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Management of Muscle-Invasive Urothelial Cancer and the Emerging Role of Immunotherapy in Advanced Urothelial Cancer

      Abstract

      The incidence of bladder cancer has increased in the past decade, and mortality from bladder cancer remains a substantial public health burden. After 3 decades of minimal progress in the treatment of advanced-stage disease, recent advances in the genomic characterization of urothelial cancer and breakthroughs in bladder cancer therapeutics have rejuvenated the field. This review highlights the landmark clinical trials of chemotherapy in both the neoadjuvant and advanced or metastatic urothelial carcinoma settings. We describe treatment paradigms for multimodal treatment of locally advanced bladder cancer, including discussion on bladder preservation strategies. Lastly, we discuss novel immunomodulatory, targeted, and combination therapies in development for the treatment of advanced urothelial carcinoma.

      Abbreviations and Acronyms:

      AKT (AKT serine/threonine kinase 1), BCG (bacillus Calmette-Guérin), CTLA4 (cytotoxic T-lymphocyte–associated protein 4), EGFR (epidermal growth factor receptor), FDA (Food and Drug Administration), FGFR (fibroblast growth factor receptor), GC (gemcitabine plus cisplatin), GCa (gemcitabine and carboplatin), HER2 (human epidermal growth factor receptor 2), IC (immune cell), MIBC (muscle-invasive bladder cancer), mTOR (mechanistic target of rapamycin), MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), NMIBC (non–muscle-invasive bladder cancer), OS (overall survival), PD-1 (programmed cell death 1), PD-L1 (programmed cell death ligand 1), PFS (progression-free survival), PI3K (phosphatidylinositol-3-OH kinase), TCGA (The Cancer Genome Atlas), UC (urothelial carcinoma)
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      Learning Objectives: On completion of this article, you should be able to (1) emphasize the multimodal collaborative approach to managing locally advanced and muscle-invasive bladder cancer, (2) describe the evolving role for immunotherapy in treating patients with advanced urothelial carcinoma and our understanding of the toxicity profile of anti–programmed cell death 1 or anti–programmed cell death ligand 1 treatments, and (3) characterize potential driver mutations in bladder cancer that may be amenable to targeted therapies.
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      In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
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      Bladder cancer is the fifth most common cancer in the United States, with an estimated 77,000 new cases diagnosed in 2016.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2016.
      At the time of diagnosis, most patients present with non–muscle-invasive bladder cancer (NMIBC), which has a 50% to 70% rate of superficial recurrence and a 10% to 30% rate of progression to muscle-invasive bladder cancer (MIBC).
      • Burger M.
      • Catto J.W.
      • Dalbagni G.
      • et al.
      Epidemiology and risk factors of urothelial bladder cancer.
      • Kamat A.M.
      • Hahn N.M.
      • Efstathiou J.A.
      • et al.
      Bladder cancer.
      One in 4 patients presents at first diagnosis with either MIBC or metastatic bladder cancer. Muscle-invasive bladder cancer outcomes remain poor despite aggressive multimodal treatment, with less than 10% survival at 5 years.
      • Abdollah F.
      • Gandaglia G.
      • Thuret R.
      • et al.
      Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis.
      After nearly 3 decades of limited advances in the treatment and systemic management of urothelial cancer, recent advances in immunotherapy are now available for controlling disease progression. Atezolizumab, nivolumab, durvalumab, and avelumab are among the exciting recent novel therapeutic advances given accelerated approvals by the US Food and Drug Administration (FDA) for treatment of advanced-stage urothelial carcinoma, (the first FDA-approved drug for urothelial carcinoma since cisplatin in 1978). An in-depth genomic characterization of urothelial tumors has shed new insights into the oncogenesis and progression of bladder cancer by evaluating the mutational landscape in urothelial carcinomas and identifying potential future molecular targets. This article describes these new developments and provides an overview of the current systemic management of MIBC, neoadjuvant and adjuvant trials in locally advanced disease, genomic profiling, biomarker development, and systemic therapies for advanced metastatic urothelial carcinoma (UC). Nonurothelial bladder cancers are mentioned briefly in this review.

      Histologic, Molecular, and Genomic Landscape of Bladder Cancer

      Histology of Bladder Cancer

      The urothelial tract is conventionally divided into the upper urinary tract (renal pelvis and ureters) and lower urinary tract (bladder and urethra). Most urothelial tract tumors originate in the lower urothelial tract, with 90% developing in the bladder. An additional 8% develop in the renal pelvis, and primary ureteral or urethral malignancies are rare.
      • Rouprêt M.
      • Babjuk M.
      • Compérat E.
      • et al.
      European Association of Urology guidelines on upper urinary tract urothelial cell carcinoma: 2015 update.
      Urothelial (or transitional cell) carcinomas are the most common histologic subtype in the United States and are categorized as flat or papillary lesions. Urothelial carcinomas have a propensity for divergent differentiation. The most common mixed morphology combines “usual type” UC with squamous (40%) or glandular (20%) features.
      • Humphrey P.A.
      • Moch H.
      • Cubilla A.L.
      • Ulbright T.M.
      • Reuter V.E.
      The 2016 WHO classification of tumours of the urinary system and male genital organs—part B: prostate and bladder tumours.
      Often, pathologic reports indicate a component percentage of each histologic subtype.
      Pure adenocarcinomas of the urothelial tract are rare and are distinguished by urachal or nonurachal origins. The urachus degenerates after embryogenesis to form the median umbilical ligament (also called the Xander ligament); adenocarcinomas arising from these remnants tend to have a better prognosis than the nonurachal adenocarcinomas.
      • Wright J.L.
      • Porter M.P.
      • Li C.I.
      • Lange P.H.
      • Lin D.W.
      Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder.
      Our discussion will focus on the predominant histologic subtype, transitional urothelial cell carcinoma.

      Comprehensive Gene Expression Profiling for Identification of Multiple Molecular Subtypes of MIBC

      The categorization and nomenclature used to describe urothelial cancer subtypes has recently shifted beyond histologic classification toward intrinsic subtypes, with hopes that it will more accurately reflect tumor biology and clinical outcomes. Several groups have conducted comprehensive whole-genome expression profiling of high-grade bladder cancer or MIBC.
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      • Damrauer J.S.
      • Hoadley K.A.
      • Chism D.D.
      • et al.
      Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology.
      • Choi W.
      • Porten S.
      • Kim S.
      • et al.
      Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.
      • Sjödahl G.
      • Lauss M.
      • Lövgren K.
      • et al.
      A molecular taxonomy for urothelial carcinoma.
      Regardless of study-specific terminology, several common biological trends have emerged (Figure 1).
      Figure thumbnail gr1
      Figure 1Muscle-invasive bladder cancer subtypes with integrated analysis linking both histologic origins, commonly observed molecular abnormalities, and clinicopathologic phenotypes. Generalized comparisons across each urothelial subtype from Lund University (Lund),
      • Sjödahl G.
      • Lauss M.
      • Lövgren K.
      • et al.
      A molecular taxonomy for urothelial carcinoma.
      the Cancer Genome Atlas (TCGA),
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      MD Anderson Cancer Center (MDA),
      • Choi W.
      • Porten S.
      • Kim S.
      • et al.
      Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.
      and the University of North Carolina (UNC)
      • Damrauer J.S.
      • Hoadley K.A.
      • Chism D.D.
      • et al.
      Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology.
      studies are represented. Selected common molecular and clinicopathologic features generally associated with each subtype are also presented. EMT = epithelial to mesenchymal; GU = genomically unstable; SCC = squamous cell carcinoma; UroB = urobasal B; for expansion of gene symbols, see www.genenames.org.
      At the broadest level, urothelial tumors are divided into basal and luminal subtypes characterized by different patterns of gene expression.
      • McConkey D.J.
      • Choi W.
      • Ochoa A.
      • Dinney C.P.
      Intrinsic subtypes and bladder cancer metastasis.
      Basal tumors are associated with squamous or sarcomatoid differentiation, advanced-stage or metastatic disease at presentation, and a more aggressive clinical course.
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      • Choi W.
      • Ochoa A.
      • McConkey D.J.
      • et al.
      Genetic alterations in the molecular subtypes of bladder cancer: illustration in the Cancer Genome Atlas dataset.
      • Aine M.
      • Eriksson P.
      • Liedberg F.
      • Sjödahl G.
      • Höglund M.
      Biological determinants of bladder cancer gene expression subtypes.
      Luminal tumors commonly contain papillary features and harbor sequence variations similar to those observed in NMIBC (such as FGFR3), raising suspicion that these malignancies develop from NMIBC.
      • Kamat A.M.
      • Hahn N.M.
      • Efstathiou J.A.
      • et al.
      Bladder cancer.
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      • Damrauer J.S.
      • Hoadley K.A.
      • Chism D.D.
      • et al.
      Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology.
      This concept is supported by lineage tracing studies in preclinical models that identify the origin of tumor cells. These studies indicate that basal tumors arise from urothelial basal cells, and luminal tumors originate from luminal or intermediate cells from the urothelium (Figure 1).
      • Choi W.
      • Porten S.
      • Kim S.
      • et al.
      Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.
      Basal and luminal MIBCs have distinct biological and clinical characteristics, and developing accessible, reliable, and affordable techniques to categorize intrinsic subtypes within MIBC are of great interest. In addition to tissue messenger RNA expression, basal and luminal subtypes of urothelial cancer can be differentiated using immunohistochemistry
      • Dadhania V.
      • Zhang M.
      • Zhang L.
      • et al.
      Meta-analysis of the luminal and basal subtypes of bladder cancer and the identification of signature immunohistochemical markers for clinical use.
      or microRNA expression.
      • Ochoa A.E.
      • Choi W.
      • Su X.
      • et al.
      Specific micro-RNA expression patterns distinguish the basal and luminal subtypes of muscle-invasive bladder cancer.
      Efforts to unify categorizations within the molecular taxonomy remain a work in progress.
      • Lerner S.P.
      • McConkey D.J.
      • Hoadley K.A.
      • et al.
      Bladder cancer molecular taxonomy: summary from a consensus meeting.

