Systemic Immunotherapy for Urothelial Cancer: Current Trends and Future Directions

Abstract

Urothelial cancer of the bladder, renal pelvis, ureter, and other urinary organs is the fifth most common cancer in the United States, and systemic platinum-based chemotherapy remains the standard of care for first-line treatment of advanced/metastatic urothelial carcinoma (UC). Until recently, there were very limited options for patients who are refractory to chemotherapy, or do not tolerate chemotherapy due to toxicities and overall outcomes have remained very poor. While the role of immunotherapy was first established in non-muscle invasive bladder cancer in the 1970s, no systemic immunotherapy was approved for advanced disease until the recent approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in patients with advanced/metastatic UC who have progressed on platinum-containing regimens. This represents a significant milestone in this disease after a void of over 30 years. In addition to atezolizumab, a variety of checkpoint inhibitors have shown a significant activity in advanced/metastatic urothelial carcinoma and are expected to gain Food and Drug Administration (FDA) approval in the near future. The introduction of novel immunotherapy agents has led to rapid changes in the field of urothelial carcinoma. Numerous checkpoint inhibitors are being tested alone or in combination in the first and subsequent-line therapies of metastatic disease, as well as neoadjuvant and adjuvant settings. They are also being studied in combination with radiation therapy and for non-muscle invasive bladder cancer refractory to BCG. Furthermore, immunotherapy is being utilized for those ineligible for first-line platinum-based chemotherapy. This review outlines the novel immunotherapy agents which have either been approved, or are currently being investigated in clinical trials in UC.

How Can Immune Checkpoint Inhibitors Cause Hyperprogression in Solid Tumors?

“…Immunotherapies targeting immune checkpoints are increasingly used in the relapse setting and are rapidly becoming a component of first-line therapies for melanoma, NSCLC, small cell lung cancer, advanced renal cell carcinoma, triple negative breast cancer, and Merkel cell carcinoma, sometimes in combination with chemotherapy and second line therapies for many tumor types (unresectable and metastatic melanoma, NSCLC, renal cell carcinoma, HNSCC, urothelial carcinoma, colorectal cancer, prostate cancer, and Hodgkin's lymphoma) with durable clinical benefits (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). This innovative approach is associated with immune-related adverse events (IRAE) which can be severe (grade 3 or 4) and involve a variety of tissues and organs (26,27).…”

Overall survival, costs, and healthcare resource use by line of therapy in Medicare patients with newly diagnosed metastatic urothelial carcinoma

“…More than half of the patients with mUC had at least one ICU visit during follow-up, with a higher proportion of patients in the chemotherapy-treated group (60%) versus no- chemotherapy group (47%) visiting the ICU (Table 2); the proportions visiting the ICU were comparable in the LOT2 only and LOT3þ groups (60% and 59%, respectively). Similarly, outpatient office visits also increased as patients received more LOTs: the median (IQR) number of office visits per patient increased from seven (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) visits in the nochemotherapy group to 32 (18-52), 47 (34-69), and 75 (55-107) visits in the LOT1, LOT2, and LOT3þ groups, respectively (p < 0.001; Table 2).…”

“…Although UC is relatively sensitive to chemotherapy, overall survival is poor for patients with mUC as chemotherapy does not result in long-term cure, even among those who initially respond 6,7 . Also, treatment options for patients who do not tolerate or are refractory to chemotherapy remain limited 8 . Before approval of an immuno-oncology agent in 2016 9 , the only approved treatment options for patients who progressed after platinum-based chemotherapy were secondline chemotherapies such as paclitaxel, docetaxel, gemcitabine, pemetrexed, alkylating agents, or possibly anthracyclines 10 .…”

Practical Molecular Testing in a Clinical Genitourinary Service

“…81 Trials are underway for similar drugs, including durvalumab, pembrolizumab, avelumab, nivolumab, and ipilimumab. 82 Thus, it is likely that testing for PD-L1 expression in biopsies and resections for UC may become more routine in the near future. Indeed, the FDA has already approved the use of several of these agents with IHC as a companion diagnostic test in select patients with UC.…”