However, a subset of patients are ineligible to receive platinum-containing chemotherapy due to poor renal function, poor performance status, heart failure, hearing loss, and/or peripheral neuropathy.2 Furthermore, for patients who experience disease progression on first-line Cisplatin-based chemotherapy, additional chemotherapy is deemed minimally effective in this population. This dilemma creates the need for contemporary immunotherapy and targeted therapy options for urothelial carcinoma.
This comprehensive review article highlights the evolution of immune checkpoint inhibitors (ICI) in the treatment landscape of bladder cancer. In phase II and III clinical trials, PD-1 inhibitors and PD-L1 inhibitors demonstrate potential as monotherapy3–5 and as components of combination regimen6–10 in the neoadjuvant setting. However, we emphasize that immune checkpoint inhibition is not yet FDA-approved in the neoadjuvant space for MIBC. In contrast, in the adjuvant setting, we explore the level I evidence from CheckMate-274 phase III trial11 supporting the FDA approval of adjuvant Nivolumab after radical cystectomy for high-risk UC (pT3-4 and/or node-positive disease). We further anticipate pending results from the phase III AMBASSADOR trial for adjuvant Pembrolizumab.12
We additionally evaluate the comparatively mature evidence supporting immune checkpoint inhibition in the first-line and salvage setting for la/mUC. Atezolizumab and Pembrolizumab are FDA-approved as first-line monotherapy for platinum-ineligible patients irrespective of PD-L1 status. Furthermore, three ICIs (Pembrolizumab, Nivolumab, Avelumab) have been FDA-approved in the salvage setting for platinum-refractory mUC. For the PD-L1 inhibitor Durvalumab, FDA approval in the first-line setting for la/mUC was withdrawn based on the phase III DANUBE clinical trial that failed to meet the primary overall survival endpoint.13 Contemporary phase III evidence (JAVELIN Bladder-100) further supports Avelumab as maintenance therapy in la/mUC that has not progressed on initial platinum-containing chemotherapy.14
We provide updated evidence to support evolving therapies including antibody-drug conjugates (ADCs) for selective targeting of cancer cells. ADCs aims to increase drug concentration in target tissues while reducing systemic cytotoxicity by conjugating a cytotoxic agent payload to tumor antigen-specific monoclonal antibodies.15 Two ADCs, Enfortumab Vedotin (EV) and Sacituzumab Govitecan (SG), currently play a role in the la/mUC space in the second-line post-chemotherapy setting or third-line post-ICI setting. The phase III EV-301 trial randomized patients with la/mUC who previously received platinum-containing chemotherapy and progressed on ICI to receive EV versus alternative chemotherapy and demonstrated both overall survival and progression-free survival benefit.16 The phase II TROPHY-U-01 trial is ongoing to evaluate SG in the third-line setting;17 interim results have been promising, leading to accelerated FDA approval of SG in 2021 in this space.18
Finally, this article reviews contemporary studies of targeted therapies in UC, including FGFR inhibitors, other tyrosine kinase inhibitors (TKIs), and poly(ADP-ribose) polymerase (PARP) inhibitors. The current evidence supporting multikinase TKIs and PARP inhibition in bladder cancer is conflicting and warrants additional investigation in la/mUC. However, the phase II BLC2001 trial examining the FGFR inhibitor Erdafitinib as third-line therapy for la/mUC showed a high objective response rate in patients who received prior ICI, driving FGFR inhibitors to the forefront as a promising candidate for patients with FGFR2/FGFR3 genetic alterations.19 As the treatment landscape of bladder cancer evolves rapidly beyond cisplatin-based chemotherapy, we anticipate a strategy shift to novel combination regimens.
Written by: JJ H. Zhang, MD & Karim Chamie MD, Institute of Urologic Oncology, Department of Urology, University of California Los Angeles (UCLA)
References:
- Flaig TW, Spiess PE, Chair V, et al. NCCN Guidelines Version 2.2022 Bladder Cancer.; 2022.
- Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer “Unfit” for cisplatin-based chemotherapy. Journal of Clinical Oncology. 2011;29(17):2432-2438. doi:10.1200/JCO.2011.34.8433
- Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): An open-label, single-arm, phase II study. Journal of Clinical Oncology. 2018;36(34):3353-3360. doi:10.1200/JCO.18.01148
- Necchi A, Raggi D, Gallina A, et al. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2020;77(4):439-446. doi:10.1016/j.eururo.2019.10.026
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- Powles T, Drakaki A, Teoh JYC, et al. A phase 3, randomized, open-label, multicenter, global study of the efficacy and safety of durvalumab (D) + tremelimumab (T) + enfortumab vedotin (EV) or D + EV for neoadjuvant treatment in cisplatin-ineligible muscle-invasive bladder cancer (MIBC) (VOLGA). Journal of Clinical Oncology. 2022;40(6_suppl):TPS579-TPS579. doi:10.1200/JCO.2022.40.6_suppl.TPS579
- Gupta S, Gibb E, Sonpavde GP, et al. Biomarker analysis and updated clinical follow-up from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in patients with muscle-invasive bladder cancer (MIBC) undergoing cystectomy. Journal of Clinical Oncology. 2022;40(6_suppl):528-528. doi:10.1200/JCO.2022.40.6_suppl.528
- Powles T, Meeks JJ, Galsky MD, et al. A phase III, randomized, open-label, multicenter, global study of efficacy and safety of durvalumab in combination with gemcitabine plus cisplatin for neoadjuvant treatment followed by durvalumab alone for adjuvant treatment in muscle-invasive bladder cancer (NIAGARA). Journal of Clinical Oncology. 2021;39(6_suppl):TPS505-TPS505. doi:10.1200/JCO.2021.39.6_suppl.TPS505
- Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. New England Journal of Medicine. 2021;384(22):2102-2114. doi:10.1056/nejmoa2034442
- Testing MK-3475 (Pembrolizumab) After Surgery for Localized Muscle-Invasive Bladder Cancer and Locally Advanced Urothelial Cancer (AMBASSADOR). ClinicalTrials.gov Identifier:NCT03244384. Published online 2017. Accessed August 18, 2022.
- Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1574-1588. doi:10.1016/S1470-2045(20)30541-6
- Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine. 2020;383(13):1218-1230. doi:10.1056/nejmoa2002788
- Nagayama A, Ellisen LW, Chabner B, Bardia A. Antibody–Drug Conjugates for the Treatment of Solid Tumors: Clinical Experience and Latest Developments. Target Oncol. 2017;12(6):719-739. doi:10.1007/s11523-017-0535-0
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- Study of Sacituzumab Govitecan in Participants With Urothelial Cancer That Cannot Be Removed or Has Spread (TROPHY U-01). ClinicalTrials.gov Identifier: NCT03547973. Published 2022. Accessed September 25, 2022.
- FDA Grants Accelerated Approval to Sacituzumab Govitecan for Advanced Urothelial Cancer.
- Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine. 2019;381(4):338-348. doi:10.1056/nejmoa1817323