      Effect of MIBC Genetic Sequence Variations on Cell Cycle Regulation, Epigenetic Regulation, and Signaling Pathways

      In 2014, the Cancer Genome Atlas (TCGA) Research Network released comprehensive profiling of 131 treatment-naive MIBC tumors that included sequencing data, DNA copy number, DNA methylation, messenger RNA expression, protein expression, microRNA expression, somatic sequence variations, and protein expression analysis.
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      Thirty-two significantly mutated genes were identified originally; updated analysis (to include the entire cohort of 412 chemotherapy-naive urothelial tumors) identified a total of 54 significantly mutated genes.
      • Choi W.
      • Ochoa A.
      • McConkey D.J.
      • et al.
      Genetic alterations in the molecular subtypes of bladder cancer: illustration in the Cancer Genome Atlas dataset.
      The integrated analysis highlighted 3 pathways with frequent abnormalities: cell cycle regulation, chromatin remodeling, and kinase and phosphatidylinositol-3-OH kinase (PI3K) signaling. TP53 (for expansion of gene symbols, see www.geneames.org), a tumor suppressor gene, was the most frequently mutated gene and was functionally inactive in 76% of samples. Another commonly inactivated tumor suppressor was RB1 (14% of samples). Alterations in epigenetic pathways were identified in 76% of tumors, including recurrent sequence variations of several chromatin-regulating genes. Lastly, integrated analysis frequently identified sequence variations, copy number abnormalities, or abnormal expression of RNA in the PI3K/AKT serine/threonine kinase 1 (AKT)/mechanistic target of rapamycin (mTOR) pathway (42%), and the receptor tyrosine kinase/Ras pathway (44%).
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.

      A High Rate of Somatic Sequence Variations and Sequence Variation-Associated Neoantigens

      Genomic profiling across 33 tumor types provided insight into the genetic instability and sequence variation of cancers. A large number of somatic DNA alterations were identified in urothelial cancer—with a mean somatic sequence variation rate of 7.7 per megabase (median, 5.5 per megabase)—which is a sequence variation burden comparable to melanoma and non–small cell lung cancer.
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      • Alexandrov L.B.
      • Nik-Zainal S.
      • Wedge D.C.
      • et al.
      Signatures of mutational processes in human cancer.
      One consequence of this sequence variation burden is the formation of sequence variation-associated neoantigens—peptides displayed on the tumor cell surface.
      • Schumacher T.N.
      • Schreiber R.D.
      Neoantigens in cancer immunotherapy.
      • Faltas B.
      • Bhinder B.
      • Beltran H.
      • et al.
      Generating a neoantigen map of advanced urothelial carcinoma by whole exome sequencing [abstract].
      Neoantigens may serve as tumor-specific targets for T cells, and a higher neoantigen count corresponds with improved outcomes in UC.
      • Choudhury N.J.
      • Kiyotani K.
      • Yap K.L.
      • et al.
      Low T-cell receptor diversity, high somatic mutation burden, and high neoantigen load as predictors of clinical outcome in muscle-invasive bladder cancer.
      Neoantigen burden also corresponds with response to immunotherapy in many solid organ malignancies, supporting the rationale for using immunomodulatory therapies in bladder cancer.
      • Rizvi N.A.
      • Hellmann M.D.
      • Snyder A.
      • et al.
      Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer.

      Non–Muscle-Invasive Bladder Cancer

      Non–muscle-invasive bladder cancer is confined to the mucosa (stage Ta or carcinoma in situ) or submucosa (stage T1). Most superficial bladder cancers are curable with local therapies. However, risk of recurrence remains a challenge, with nearly a 30% to 70% risk of superficial recurrence and 1% to 30% progression to muscle-invasive disease at 5 years.
      • Sylvester R.J.
      • van der Meijden A.P.
      • Oosterlinck W.
      • et al.
      Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials.
      • Fernandez-Gomez J.
      • Madero R.
      • Solsona E.
      • et al.
      Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model.
      Several nomograms predict risk of recurrence or progression to muscle-invasive disease.
      • Sylvester R.J.
      • van der Meijden A.P.
      • Oosterlinck W.
      • et al.
      Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials.
      • Fernandez-Gomez J.
      • Madero R.
      • Solsona E.
      • et al.
      Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model.
      Urologic associations have translated these probabilities to risk stratify patients into low-, intermediate-, and high-risk categories based on prior recurrences, number of tumors, tumor size, tumor grade, tumor stage, and presence of carcinoma in situ.
      • Babjuk M.
      • Böhle A.
      • Burger M.
      • et al.
      EAU guidelines on non–muscle-invasive urothelial carcinoma of the bladder: update 2016.
      • Chang S.S.
      • Boorjian S.A.
      • Chou R.
      • et al.
      Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline.
      Management is guided by risk categories and consists of transurethral resection of the bladder tumor, followed by monotherapy or combination therapy with intravesicular chemotherapy or intravesicular bacillus Calmette-Guérin (BCG) immunotherapy.
      • Kamat A.M.
      • Hahn N.M.
      • Efstathiou J.A.
      • et al.
      Bladder cancer.
      • Babjuk M.
      • Böhle A.
      • Burger M.
      • et al.
      EAU guidelines on non–muscle-invasive urothelial carcinoma of the bladder: update 2016.
      • Chang S.S.
      • Boorjian S.A.
      • Chou R.
      • et al.
      Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline.

      Treatment for MIBC

      Historical Perspective on Chemotherapy in Bladder Cancer

      The therapeutic benefit of platinum-based chemotherapy was established in the 1970s.
      • Yagoda A.
      • Watson R.C.
      • Gonzalez-Vitale J.C.
      • Grabstald H.
      • Whitmore W.F.
      Cis-dichlorodiammineplatinum(II) in advanced bladder cancer.
      • Yagoda A.
      Phase II trials with cis-dichlorodiammineplatinum(II) in the treatment of urothelial cancer.
      In the modern era, the 2 most commonly used regimens are gemcitabine plus cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC; also referred to as high-dose intensity MVAC or accelerated MVAC). These regimens were first studied in the metastatic setting, and the landmark studies leading to these regimens are summarized in Table 1.
      Table 1Landmark Phase 3 Trials of Chemotherapy in Bladder Cancer
      RegimenNo. of patientsOverall response rate (%), P valueMedian OS (mo), P valueBetter toleratedHighlightReference, year
      Metastatic: first-line treatment
       Cisplatin vs MVAC126

      120
      12

      39
      P<.0018.2

      12.5
      P<.001CisplatinEstablished combination chemotherapy as superior to single agentLoehrer et al,
      • Loehrer Sr., P.J.
      • Einhorn L.H.
      • Elson P.J.
      • et al.
      A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
      1992
       GC vs MVAC202

      203
      49

      46
      P=.5113.8

      14.8
      P=.75GCGC better tolerated than MVAC with similar efficacyvon der Maase et al,
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • et al.
      Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • et al.
      Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.
      2000, 2005
       ddMVAC vs MVAC134

      129
      62

      50
      P=.0615.1

      14.9
      P=.042ddMVACddMVAC better tolerated and is preferred over standard MVACSternberg et al,
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • et al.
      EORTC Genito-Urinary Cancer Group
      Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours.
      • Sternberg C.N.
      • de Mulder P.H.
      • Schornagel J.H.
      • et al.
      European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group
      Randomized phase III trial of high–dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924.
      2001, 2006
       GC vs PCG312

      314
      43.6

      55.5
      P=.03112.7

      15.8
      P=.075GCAddition of paclitaxel to GC had modest improvement in ORR with increase in toxicitiesBellmunt et al,
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • et al.
      Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987.
      2012
       ddGC vs ddMVAC64

      66
      65.3

      60.0
      P=.6719

      18
      P=.98ddGCRedemonstrates GC has similar efficacy with fewer adverse effectsBamias et al,
      • Bamias A.
      • Dafni U.
      • Karadimou A.
      • et al.
      Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
      2013
      Metastatic: platinum-ineligible
       GCa vs M-CAVI119

