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To describe the role of anti-angiogenic agents that have been used as a treatment approach for locally advanced or metastatic urothelial cancers and to propose future directions. PubMed/MEDLINE was searched for articles related to VEGF inhibition and locally advanced or metastatic urothelial cancer. Angiogenesis is a fundamental process for urothelial cancer initiation and progression. First-line therapy for locally advanced or metastatic urothelial cancer includes cisplatin-based chemotherapy combinations; subsequent systemic therapy includes taxanes, nanoparticle albumin-bound (nab) paclitaxel, or pemetrexed. More recently, several anti-PD-L1 and anti-PD-1 antibodies have shown promising activity in the first-line and post-platinum setting; however, immunotherapy remains ineffective in most patients. FGFR inhibitor erdafitinib was recently approved in the third-line setting. Studies on bevacizumab, pazopanib and ramucirumab have shown improved response rates when added to chemotherapy in selected patients, but have not led to overall survival (OS) benefit in randomized controlled studies. Anti-angiogenic agents have shown promise in recent studies treating locally advanced or metastatic urothelial cancer. However, further work is needed to elucidate ideal treatment combinations in selected patient populations to maximize benefit, with the ultimate goal of being added to the FDA-approved treatment armamentarium for this disease.

Metastatic urothelial carcinoma (UC) carries a poor prognosis and a 5-year overall survival of less than 5%, despite standard of care therapy using cisplatin-based chemotherapy and immune checkpoint inhibitors. Thus, novel agents that improve survival and have an acceptable toxicity profile are urgently needed. Antibody-drug conjugates (ADCs) represent a promising new treatment option that utilizes the targeting ability of an antibody to deliver cytotoxic drugs directly to tumors. Many ADCs are currently being investigated for treatment of UC, with enfortumab vedotin being recently approved by the US Food and Drug Administration for treatment of metastatic UC with progressive disease after chemotherapy and/or immune checkpoint inhibitors. Overall, ADCs hold promise as a long-awaited treatment option for UC.

Venetoclax (VEN) is a selective BCL-2 inhibitor that has been shown to be effective when used in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) for treatment-naive, elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Data on its use in the relapsed/refractory setting are limited. A retrospective analysis was performed among 14 patients with relapsed or refractory AML treated with VEN combination therapy at the University of California Los Angeles from 2018-2019. Eight patients received VEN in combination with azacitidine, 5 patients with decitabine, and 1 patient with LDAC. The majority (10 patients, 71.4%) had adverse cytogenetics. Three patients (21.4%) had undergone an allogeneic stem cell transplant prior to VEN therapy, and 5 patients (35.7%) had leukemia that failed HMA therapy prior. The objective response rate (ORR) was 35.7% (3 patients achieved complete remission with incomplete hematologic recovery and 2 patients achieved partial remission). Three patients (21.4%) were successfully transitioned to either allogeneic bone marrow transplant (2 patients) or donor lymphocyte infusion (1 patient). Seven patients (50.0%) developed a grade 3 or greater infection following VEN therapy, and 3 patients (21.4%) developed a grade 3 or greater intracranial hemorrhage. Three patients experienced early death within 30 days of therapy (2 from infection, 1 from bleeding). The median overall survival (OS) was 4.7 months, and the 1-year OS rate was 23.6% (95% CI 4.4-51.2) for the entire patient cohort. Overall, the response rate was not inferior to that with conventional salvage chemotherapy, but there were notable complications as a result of prolonged cytopenias.