New and Emerging Therapies in the Management of Bladder Cancer
The treatment landscape for bladder cancer has undergone a rapid evolution in the past five years with the approval of seven new agents. New classes of medications have improved outcomes for many patients who previously had limited treatment options, but there is still much to learn about how to optimize patient selection for these agents and the role of combination therapies. The aims of this review are to discuss these newly approved agents for bladder cancer and to feature promising drugs and combinations—including immune checkpoint inhibitors, targeted therapies, and antibody–drug conjugates—that are in development.
Keywords: urothelial carcinoma, metastatic, muscle-invasive bladder cancer, immunotherapy, targeted therapy, antibody-drug conjugate
Bladder cancer is the sixth most common malignancy in the US, where over 80,000 new cases are diagnosed per year
1. Non-muscle-invasive bladder cancer (NMIBC) is typically managed with local therapy, including transurethral resection of bladder tumors (TURBT) and intravesical bacillus Calmette–Guérin (BCG) or chemotherapy. NMIBC has an excellent 5-year overall survival (OS) of 70 to 96%
1. However, there is also a high rate of recurrence and potential for disease progression
2. For muscle-invasive bladder cancer (MIBC), survival outcomes are significantly decreased and treatment, including cystectomy with perioperative chemotherapy or tri-modality therapy (TMT) that includes TURBT, chemotherapy, and radiation therapy, is more aggressive, whereas metastatic disease is generally managed with palliative systemic therapy and has a 5-year OS of about 5%
Platinum-based chemotherapy has been the first-line treatment for metastatic bladder cancer for over 20 years. Overall response rates (ORRs) range from 40 to 50% but this response is generally short-lived
3. Until recently, options for second-line treatment or platinum-ineligible patients have been limited. However, since 2016, seven new agents have been approved by the US Food and Drug Administration (FDA) for locally advanced (LA) or metastatic urothelial carcinoma (mUC) and this has dramatically changed the treatment landscape. The aims of this review are to highlight these newly approved therapies and to discuss promising new treatment strategies for bladder cancer that are on the horizon.
Immune checkpoint inhibitors
The introduction of immunotherapy with agents targeting programmed cell death protein 1 or its ligand (anti-PD-[L]1) marked an important turning point in the management of bladder cancer. Currently, five anti-PD-(L)1 drugs are approved by the FDA for urothelial carcinoma: atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab. Following initial success in the mUC setting, numerous trials now use these and other anti-PD-(L)1 agents alone and in combination across the continuum of bladder cancer.
Immunotherapy for metastatic urothelial carcinoma post-platinum
All five of the anti-PD-(L)1 agents for urothelial carcinoma are currently approved by the FDA as treatment for LA/mUC patients who have disease progression during or following platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment for localized disease with platinum-based chemotherapy. In the trials leading to their approval
8, ORRs across all patients ranged from 15% with atezolizumab in IMvigor210
6 to 21.1% with pembrolizumab in KEYNOTE-045
8. Median OS ranged from 6.5 months with avelumab
4 to 18.2 months with durvalumab
5. Importantly, the phase III KEYNOTE-045 trial of pembrolizumab now has over 2 years of patient follow-up demonstrating a continued OS benefit over second-line chemotherapy with median OS of 10.1 months with pembrolizumab and 7.3 months with chemotherapy (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.57–0.85)
9. The IMvigor211 study was a similarly designed phase III randomized trial comparing atezolizumab versus chemotherapy. However, the primary endpoint, OS, was tested hierarchically in prespecified populations—that is, IC2/3 (PD-L1 expression on at least 5% of tumor-infiltrating immune cells), followed by IC1/2/3, and then the intention-to-treat population. In the IC2/3 population, there was no significant difference in median OS (atezolizumab 11.1 months versus chemotherapy 10.6 months; HR 0.87, 95% CI 0.63–1.21), precluding further formal statistical analyses in the other prespecified populations and thereby resulting in an overall negative study
Investigation into the use of immunotherapy combinations post-platinum is ongoing, but early data are promising (
). The phase II CheckMate 032 trial compared nivolumab monotherapy with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3)
11. In PD-L1 unselected patients, ORR ranged from 25.6% with nivolumab alone to 38% with NIVO1+IPI3. In patients with PD-L1 expression of at least 1%, ORRs were 26.9% with nivolumab alone but 58.1% with NIVO1+IPI3. Furthermore, median OS was 9.9 months with nivolumab alone and 15.3 months with NIVO1+IPI3 across all patients but was 12.9 and 24.1 months, respectively, in patients with PD-L1 expression of at least 1%. Although grade 3 or 4 treatment-related adverse events were more common with NIVO1+IPI3 compared with nivolumab (39.1% versus 26.9%), these results suggest that combination therapy may provide a significant benefit over monotherapy, particularly for patients whose tumors express PD-L1.
Selected trials in locally advanced/metastatic urothelial carcinoma with available results.