      119
      41.2

      30.3
      P=.089.3

      8.1
      P=.64GCaEstablished GCa as preferred regimen in unfit patientsDe Santis et al,
      • De Santis M.
      • Bellmunt J.
      • Mead G.
      • et al.
      Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986.
      2012
      Metastatic: second-line treatment
       Vinflunine vs BSC253

      117
      8.6

      0
      P=.0066.9

      4.3
      P=.287BSCApproved for use in second-line treatment in Europe, not approved in the United StatesBellmunt et al,
      • Bellmunt J.
      • Théodore C.
      • Demkov T.
      • et al.
      Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract.
      2009
      BSC = best supportive care; dd = dose-dense; GC = gemcitabine and cisplatin; GCa = gemcitabine and carboplatin; M-CAVI = methotrexate, carboplatin, and vinblastine; MVAC = methotrexate, vinblastine, doxorubicin, and cisplatin; ORR = overall response rate; OS = overall survival; PCG = paclitaxel, gemcitabine, and cisplatin.
      The effectiveness of MVAC was established the mid-1980s
      • Sternberg C.N.
      • Yagoda A.
      • Scher H.I.
      • et al.
      Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium.
      with evidence of improvement in survival compared with single-agent cisplatin and combination chemotherapy with cisplatin, cyclophosphamide, and doxorubicin.
      • Troner M.
      • Birch R.
      • Omura G.A.
      • Williams S.
      Phase III comparison of cisplatin alone versus cisplatin, doxorubicin and cyclophosphamide in the treatment of bladder (urothelial) cancer: a Southeastern Cancer Study Group trial.
      • Logothetis C.J.
      • Dexeus F.H.
      • Finn L.
      • et al.
      A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.
      The response rates of MVAC and improvement in survival were promising, but patients experienced considerable toxicity, primarily neutropenic fever, mucositis, and a small but significant degree of toxicity-related death. The excessive toxicities associated with MVAC limited widespread adoption of MVAC, and multiple other chemotherapeutic agents were evaluated, with limited success, until encouraging results with gemcitabine emerged in 1994.
      • Pollera C.F.
      • Ceribelli A.
      • Crecco M.
      • Calabresi F.
      Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study.
      A caveat when comparing chemotherapeutic regimen efficacy in urothelial cancer across multiple decades is that the TNM staging criteria were modified in 1997, when MIBCs were further subdivided by depth of invasion.
      Gemcitabine plus cisplatin had promising efficacy with a better safety profile in phase 2 studies.
      • von der Maase H.
      • Andersen L.
      • Crinò L.
      • Weinknecht S.
      • Dogliotti L.
      Weekly gemcitabine and cisplatin combination therapy in patients with transitional cell carcinoma of the urothelium: a phase II clinical trial.
      • Moore M.J.
      • Winquist E.W.
      • Murray N.
      • et al.
      Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group.
      This finding prompted an international noninferiority phase 3 study of 405 patients with advanced or metastatic bladder cancer comparing GC to standard MVAC.
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • et al.
      Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.
      In the 5-year survival analysis, the progression-free survival (PFS) and overall survival (OS) were similar in both treatment arms.
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • et al.
      Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.
      Gemcitabine plus cisplatin was better tolerated with lower rates of neutropenic sepsis and mucositis, decreased need for dose adjustments, and a nonstatistically significant decrease in toxicity-related deaths.
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • et al.
      Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.
      Therefore, although current practice is that GC and MVAC are considered equivalent in efficacy, on the basis of toxicity profiles, GC is overwhelmingly preferred over MVAC.
      To improve the tolerability of conventional MVAC, an intensified schedule for MVAC was evaluated with dose-dense MVAC with granulocyte colony-stimulating factor every 2 weeks compared with conventional MVAC given every 4 weeks.
      • Sternberg C.N.
      • de Mulder P.H.
      • Schornagel J.H.
      • et al.
      European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group
      Randomized phase III trial of high–dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924.
      A higher rate of complete responses was achieved with dose-dense MVAC, and with longer follow-up, a survival benefit was observed as well.
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • et al.
      EORTC Genito-Urinary Cancer Group
      Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours.
      Further, dose-dense MVAC was better tolerated, with a lower rate of neutropenia, thrombocytopenia, and mucositis. The results of this trial support dose-dense MVAC as the preferred regimen over standard MVAC.

      Neoadjuvant Chemotherapy for MIBC

      Neoadjuvant platinum-based combination therapy followed by radical cystectomy with pelvic lymph node dissection is the accepted standard of care for clinical T2 to T4a MIBC.
      • Clark P.E.
      • Spiess P.E.
      • Agarwal N.
      • et al.
      NCCN Guidelines Insights: Bladder Cancer, Version 2.2016.
      • Witjes J.
      • Lebret T.
      • Compérat E.M.
      • et al.
      Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer.
      • Milowsky M.I.
      • Rumble R.B.
      • Booth C.M.
      • et al.
      Guideline on muscle-invasive and metastatic bladder cancer (European Association of Urology Guideline): American Society of Clinical Oncology clinical practice guideline endorsement.
      The stage of muscle invasion that has been incorporated into the TNM staging relates to depth of tumor invasion and increases as the tumor invades the superficial muscle (T2a), deep muscle (T2b), perivesicular soft tissue (T3), and into adjacent organs (T4).
      • Robins D.J.
      • Small A.C.
      • Amin M.B.
      • et al.
      The 2017 American Joint Committee on Cancer eighth edition Cancer Staging Manual: changes in staging guidelines for cancers of the kidney, renal pelvis and ureter, bladder, and urethra.
      If a patient is unable to receive cisplatin-based combination therapy in the neoadjuvant setting, proceeding directly to radical cystectomy is recommended. A reasonable exception is if the goal is to downstage surgically unresectable tumors.
      • Milowsky M.I.
      • Rumble R.B.
      • Booth C.M.
      • et al.
      Guideline on muscle-invasive and metastatic bladder cancer (European Association of Urology Guideline): American Society of Clinical Oncology clinical practice guideline endorsement.
      Although adjuvant chemotherapy may be equally effective in eradicating micrometastatic disease, the current body of high-quality level 1 evidence from clinical trials was performed in the neoadjuvant setting. One practical concern is that many patients who undergo up-front cystectomy never receive adjuvant chemotherapy for several reasons. In a single-institution review of 1142 patients undergoing radical cystectomy, 64% experienced one or more complications, and the authors concluded that postoperative complications may have limited the ability to receive adjuvant chemotherapy in 30% of patients.
      • Donat S.M.
      • Shabsigh A.
      • Savage C.
      • et al.
      Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience.

      Slow But Increasing Adoption of Neoadjuvant Chemotherapy Into Clinical Practice

      In the early 2000s, several studies reported a modest but significant survival advantage of neoadjuvant chemotherapy. In 2005, a meta-analysis of 11 clinical trials including 3005 patients who received neoadjuvant chemotherapy for MIBC revealed a 5% absolute survival benefit at 5 years (survival improved from 45% to 50%).
      Advanced Bladder Cancer (ABC) Meta-analysis Collaboration
      Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data.
      However, the application of these findings into routine practice was lagging. Even in an academic setting, a retrospective review from 2003 to 2008 found that less than 20% of eligible patients received cisplatin-based chemotherapy.
      • Raj G.V.
      • Karavadia S.
      • Schlomer B.
      • et al.
      Contemporary use of perioperative cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer.
      More recent evidence indicates an increasing shift toward more patients receiving neoadjuvant chemotherapy.
      • Reardon Z.D.
      • Patel S.G.
      • Zaid H.B.
      • et al.
      Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides.

      Selection of Neoadjuvant Regimen

      Regimens that have proven efficacy in the metastatic setting were subsequently evaluated in the neoadjuvant setting. Platinum-based combination chemotherapy is preferred, and the 2 most commonly used regimens currently are MVAC (usually dose-dense with growth factor support) or GC. The seminal phase 3 intergroup study confirming the benefit of neoadjuvant chemotherapy randomized over 300 patients to conventional MVAC or no chemotherapy followed by radical cystectomy. An absolute survival benefit of 14% was observed at 5 years in those who received neoadjuvant chemotherapy.
      • Grossman H.B.
      • Natale R.B.
      • Tangen C.M.
      • et al.
      Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.
      After GC was found to have comparable efficacy with better tolerability than MVAC in the metastatic setting, the use of GC was extrapolated into the neoadjuvant setting. A retrospective analysis of neoadjuvant chemotherapy across 19 North American and European institutions evaluated neoadjuvant chemotherapeutic regimens in nearly 1000 patients with MIBC. Most patients received GC (64.4%), 19.6% received MVAC, and the remaining 15.4% received alternative regimens. The rate of pathologic complete response was similar between GC and MVAC, and no differences were noted in survival.
      • Zargar H.
      • Espiritu P.N.
      • Fairey A.S.
      • et al.
      Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer.
      Although never compared prospectively to MVAC in the neoadjuvant setting, based on similar efficacy and improved tolerability, GC is endorsed as an acceptable neoadjuvant regimen (Figure 2).
      Figure thumbnail gr2
      Figure 2Suggested algorithm for muscle-invasive bladder cancer. * Indicates specific systemic treatment regimens supported by level 1 evidence. aAccelerated FDA approval; bUnder FDA priority review. dd = dose-dense; ECOG = Eastern Cooperative Oncology Group (performance score); 5-FU = 5-fluorouracil; MVAC = methotrexate, vinblastine, doxorubicin, and cisplatin; NYHA = New York Heart Association; post-op = postoperative; TURBT = transurethral resection of bladder tumor; UC = urethelial carcinoma.

