailbeds and, in some cases, the fingernails can actually lift off the fingers. This AE can be particularly painful and may limit a patient’s ability to use their hands in the way they’re used to. Close monitoring and prompt dose holds and reductions can also help mitigate these AEs.
We counsel patients about each of these potential AEs before we start therapy, and we monitor closely for each of these potential problems, but generally, with the appropriate holds and reductions, we can achieve a therapeutic dose of erdafitinib for patients to allow them to stay on their therapy for a prolonged time. For these patients with FGFR2/3 alterations who can tolerate erdafitinib, it can be very effective for their metastatic UC.
Enfortumab vedotin is an antibody-drug conjugate that targets nectin‑4, which is expressed on almost all urothelial tumors, and releases the small-molecule toxin monomethyl auristatin E (MMAE) as the payload. MMAE is a microtubule inhibitor similar to a taxane. The way I think of enfortumab vedotin and the way I explain it to patients is that it is sort of a targeted chemotherapy, although it is notably more effective than traditional taxanes are in this setting. In the pivotal EV-201 clinical trial, 84% of patients were noted to have tumor shrinkage, and the ORR was 44% in patients who received previous checkpoint inhibitors and platinum-based chemotherapy, which is impressive. Based on these data, enfortumab vedotin was approved by the FDA in December 2019 for patients with UC after previous treatment with an immune checkpoint inhibitor and platinum-based chemotherapy.
Enfortumab vedotin is an important new tool for the treatment of patients with bladder cancer, but, just like with any new therapy, it is important to know how to best use it in clinical practice.
The dosing schedule for enfortumab vedotin requires frequent infusion—weekly for 3 weeks in a row, then 1 week off. This is a similar schedule to one used for paclitaxel in bladder cancer, so it can be easy to remember that way. In terms of counseling patients who are considering enfortumab vedotin, we tend to use a similar approach to patient counseling as we do for taxane chemotherapy, with the modification that the expected outcomes are likely to be better.
The most common AEs with enfortumab vedotin are similar to what we see with taxane chemotherapy: Low platelet, white blood cell, and red blood cell counts. Some patients may experience alopecia, where the patient loses all their hair and, over time, patients can develop neuropathy. In fact, neuropathy has been the dose‑limiting toxicity for most patients who have achieved a benefit and have been receiving enfortumab vedotin for an extended period of time. Another issue to watch for is hyperglycemia, particularly in patients with diabetes. For these patients, diabetes should be well controlled before initiating therapy with enfortumab vedotin. For each of these AEs, dose reduction or holds can help mitigate the toxicity and keep patients on therapy for optimal outcomes.
The latest new development in UC was the release of the phase III JAVELIN 100 trial data. This clinical trial enrolled patients who had achieved a response (CR, PR, or stable disease) to a first-line platinum‑based chemotherapy, either cisplatin plus gemcitabine or carboplatin plus gemcitabine, and randomized them to receive maintenance avelumab every 2 weeks or best supportive care with a treatment break (the current standard of care).
This study showed a nice OS benefit with maintenance avelumab vs standard of care, and a really excellent OS benefit in comparison with historical studies, with a median OS of 21.4 months. Based on these data, the FDA approved maintenance avelumab for patients who have not progressed on first-line platinum-based chemotherapy. What these data indicate to us is that, with rare exception, we probably should not recommend the usual treatment break following first-line chemotherapy, but rather that chemotherapy be followed by maintenance immune checkpoint therapy for best results.
For me, the JAVELIN Bladder 100 data have really changed my clinical practice. For our patients who are cisplatin‑eligible, we have always used cisplatin-based chemotherapy, but now we will follow 4 to 6 cycles of chemotherapy with a switch maintenance with an immune checkpoint inhibitor. For patients who are ineligible for cisplatin but are able to receive carboplatin, rather than assess their PD-L1 expression with the aim of upfront immune checkpoint inhibitor therapy, we recommend they start with carboplatin plus gemcitabine for 4 to 6 cycles and switching to maintenance an immune checkpoint inhibitor for the majority of patients. Certainly use of first-line atezolizumab or pembrolizumab remains a reasonable option for PD-L1–positive, cisplatin‑ineligible patients, but pretreatment with carboplatin will increase the overall likelihood of benefit for a given patient.
Using These New Agents in Clinical Practice
In my clinical practice, there are a few things we do to help us decide the best sequence of available treatment options. For most of our patients with UC, we are now recommending broad-panel biomarker testing early on. Not only does this allow us to know patients’ PD-L1 status, but we are also able see if they have the appropriate FGFR alteration that would make erdafitinib an option for them, along with getting a general sense of their overall genetic profile. With this information, we usually begin frontline therapy with a platinum‑based chemotherapy, followed by maintenance immune checkpoint inhibitor therapy. In rare cases, we may consider immunotherapy first if they are PD-L1 positive and cisplatin‑ineligible. Once a patient’s disease progresses through both an immune checkpoint inhibitor and platinum‑based chemotherapy, we usually move on to enfortumab vedotin for most patients. For a patient with an FGFR2/3 alteration, you have a choice between enfortumab vedotin and erdafitinib. This choice is generally made based on clinician and patient preference. For a patient who may do poorly with the chemotherapy-type AEs associated with enfortumab vedotin, consider erdafitinib first. For someone who would be expected to do poorly with the potential for skin, eye, and electrolyte abnormalities with erdafitinib, consider enfortumab vedotin first. Overall, for these patients, you are not choosing either/or, you are ultimately choosing which one of these new agents to use first, because it is not uncommon for our patients with UC to cycle through all 4 lines of therapy.
I also always consider clinical trials for my patients with cancer, and there are currently many exciting new treatment approaches being explored in trials.
Learn More About Using These New Treatment Options
Be sure to check back on this site as we develop more online resources to help frontline oncology clinicians, including short video segments on optimizing treatment decision for patients with UC with perspectives from an oncology nurse practitioner and a pharmacist, downloadable slides from the videos, and downloadable PDFs with key clinical practice considerations for clinicians and patients.