Precision Therapy in Urothelial Cancer: New Molecular Enrichment Approaches

• It is easily reproducible: anyone can do it, it’s not open to interpretation (everyone agrees), and it does not fluctuate or change
• It is beneficial: it predicts response in that it selects patients that should or should not receive specific therapy, and it predicts toxicity 

There are several biomarkers that are currently in use for urothelial cancer, including (i) PD-L1, which is front-line treatment (atezolizumab or pembrolizumab) for metastatic/unresectable urothelial cancer for patients not eligible for platinum-based therapy, and (ii) FGFR3 (erdafitinib), which is for previously treated metastatic/unresectable urothelial cancer. 

Erdafitinib gained prominence last year through the BLC2001 trial published in the New England Journal of Medicine.¹ This was an open-label, phase 2 study, for patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified FGFR alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. The primary endpoint was the objective response rate, and key secondary endpoints included progression-free survival, duration of response, and overall survival. There were 99 patients that received a median of five cycles of erdafitinib, with a rate of confirmed response to erdafitinib therapy of 40% (3% with a complete response and 37% with a partial response). The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Importantly, based on these results, erdafitinib received FDA accelerated approval in April 2019. 

According to Dr. Siefker-Radtke, the best biomarker for benefit from immunotherapy is the response to immunotherapy. The first biomarker in urothelial carcinoma was PD-L1 testing, however, this proved to be too dynamic (increased levels post-chemotherapy, post-BCG, and after PD-L1 therapy) with too much antibody variability. Other biomarkers that have been assessed include the IFN-gamma signature, CD8 cells (which predicted response in Imvigor 210² and CheckMate 275³), and chemokines involved in these pathways, including CXCL9 and CXCL10. Additionally, tumor mutational burden and DDR mutations have been utilized, notably leading to FDA approval for pembrolizumab for MSI-high and high tumor mutational burden solid tumors. Stromal factors, including TGFbeta, EMT, and T-cell expression have also been assessed. Furthermore, regarding stromal pathways, patients with FGFR alterations may respond to FGFR inhibition better than to immune-oncology therapy. In data presented at ASCO 2018, among patients treated with prior immunotherapy, patients subsequently treated with erdafitinib had an objective response rate of 59%:
Dr. Siefker-Radtke concluded with the following take-home messages regarding biomarkers in immunotherapy response:

• Response matters and may be associated with long-term benefit
• PD-L1 has limitations
• Multiple other markers may help us understand the immune response
• It is possible that we can impact the immune environment to induce a response, as well as mechanisms to resistance

1. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2019 Jul 25;381(4):338-348.
2. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 2016;387(10031):1909-1920.
3. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18(3):312-322.