      Dose-Dense Strategies for Neoadjuvant Chemotherapy

      The improved clinical response of dose-dense MVAC in the metastatic setting sparked great interest in exploring a dose-dense approach in the neoadjuvant setting. In June 2014, 2 prospective, single-arm phase 2 studies were reported using 3 cycles
      • Plimack E.R.
      • Hoffman-Censits J.H.
      • Viterbo R.
      • et al.
      Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity.
      or 4 cycles
      • Choueiri T.K.
      • Jacobus S.
      • Bellmunt J.
      • et al.
      Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.
      of dose-dense MVAC with growth factor support. Overall, dose-dense MVAC was safe and effective with more than 90% of patients completing the intended number of chemotherapy cycles. The rates of complete pathologic responses were 38%
      • Plimack E.R.
      • Hoffman-Censits J.H.
      • Viterbo R.
      • et al.
      Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity.
      and 28%,
      • Choueiri T.K.
      • Jacobus S.
      • Bellmunt J.
      • et al.
      Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.
      likely due to differences in the number of patients enrolled with nodal metastases.
      The dose-dense approach has also been attempted with GC treatment. The first study to evaluate dose-dense GC was closed early because of an increased rate of cardiovascular toxicity.
      • Plimack E.R.
      • Hoffman-Censits J.H.
      • Kutikov A.
      • et al.
      Neoadjuvant dose-dense gemcitabine and cisplatin (DDGC) in patients (pts) with muscle-invasive bladder cancer (MIBC): final results of a multicenter phase II study [abstract].
      A subsequent phase 2 study excluding patients with cardiovascular events reported improved tolerability, but further investigation is warranted before dose-dense GC is adopted into routine clinical practice.
      • Balar A.V.
      • Iyer G.
      • Milowsky M.I.
      • et al.
      Multicenter prospective phase II trial of neoadjuvant (neo) dose dense gemcitabine and cisplatin (DD-GC) in patients (pts) with muscle-invasive bladder cancer (MIBC) [abstract].

      Multimodal Therapy for Bladder Preservation

      Similar to the nonoperative, organ-preserving treatment strategies utilized in other malignancies, multimodal therapy with the goal of bladder preservation is a reasonable strategy for some patients with bladder cancer. No existing or forthcoming randomized trials have directly compared radical cystectomy to definitive chemoradiation. Although radical cystectomy remains the preferred approach, bladder preservation with initial maximal transurethral resection of the bladder tumor followed by radiation therapy with concurrent chemotherapy for patients with MIBC who are motivated to preserve the bladder and willing to undergo surveillance cystoscopy is a reasonable alternative. Patients with hydronephrosis, carcinoma in situ, nodal disease, or poor baseline bladder function are considered poor candidates for a bladder preservation approach.
      • Ploussard G.
      • Daneshmand S.
      • Efstathiou J.A.
      • et al.
      Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review.
      The addition of concurrent chemotherapy to radiation improves local control rate and OS.
      • Coppin C.M.
      • Gospodarowicz M.K.
      • James K.
      • et al.
      Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation: the National Cancer Institute of Canada Clinical Trials Group.
      • James N.D.
      • Hussain S.A.
      • Hall E.
      • et al.
      BC2001 Investigators
      Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.
      A review of 6 Radiation Therapy Oncology Group phase 1-3 trials using various doses and schedules of radiation found a low rate of local failure and concluded that multimodal bladder sparing is a reasonable strategy for appropriately selected patients.
      • Shipley W.U.
      • Kaufman D.S.
      • Tester W.J.
      • Pilepich M.V.
      • Sandler H.M.
      Overview of bladder cancer trials in the Radiation Therapy Oncology Group.
      Cisplatin-containing doublets (paired with 5-fluorouracil, gemcitabine, or paclitaxel) were evaluated in Radiation Therapy Oncology Group trials and are generally preferred regimens. In cisplatin-ineligible patients, 5-fluorouracil with mitomycin C is an accepted alternative (Figure 2).
      • Plimack E.R.
      • Hoffman-Censits J.H.
      • Viterbo R.
      • et al.
      Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity.

      Predictive Biomarkers for Optimizing Patient Selection for Definitive Local Management

      Currently, only a fraction of patients who receive neoadjuvant cisplatin-based chemotherapy gain a benefit. To save 1 life, 15 to 20 individuals are treated, exposing them to the known, potentially long-term toxicities of platinums (eg, hearing loss, renal impairment, neuropathy) for limited clinical benefit. Discovering predictive biomarkers for chemotherapy or radiation response would optimize patient selections to derive benefit from treatment, and several predictive biomarkers are in development.
      Because both radiation therapy and cisplatin induce DNA damage, deficiencies in DNA repair mechanisms have been evaluated as predictive biomarkers. DNA repair mechanisms may work against radiation or cisplatin by repairing DNA damage in malignant cells damaged during treatment, thus “rescuing” them from degradation. The primary pathway involved in repairing cisplatin-induced DNA damage is nucleotide excision repair, which involves ERCC2. Sequence variations in ERCC2, identified in 12% of MIBC tumors,
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      are associated with an increased rate of pathologic complete response to adjuvant chemotherapy.
      • Van Allen E.M.
      • Mouw K.W.
      • Kim P.
      • et al.
      Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.
      • Liu D.
      • Plimack E.R.
      • Hoffman-Censits J.
      • et al.
      Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma.
      Supporting the notion that defective DNA repair increases sensitivity to cisplatin, patients with somatic defects in DNA repair genes (ATM, RB1, and FANCC) are more likely to have a pathologic response.
      • Plimack E.R.
      • Dunbrack R.L.
      • Brennan T.A.
      • et al.
      Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer.
      Higher baseline expression of MRE11, part of a complex involved in recruiting DNA repair proteins, was associated with improved survival in patients treated with radiation.
      • Choudhury A.
      • Nelson L.D.
      • Teo M.T.
      • et al.
      MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer.
      • Laurberg J.R.
      • Brems-Eskildsen A.S.
      • Nordentoft I.
      • et al.
      Expression of TIP60 (tat-interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment-specific outcome of localised invasive bladder cancer.
      • Magliocco A.M.
      • Moughan J.
      • Simko J.
      • et al.
      The impact of MRE11 in nuclear to cytoplasmic ratio on outcomes in muscle invasive bladder cancer: an analysis of NRG/RTOG 8802, 8903, 9506, 9706, 9906, and 0233 [abstract].
      A possible explanation is that a threshold of MRE11 is needed to induce apoptosis in response to radiation-induced DNA damage. Although none have been adequately prospectively validated for adoption into routine clinical practice, several of these promising biomarkers are undergoing further development. Further, biomarker-directed algorithms to guide neoadjuvant chemotherapy are currently being validated in a phase 2 clinical trial using the COXEN algorithm (ClinicalTrials.gov Identifier: NCT02177695).

      Systemic Treatment for Metastatic Urothelial Cancer

      In general, metastatic UC is considered incurable and is managed primarily with systemic treatment. However, in selected patients with oligometastatic disease, long-term cancer control is possible through metastasectomy and may be considered as part of multimodal treatment.
      • Lehmann J.
      • Suttmann H.
      • Albers P.
      • et al.
      Surgery for metastatic urothelial carcinoma with curative intent: the German experience (AUO AB 30/05).

      First-Line Chemotherapeutic Treatments for Fit Patients

      Gemcitabine plus cisplatin and dose-dense MVAC are accepted standard of care first-line treatments of metastatic urothelial cancer (Table 1, Figure 2). Several trials have attempted to improve upon a GC backbone with inclusion of additional chemotherapeutic agents. The only combination that moved on to a phase 3 study evaluated the addition of paclitaxel to GC in 626 patients with metastatic UC; however, this combination did not improve median OS.
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • et al.
      Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987.
      With an increased risk of neutropenic fever and neuropathies, most believe the risks of paclitaxel plus GC outweigh any incremental benefit.

