The evolving role of biomarker testing, including PD-L1 expression and mutations like FGFR3, in guiding treatment decisions for urothelial cancer patients, shedding light on their clinical significance and potential impact on therapeutic choices.
Arlene O. Siefker-Radtke, MD: [I am] also frequently asked what types of additional tests we should be doing for our urothelial cancer patients. I think most of us know the typical staging with CT scans and the typical blood work criteria, but we are seeing the development of markers that might be associated with prognosis and clinical outcomes and targeted strategies. Testing for PD-L1 was one of the earliest markers that was pursued for the treatment of urothelial cancer patients. However, it currently does not play much of a role for the treatment of urothelial cancer patients. In the frontline setting, we saw for frontline metastatic disease, PD-L1 expression might be associated with improved response rate to immune checkpoint inhibitors.
However, given the potential for benefit with the novel chemotherapy and IO [immune-oncology] options in combination with novel agents, we really don’t see as much single-agent immunotherapy being used in academic centers. Now, that being said, we realize there’s a large unmet need for patients who are not eligible for any chemotherapy and may receive treatment with an immune checkpoint inhibitor regardless of PD-L1 expression levels. In the subsequent lines of treatment, PD-L1 expression has not played an important role in clinical outcomes, and checkpoint inhibitors are given regardless of whether the patient has high or low expression of PD-L1 by the different prognostic scores, including CPS [combined positive score].
An additional marker that’s gaining favor is testing for known mutations that might be associated with potential treatment options. We recently saw approval of erdafitinib for patients with FGFR3 alterations. However, these alterations, which are typically mutations or fusions, are present in about 15% to 20% of urothelial tumors of the bladder and up to 35% of urothelial tumors of the upper tract, which include the renal pelvis and ureter. So I would definitely argue testing for these mutations is important as it may be clinically relevant if your patient has an FGFR3 alteration present.
There may also be clinical trials targeting additional mutation strategies. So if you have a patient who may be interested in clinical trials, having a full panel of mutations may be highly applicable. Additional questions often come up regarding the antibody drug conjugates. We have enfortumab vedotin, which targets nectin-4 expression, but nectin-4 expression is present in a high percentage of urothelial cancer patients. Over 90% will have nectin-4 expression. So testing for nectin-4 is not a requirement for treatment with agents like enfortumab vedotin. We also have another novel antibody drug conjugate, sacituzumab govitecan, which targets TROP2 expression and TROP2 is also highly expressed in urothelial cancer patients…so there’s no testing required for TROP2 expression to consider sacituzumab govitecan.
There [are] additional predictive and potential prognostic markers, such as circulating free DNA, which are being tested in the neoadjuvant and adjuvant spaces to detect early biologic progresses before…metastatic disease is evident on imaging. The current role of these assays in treatment of our metastatic urothelial cancer patients is certainly still under review. More work should be done before we’re doing it routinely, I would argue, across all patient populations until we see definitive subsets that benefit from the ability to detect biologic tumor in the blood or in the circulation before it is evident on CT imaging.
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Case: A 73-Year-Old Man with Metastatic Urothelial Carcinoma
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