      First-Line Chemotherapeutic Treatment in Cisplatin-Ineligible Patients

      Cisplatin is the preferred drug for the treatment for urothelial cancer, as a meta-analysis of 4 trials reported the inferiority of carboplatin.
      • Galsky M.
      • Chen G.
      • Oh W.K.
      • et al.
      Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma.
      However, because bladder cancer is a disease of the elderly, existing medical comorbidities may limit the ability to offer cisplatin-based chemotherapy. A global working group of bladder cancer experts arrived at a consensus definition, classifying a patient as cisplatin-ineligible if any of the following criteria were met: performance status score of 2 or higher, creatinine clearance of less than 1 mL/s, grade 2 or higher audiometric hearing loss, 2 or more peripheral neuropathies, or New York Heart Association class III heart failure.
      • Galsky M.D.
      • Hahn N.M.
      • Rosenberg J.
      • et al.
      A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy.
      In fact, up to 50% of patients presenting with advanced urothelial cancer are unfit to receive cisplatin because of underlying renal impairment, poor functional status, or medical comorbidities.
      • Dash A.
      • Galsky M.D.
      • Vickers A.J.
      • et al.
      Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder.
      • Balducci L.
      • Extermann M.
      Management of cancer in the older person: a practical approach.
      The European Organisation for the Research and Treatment of Cancer led the first trial, which evaluated the optimal first-line metastatic regimen for cisplatin-ineligible patients by comparing gemcitabine and carboplatin (GCa) to the older regimen of methotrexate, carboplatin, and vinblastine. In that study, cisplatin-ineligible criteria were an estimated glomerular filtration rate between 30 and 60 mL/min and/or a performance score of 2. Both the overall response rate and toxicity profile favored GCa, establishing GCa as the preferred regimen in cisplatin-ineligible patients (Table 1).
      • De Santis M.
      • Bellmunt J.
      • Mead G.
      • et al.
      Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986.

      Second-Line Chemotherapeutic Options for Metastatic Disease After Progression During Treatment With a Platinum Agent

      Only a small proportion of patients with metastatic bladder cancers achieve a durable remission after first-line treatment.
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • et al.
      Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.
      Although numerous agents have been evaluated for efficacy in the second-line setting, no phase 3 study has reported proven benefit of a second-line agent over best supportive care.
      • Yafi F.A.
      • North S.
      • Kassouf W.
      First- and second-line therapy for metastatic urothelial carcinoma of the bladder.
      In phase 1 and 2 studies evaluating pemetrexed,
      • Sweeney C.J.
      • Roth B.J.
      • Kabbinavar F.F.
      • et al.
      Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium.
      vinflunine,
      • Bellmunt J.
      • Théodore C.
      • Demkov T.
      • et al.
      Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract.
      paclitaxel,
      • Joly F.
      • Tchen N.
      • Chevreau C.
      • et al.
      Clinical benefit of second line weekly paclitaxel in advanced urothelial carcinoma (AUC): a GETUG phase II study [abstract].
      docetaxel,
      • McCaffrey J.A.
      • Hilton S.
      • Mazumdar M.
      • et al.
      Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma.
      gemcitabine,
      • Lorusso V.
      • Pollera C.F.
      • Antimi M.
      • et al.
      Italian Co-operative Group on Bladder Cancer
      A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum.
      ifosfamide,
      • Witte R.S.
      • Elson P.
      • Bono B.
      • et al.
      Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma.
      and oxaliplatin,
      • Winquist E.
      • Vokes E.
      • Moore M.J.
      • Schumm L.P.
      • Hoving K.
      • Stadler W.M.
      A phase II study of oxaliplatin in urothelial cancer.
      response rates ranged from 0% to 29%. The only phase 3 study in the second-line setting comparing vinflunine to best supportive care reported a modest 2.4-month improvement in OS that did not achieve statistical significance (Table 1).
      • Bellmunt J.
      • Théodore C.
      • Demkov T.
      • et al.
      Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract.
      An improvement in response rate and PFS was observed, leading to approval by the European Medicines Agency but not by the FDA.
      Several combination regimens have been evaluated in the second-line setting.
      • Yafi F.A.
      • North S.
      • Kassouf W.
      First- and second-line therapy for metastatic urothelial carcinoma of the bladder.
      A retrospective analysis of 8 trials using taxane-based combination chemotherapy found that doublets may improve survival compared with taxane monotherapy.
      • Sonpavde G.
      • Pond G.R.
      • Choueiri T.K.
      • et al.
      Single-agent taxane versus taxane-containing combination chemotherapy as salvage therapy for advanced urothelial carcinoma.
      In terms of choice of agent, no particular regimen is considered to be preferred, and decisions are largely based on previous response to chemotherapy and comorbidities. Revisiting a platinum agent may be a reasonable strategy if recurrence or progression developed after at least 6 to 12 months of prior treatment.

      Immunotherapy

      The lack of chemotherapeutic options after progression during platinum-based therapy and the observation of a high sequence variation-associated neoantigen incidence in urothelial cancer led to testing immunotherapy in this setting. The foundations of this concept also date back several decades, with the antitumoral effects of BCG in bladder cancer first reported in 1976 in mouse models.
      • Herr H.W.
      • Morales A.
      History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story.
      Because BCG has a low pathogenic potential yet remains capable of eliciting an immune response, intravesicular administration of BCG has been used as an immunotherapeutic approach to localized bladder cancer for more than 2 decades.
      • Herr H.W.
      • Morales A.
      History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story.
      One mechanism by which malignant cells are able to escape immune detection is by altering expression of regulatory cell surface molecules (inhibitory and stimulatory), commonly referred to as “checkpoints,” to create an immunosuppressive tumor microenvironment. Checkpoint inhibitors antagonize this adaptation against the immune system with hopes of achieving an antitumoral effect.

      Targeting the Programmed Cell Death Axis

      Interaction of programmed cell death ligand 1 (PD-L1), a type of inhibitory check point molecule, on the surface of tumor cells with programmed cell death 1 (PD-1) on activated T and B cells leads to decreased immune response and enables tumor cells to proliferate more rampantly. A number of studies using checkpoint inhibitors have reported efficacy (Table 2),
      • Rosenberg J.E.
      • 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.
      • Bellmunt J.
      • de Wit R.
      • Vaughn D.J.
      • et al.
      Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
      • Massard C.
      • Gordon M.S.
      • Sharma S.
      • et al.
      Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
      • Apolo A.B.
      • Infante J.R.
      • Hamid O.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: analysis of safety, clinical activity, and PD-L1 expression [abstract].
      • 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.
      with 4 having received accelerated FDA approval (atezolizumab, nivolumab, durvalumab, and avelumab).
      Table 2Selected Trials of PD-L1 and PD-1 Inhibitors in Second-Line Treatment of Metastatic or Advanced UC
      AE = adverse event; FU = follow-up; IC = immune cells; IV = intravenously; mAb = monoclonal antibody; NR = not reported; ORR = overall response rate; PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1; TC = tumor cell; UC = urothelial carcinoma.
      VariableRosenberg et al,
      • Rosenberg J.E.
      • 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.
      2016
      Bellmunt et al,
      • Bellmunt J.
      • de Wit R.
      • Vaughn D.J.
      • et al.
      Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
      2017
      Massard et al,
      • Massard C.
      • Gordon M.S.
      • Sharma S.
      • et al.
      Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
      2016
      Apolo et al,
      • Apolo A.B.
      • Infante J.R.
      • Hamid O.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: analysis of safety, clinical activity, and PD-L1 expression [abstract].
      2016
      Sharma et al,
      • 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.
      2017
      Trial nameIMvigor 210KEYNOTE-045Study 1108JAVELINCheckMate 275
      Phase231/31b2
      DrugAtezolizumabPembrolizumabDurvalumabAvelumabNivolumab
      Antibody targetPD-L1PD-1PD-L1PD-L1PD-1
      Dose/schedule1200 IV every 3 wk200 IV every 3 wk10 mg/kg IV every 2 wk10 mg/kg IV every 2 wk3 mg/IV every 2 wk
      No. of patients
      No. of patients evaluable for responses.
      3102704244265
      Median FU (mo)11.714.14.3117
      ORR (%)1521.13118.219.6
      Survival at 12 mo (%)3643.9NR53.543
      PD-L1 evaluationTumor-infiltrating immune cellsCombined TCs and infiltrating ICs relative to total No. of TCsTCs and ICs expressing any intensity above backgroundTCs and tumor-infiltrating ICs by % or intensity of stainTCs surface expression
      PD-L1 positivity: score (% of patients)<1%: IC0 (33)

      1%-5%: IC1 (35)

      ≥5%: IC2/3 (32)
      <10% (72)

      ≥10% (28)
      Negative: <25% both TC and IC (34)

      Positive: ≥25% in TC or IC (66)
      Negative: <5% TCs (63.9)

      Positive: ≥5% TCs (36.1)
      <1% (53)

      ≥1% (45)

      ≥5% (30)
      ORR (%) by PD-L1IC0: 8

      IC1: 10

      IC2/3: 26
      <10%: NR

      ≥10%: 22
      Negative: 0

      Positive: 46.4
      Negative: 4.3

      Positive: 53.8
      <1%: 16.1

      ≥1%: 23.8

      ≥5%: 28.4
      Grade 3-4 AEs (%)16154.99.118
      PDL-1 antibody testedVENTANA SP142 (rabbit mAb)Dako clone 22C3 (mouse mAb)VENTANA SP263 (rabbit mAb)Dako clone 73-10 (rabbit mAb)Dako clone 28-8
      a AE = adverse event; FU = follow-up; IC = immune cells; IV = intravenously; mAb = monoclonal antibody; NR = not reported; ORR = overall response rate; PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1; TC = tumor cell; UC = urothelial carcinoma.
      b No. of patients evaluable for responses.

      Anti–PD-L1 Monoclonal Antibodies

      Atezolizumab, a fully humanized monoclonal antibody against PD-L1, received accelerated approval by the FDA in May 2016 for the treatment of advanced UC after prior platinum therapy. This approval was based on the single-arm phase 2 IMvigor 210 trial of 310 patients with advanced or unresectable urothelial cancer who had progression within 12 months of platinum-based chemotherapy.
      • Rosenberg J.E.
      • 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.
      At a median follow-up of 11.7 months, treatment with atezolizumab resulted in an overall response rate of 15% and stable disease in another 19%. Notably, of those who responded, the benefit was durable, with 84% continuing to respond at 12 months. Atezolizumab was well tolerated, and the most common grade 3-4 adverse event was fatigue. Serious immune-mediated adverse events were observed in 5% of patients, including pneumonitis, elevation of transaminase levels, and rash.
      • Rosenberg J.E.
      • 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.
      In a separate cohort of the IMvigor 210 trial, cisplatin-ineligible patients with advanced bladder cancer were treated with first-line atezolizumab.
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • et al.
      Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
      Eligibility for cisplatin-based therapy was determined using the previously mentioned 2011 consensus definition.
      • Galsky M.D.
      • Hahn N.M.
      • Rosenberg J.
      • et al.
      A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy.
      With a median follow-up of 17.2 months, a 23% response rate was observed, and the median OS was 15.9 months. Again, durable responses were observed with 70% of responders remaining on treatment. A similar adverse effect profile was observed, with only 8% of treatment discontinuations due to adverse events.
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • et al.
      Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
      In April 2017, the FDA granted accelerated approval for atezolizumab for first-line treatment in cisplatin-ineligible patients with locally advanced or metastatic bladder cancer.
      Durvalumab (MEDI4736) is a human IgG1κ monoclonal antibody directed against PD-L1. In the phase 1/2 dose-escalation study, a preliminary response evaluation of the first 20 patients enrolled revealed that all responders were in the PD-L1–positive subgroup. Subsequent patients were required to have a minimum of 5% PD-L1 expression on tumor cells. A higher rate of disease control at 12 weeks was observed in PD-L1–positive patients compared with PD-L1–negative patients.
      • Massard C.
      • Gordon M.S.
      • Sharma S.
      • et al.
      Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
      In updated analysis after a median follow-up of 7.3 months, response rates were more than 3-fold higher in the PD-L1–positive group, although a small proportion of PD-L1–negative patients did respond to treatment.
      • Powles T.
      • O'Donnell P.H.
      • Massard C.
      • et al.
      Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma [abstract].
      Fewer than 5% of patients experienced grade 3 or higher adverse events, which were biopsy-proven acute kidney injury from nephritis, infusion-related reaction, and tumor flare.
      • Massard C.
      • Gordon M.S.
      • Sharma S.
      • et al.
      Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
      In December 2016, durvalumab received breakthrough therapy designation for patients with PD-L1–positive metastatic or unresectable UC after prior platinum-based chemotherapy.
      Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody against PD-L1 that was evaluated in a phase 1 trial (JAVELIN 100) of patients with metastatic or unresectable UC as second-line therapy after platinum-based treatment.
      • Apolo A.B.
      • Infante J.R.
      • Hamid O.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: analysis of safety, clinical activity, and PD-L1 expression [abstract].
      Preliminary analyses of 44 patients after a median follow-up of 11.4 months revealed an objective response rate of 18.2% and a median OS of 12.9 months, leading to accelerated FDA approval in May 2017. A higher disease control rate at 24 weeks was observed in PD-L1–positive patients compared with PD-L1–negative patients. Avelumab was well tolerated, with 4 patients (9%) having grade 3 to 4 treatment-related adverse events, which were increased levels of creatine phosphokinase and aspartate aminotransferase, decreased appetite, asthenia, and decreased lymphocyte count.
      • Apolo A.B.
      • Infante J.R.
      • Hamid O.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: analysis of safety, clinical activity, and PD-L1 expression [abstract].
      A phase 3 study of maintenance avelumab after chemotherapy is ongoing (ClinicalTrials.gov Identifier: NCT02603432).

      Anti–PD-1 Monoclonal Antibodies

      The first reported phase 3 study of checkpoint inhibitors in metastatic bladder cancer used pembrolizumab, a humanized monoclonal antibody against PD-1. After promising results from the phase 1b KEYNOTE-012 study in refractory UC,
      • Seiwert T.Y.
      • Burtness B.
      • Mehra R.
      • et al.
      Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial.
      the landmark phase 3 KEYNOTE-045 study evaluated pembrolizumab in the second-line setting of prior platinum-based chemotherapy.
      • Bellmunt J.
      • de Wit R.
      • Vaughn D.J.
      • et al.
      Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
      In KEYNOTE-045, 542 patients were randomized to either pembrolizumab or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The overall response rate was significantly higher in patients receiving pembrolizumab compared with chemotherapy (21.1% vs 11.4%). Although there was no significant difference in PFS between the 2 groups, the median OS was nearly 3 months longer in the pembrolizumab group. Further, in responders, a rate of durable responses was more than double the rate observed with chemotherapy. As expected, pembrolizumab had a much lower rate of grade 3 or 4 adverse events (15%) compared with chemotherapy (49.4%) and lower rates of treatment discontinuation.
      • Bellmunt J.
      • de Wit R.
      • Vaughn D.J.
      • et al.
      Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
      Early results from the first 100 patients enrolled in KEYNOTE-052, a phase 2 study of pembrolizumab in cisplatin-ineligible patients for first-line treatment of metastatic or unresectable UC, were presented as an abstract at the European Society for Medical Oncology meeting in 2016.
      • Balar A.
      • Bellmunt J.
      • O'Donnell P.H.
      • et al.
      Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: preliminary results from the phase 2 KEYNOTE-052 study.
      After a median follow-up of 8 months, the overall response rate was 24%, with 83% of responders continuing to respond for more than 6 months.
      • Balar A.
      • Bellmunt J.
      • O'Donnell P.H.
      • et al.
      Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: preliminary results from the phase 2 KEYNOTE-052 study.
      Pembrolizumab for first-line (cisplatin-ineligible) and second-line treatment of unresectable or metastatic UC is under priority review at the FDA.
      Nivolumab is a human IgG4 monoclonal antibody against PD-1 that blocks the interaction between PD-1 expressed on activated T cells and PD-L1 or programmed cell death ligand 2 expressed on tumor cells. In the second-line treatment of metastatic or unresectable UC, nivolumab showed promise in the phase 1/2 study of 86 patients (CheckMate 032)
      • Sharma P.
      • Callahan M.K.
      • Bono P.
      • et al.
      Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.
      and was further evaluated in 270 patients in the CheckMate 275 trial, an open-label single-arm phase 2 study.
      • 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.
      Of the evaluable 265 patients, after a median follow-up of 7 months, the overall response rate was 19.6%, median PFS was 2.0 months, and OS was 8.74 months. Similar to other checkpoint inhibitors, the duration of response in responders was high, with 77% of responders having ongoing response at the time of analysis. Treatment-related grade 3-4 adverse events were noted in 18%, most commonly grade 3 fatigue or diarrhea. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure).

      CTLA4 Receptor Inhibitors

      CTLA4 (cytotoxic T-lymphocyte–associated protein 4) is a checkpoint inhibitor receptor expressed on the surface of T cells and is essential in T-cell activation. Ipilimumab is a monoclonal antibody against CTLA4 that increases T-cell effector activity. The safety of neoadjuvant ipilimumab monotherapy was evaluated in a small cohort of 12 patients with T1-T2 UC. Ipilimumab resulted in downstaging of tumor size in 66% patients after cystectomy.
      • Carthon B.C.
      • Wolchok J.D.
      • Yuan J.
      • et al.
      Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial.
      Ipilimumab in combination with chemotherapy or PD-1 blockade has been explored in metastatic or unresectable UC. A phase 2 study combined ipilimumab with GC for first-line treatment of metastatic UC.
      • Galsky M.D.
      • Hahn N.M.
      • Albany C.
      • et al.
      Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer [abstract].
      Presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in 2016, this study did not meet the primary end point of survival at 12 months, nor did it improve OS compared with historical controls. Ipilimumab increased the rate of nonimmune- and immune-related adverse effects, including grade 3-4 neutropenia (38%), anemia (28%), diarrhea (8%), colitis (6%), hypophysitis (3%), rash (1%), or hypothyroidism (1%).
      • Galsky M.D.
      • Hahn N.M.
      • Albany C.
      • et al.
      Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer [abstract].
      In the previously mentioned nivolumab CheckMate 032 trial, an additional combination of nivolumab with ipilimumab was performed, although the results have not yet been reported.
      • Sharma P.
      • Callahan M.K.
      • Bono P.
      • et al.
      Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.
      A phase 3 study of first-line treatment of advanced or metastatic UC with nivolumab and ipilimumab vs chemotherapy is ongoing (CheckMate 901; ClinicalTrials.gov Identifier: NCT03036098).

      Identifying Predictive Biomarkers Associated With Response to Immunotherapy

      The promise of immunotherapy as an effective, tolerable treatment with durable responses in urothelial cancer is tempered by the low rate of responders. At best, 1 of 3 patients treated with immunotherapy will have a response. Identifying predictive biomarkers to help enrich responses to immunotherapy is an area of avid interest. Programmed cell death ligand 1 expression, intrinsic subtype, sequence variation burden, and immune signatures have all been evaluated as predictive biomarkers.
      The results of PD-L1 expression and response rates in UC have been inconsistent. A preplanned analysis by expression of PD-L1 on tumor-infiltrating immune cells (ICs) on biopsy specimens categorized according to the percentage of PD-L1–positive ICs as IC0 (<1%), IC1 (≥1 to <5%), and IC2/3 (≥5%) identified a higher response rate (26%) in the IC2/3 group. However, responders included patients with low or absent PD-L1 expression, indicating that it is an imperfect marker.
      • Rosenberg J.E.
      • 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.
      Somewhat surprisingly, enrichment of PD-L1 on tumor-infiltrating results did not improve response rates in cohort 1 of the IMvigor 210 study.
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • et al.
      Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
      In KEYNOTE-045, which used a combined score evaluating PD-L1 on both tumor-infiltrating ICs and tumor cells, an expression threshold of 10% was not correlated with response rates or survival.
      • Bellmunt J.
      • de Wit R.
      • Vaughn D.J.
      • et al.
      Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
      Evaluation of PD-L1 suffers from a lack of standardized assays for staining PD-L1 and accepted metrics to define PD-L1 expression thresholds. Additional inconsistencies arise from whether the evaluation involves infiltrating ICs or tumor cells. Each of the studies reported in Table 2 used a different assay to determine PD-L1 expression and different criteria for defining PD-L1 positivity.
      Both the IMvigor 210 and CheckMate 275 studies evaluated the potential role of intrinsic subtype as a predictor of response to immunotherapy. In the IMvigor study, a higher proportion of responses were noted in the luminal subtype (TCGA cluster II).
      • Rosenberg J.E.
      • 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.
      CheckMate 275 similarly analyzed patient tumors by subtypes, and the basal 1 subtype had the highest proportion of responses.
      • 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.
      In both studies, responses were noted across all intrinsic subtypes, limiting the appeal of intrinsic subtype as a predictive biomarker for response to checkpoint inhibitors. As observed in lung cancers, sequence variation frequency was nearly doubled in responders (12.4 sequence variations per million base) compared with nonresponders (6.4 sequence variations per million base).
      • Rosenberg J.E.
      • 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.
      Lastly, interferon gamma and chemokine signatures were enriched for nivolumab responders.
      • 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.
      At this time, no routinely available predictive biomarker is suitable for clinical practice to select patients for immunotherapy.

      Developing Targeted Therapies

      As our genomic understanding of bladder malignancies has evolved, there is increasing interest in identifying targeted treatments. Targeted inhibition is an appealing concept given the high rate of sequence variations observed in the mTOR, fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2) pathways. However, urothelial cancers have a high rate of mutagenesis and evolution, and it is rare that a single pathway is the oncogenic driver. Results with a targeted approach have been lackluster. Studies evaluating single treatment with everolimus, temsirolimus, cetuximab, gefitinib, sorafenib, sunitinib, pazopanib, trastuzumab, and bortezomib all had response rates of less than 10%.
      • Plimack E.R.
      • Geynisman D.M.
      Targeted therapy for metastatic urothelial cancer: a work in progress.
      In the following sections, we highlight promising targeted therapeutic strategies that have had modest success and future clinical trials (Table 3).
      Table 3Selected Clinical Trials in Development for Muscle-Invasive Bladder Cancer
      VariablePhasePrimary end pointStudy number/name
      Neoadjuvant
       Durvalumab plus tremelimumab (anti-CTLA4) in patients with MIBC who are ineligible for cisplatin based neoadjuvant chemotherapy1ToxicityNCT02812420
       Pembrolizumab in combination with gemcitabine and cisplatin as neoadjuvant therapy2Pathologic downstaging to <pT2NCT02690558
       Neoadjuvant nivolumab with or without urelumab (anti-CD137 monoclonal antibody) in cisplatin-ineligible patients with MIBC2Tumor-infiltrating CD8+ T-cell density on cystectomyNCT02845323
       A randomized placebo-controlled neoadjuvant nintedanib (FGFR inhibitor) or placebo with gemcitabine and cisplatin for patients with invasive bladder cancer2Pathologic CRISRCTN56349930/NEOBLADE
      Adjuvant
       A study of atezolizumab vs observation as adjuvant therapy in participants with high-risk muscle-invasive UC after resection3DFSNCT02450331/IMvigor 010
       Adjuvant nivolumab vs placebo in patients with high-risk invasive UC3DFSNCT02632409/CheckMate 274
      Metastatic or unresectable
       Biomarker-directed multiarm study in patients with MIBC who have progression on prior treatment (combinations of FGFR inhibitor AZD4547, durvalumab, olaparib and mTOR inhibitor vistusertib)1bSafetyNCT02546661/BISCAY
       Durvalumab with or without tremelimumab vs standard of care chemotherapy (gemcitabine plus cisplatin or carboplatin)3PFS, OSNCT02516241
       Nivolumab in combination with ipilimumab compared with standard of care chemotherapy (gemcitabine plus cisplatin or carboplatin) in inoperable or metastatic UC3PFS, OSNCT03036098/CheckMate 901
       Avelumab plus BSC vs BSC alone as maintenance treatment in patients with advanced UC who did not have progression after first-line platinum therapy3OSNCT02603432/JAVELIN Bladder 100
       Atezolizumab (or placebo) as monotherapy and in combination with platinum-based chemotherapy in patients with untreated advanced or metastatic UC3PFS, OSNCT02807636
       Pembrolizumab with or without platinum-based chemotherapy vs chemotherapy in patients with advanced or metastatic UC3PFS, OSNCT02853305/KEYNOTE-361
       Gemcitabine and cisplatin with or without bevacizumab in patients with advanced UC3OSNCT00942331/CALGB 90601
       Ramucirumab plus docetaxel vs placebo plus docetaxel in patients with advanced or metastatic UC who had progression on or after platinum-based therapy3PFSNCT02426125/RANGE
       An efficacy and safety study of JNJ-42756493 (pan-FGFR inhibitor) in patients with metastatic or unresectable UC with FGFR genomic alterations2ORRNCT02365597
       Nintedanib (FGFR inhibitor) in patients with advanced FGFR3-mutated, FGFR3-overexpressed, or FGFR3–wild type UC in whom platinum-based chemotherapy failed2ORRNCT02278978
       B-701 (FGFR3 monoclonal antibody) plus docetaxel vs placebo plus docetaxel in the treatment of locally advanced or metastatic, relapsed or refractory UC1b/2PFSNCT02401542
       Afatinib monotherapy in patients with ERBB2-deregulated metastatic UC after failure of platinum-based chemotherapy2PFS at 6 moNCT02780687
       Sapanisertib (mTOR inhibitor) in patients with locally advanced or metastatic UC who harbor a TSC1 and/or TSC2 sequence variation2ORRNCT03047213
       Palbociclib in patients with metastatic UC with cyclin-dependent kinase inhibitor 2A loss and positive retinoblastoma expression after failure of first-line therapy2PFSNCT02334527
       A pilot trial of genomic-based assignment of therapy in advanced UC (75 drugs assigned using COXEN model)2Percentage of patients assigned to treatment in 10 wkNCT02788201
       LY3076226, an FGFR3 antibody–drug conjugate, in patients with advanced or metastatic cancer1MTDNCT02529553
      Anti-CTLA4 = antibody against cytotoxic T-lymphocyte antigen 4; BSC = best supportive care; CR = complete response; DFS = disease-free survival; ERBB2 = erb-b2 receptor tyrosine kinase 2; FGFR = fibroblast growth factor receptor; MIBC = muscle-invasive bladder cancer; MTD = maximum tolerated dose; mTOR = mechanistic target of rapamycin; OS = overall survival; ORR = overall response rate; PFS = progression-free survival; TSC = tuberous sclerosis complex; UC = urothelial carcinoma.

      Mixed Success With FGFR3 Inhibitors

      Fibroblast growth factor receptor 3 is a transmembrane receptor that regulates cell proliferation and survival. Enhanced activity of FGFR3 most commonly occurs because of activating point sequence variations, through fusion rearrangements and copy number gain.
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      Dovitinib, an oral angiogenesis inhibitor of multiple kinases (including FGFR3), was evaluated in a phase 2 trial of 44 pretreated patients with advanced UC. After screening 250 patients, 12 patients harboring FGFR3 sequence variations and 31 patients with wild-type FGFR3 were enrolled. Disappointingly, only one partial response was observed in a patient with wild-type FGFR3, and the median PFS was 3 months.
      • Milowsky M.I.
      • Dittrich C.
      • Durán I.
      • et al.
      Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma.
      Other efforts at targeting FGFR3 have had more success by selecting patients with activating sequence variations. In a phase 2 study, the pan-FGFR inhibitor BGJ398 showed promise in 33 heavily pretreated patients screened for activating FGFR3 sequence variations or fusions. The overall response rate was 36%, and the most common grade 3 or higher adverse events were hyperphosphatemia (6%), fatigue (6%), or elevated creatinine 3%.
      • Pal S.K.
      • Rosenberg J.E.
      • Keam B.
      • et al.
      Efficacy of BGJ398, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, in patients (pts) with previously treated advanced/metastatic urothelial carcinoma (mUC) with FGFR3 alterations [abstract].
      Several additional phase 2 trials with FGFR inhibitors in UC are ongoing, including a new monoclonal antibody against FGFR3 (Table 3).

      Identifying Patients for EGFR- and HER2/neu-Targeted Therapy Remains a Challenge

      Human epidermal growth factor receptor 2 (ERBB2) is part of the EGFR family, and activation of HER2 leads to cell proliferation, survival, and invasiveness. In the TCGA analysis, ERBB2 alterations were identified nearly as frequently as observed in breast cancer
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      and were typically identified in the luminal bladder cancer subtype.
      • Kiss B.
      • Wyatt A.W.
      • Douglas J.
      • et al.
      Her2 alterations in muscle-invasive bladder cancer: patient selection beyond protein expression for targeted therapy.
      Even in trials selecting for UC patients with HER2 overexpression or amplification, the results have been limited. In a second-line study of 59 patients with 1+ or higher HER2 expression on immunohistochemistry, single-agent lapatinib had a response rate of 1.8%, failing to meet the primary end point.
      • Wülfing C.
      • Machiels J.P.
      • Richel D.J.
      • et al.
      A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma.
      In a phase 3 study evaluating the benefit of maintenance lapatinib after completion of first-line chemotherapy for metastatic disease, 232 prescreened patients with 2+ or 3+ expression on immunohistochemistry for HER1 or HER2 were randomized to either maintenance lapatinib or placebo. Maintenance lapatinib did not improve PFS or OS.
      • Powles T.
      • Huddart R.A.
      • Elliott T.
      • et al.
      Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2–positive metastatic bladder cancer.
      A sliver of promise arose from a phase 2 study evaluating afatinib in 23 patients with platinum-refractory metastatic UC not prescreened for HER2 or EGFR overexpression. Although this study failed to meet the prespecified threshold of 30% PFS at 3 months, interesting insights were gleaned from the next-generation sequencing as part of the correlative studies. Of the 6 patients who had PFS at 3 months, 5 harbored HER2 or ERBB3 alterations.
      • Choudhury N.J.
      • Campanile A.
      • Antic T.
      • et al.
      Afatinib activity in platinum-refractory metastatic urothelial carcinoma in patients with ERBB alterations.
      Identifying a successful predictive biomarker to enrich responses to HER2 therapy remains a challenge. A study of afatinib monotherapy in platinum-refractory metastatic UC is currently specifically enrolling patients with ERBB receptor deregulation (ClinicalTrials.gov Identifier: NCT02780687).

      mTOR Inhibition May Be Effective in TSC1- or TSC2-Mutant Bladder Cancer

      The PI3K/AKT/mTOR pathway is activated by numerous receptor tyrosine kinases, cross-talks with the RAS/RAF/MEK/ERK pathway, and is involved in cell proliferation, cell survival, and invasion.
      • Houédé N.
      • Pourquier P.
      Targeting the genetic alterations of the PI3K-AKT-mTOR pathway: its potential use in the treatment of bladder cancers.
      Alterations in the PI3K/AKT/mTOR pathway were identified in 42% of urothelial carcinomas.
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of urothelial bladder carcinoma.
      In a phase 2 study of 45 patients with metastatic UC pretreated with everolimus, an oral mTOR inhibitor, the median PFS was 2.6 months with only 2 patients achieving a partial response.
      • Milowsky M.I.
      • Iyer G.
      • Regazzi A.M.
      • et al.
      Phase II study of everolimus in metastatic urothelial cancer.
      One of the 2 responding patients had a tremendous response, with a 94% decrease in metastatic sites lasting for more than 2 years. Further evaluation of this extraordinary responder identified a loss of function in TSC 1.
      • Iyer G.
      • Hanrahan A.J.
      • Milowsky M.I.
      • et al.
      Genome sequencing identifies a basis for everolimus sensitivity.
      The tuberous sclerosis complex TSC1/TSC2 is a tumor suppressor gene found on 9q and negatively regulates mTOR signaling. This finding prompted deep sequencing of an additional 13 patients treated in the same phase 2 trial of everolimus, identifying 3 additional nonsense sequence variations in TSC1 and 1 missense variant of unknown significance. Patients with TSC1-mutant tumors had a much longer PFS (7.7 months vs 2 months; P=.004).
      • Iyer G.
      • Hanrahan A.J.
      • Milowsky M.I.
      • et al.
      Genome sequencing identifies a basis for everolimus sensitivity.
      A National Cancer Institute study is ongoing to evaluate sapanisertib in advanced UC with known TSC1 or TSC2 sequence variations (ClinicalTrials.gov Identifier: NCT03047213).

      Results of Phase 3 Studies With Antiangiogenesis Agents Are Pending

      Antiangiogenic signaling was among the first targeted therapies attempted in bladder cancer. A phase 2 study of gemcitabine and cisplatin with bevacizumab in the first-line treatment of advanced UC reported an overall response rate of 72% and median OS of 19.1 months.
      • Hahn N.M.
      • Stadler W.M.
      • Zon R.T.
      • et al.
      Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75.
      These results led to a phase 3 Cancer and Leukemia Group B trial (CALBG 90601) that has finished accruing (ClinicalTrials.gov Identifier: NCT00234494), although results are not yet available.
      Ramucirumab, a monoclonal antibody specifically directed against vascular endothelial growth factor receptor 2, showed promise in the second-line treatment of advanced UC in combination with docetaxel. In a phase 2 study, 140 patients were randomized to docetaxel with ramucirumab, docetaxel with icrucumab, or docetaxel alone. The PFS in docetaxel with ramucirumab of 5.4 months was considerably better than those for both other groups (2.8 months for docetaxel and icrucumab and 1.6 months for docetaxel monotherapy).
      • Petrylak D.P.
      • Tagawa S.T.
      • Kohli M.
      • et al.
      Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial.
      The RANGE phase 3 study is further evaluating the combination of docetaxel and ramucirumab compared with docetaxel alone in the second-line treatment of advanced UC (ClinicalTrials.gov Idenfitier: NCT02426125).

      Future Targets of Interest

      Several other targeted therapies are being evaluated in advanced bladder cancer. A high rate of abnormalities in retinoblastoma or cyclin-dependent kinases coupled with frequent cell cycle dysregulation observed in MIBC prompted interest cell cycle inhibitors. The CDK4/CDK6 inhibitor palbociclib is being evaluated in the second-line treatment of advanced UC (ClinicalTrials.gov Identifier: NCT02334527). Heat shock proteins are up-regulated in bladder cancer and associated with poor prognosis and resistance to treatment. A novel strategy combining the antisense oligonucleotide OGX-427 to selectively target heat shock protein 27 with docetaxel led to a modest improvement in survival in poorer-risk patients.
      • Choueiri T.K.
      • Hahn N.M.
      • Werner L.
      • Regan M.M.
      • Rosenberg J.E.
      Borealis-2: a randomized phase II study of OGX-427 (apatorsen) plus docetaxel versus docetaxel alone in platinum-resistant metastatic urothelial cancer (mUC) (Hoosier Cancer Research Network GU12-GU160) [abstract].
      Several other strategies combining immunotherapy with either chemotherapy or targeted therapy are also in development (Table 3). The use of immunotherapy for treatment of locally advanced MIBC is currently being explored in the neoadjuvant, adjuvant, and first-line metastatic settings.

      Conclusion

      After several decades, the management of advanced urothelial cancer has seen promising recent developments. Innovations in treatment strategies and ongoing trials exploring novel therapeutics have potential for clinical benefit. However, challenges for the future include the widespread adoption of neoadjuvant chemotherapeutic treatment guidelines, a better understanding and application of the genetic, molecular, cellular, and immunologic mechanisms driving disease, and development of companion diagnostic molecular markers for prediction of treatment outcomes, prognosis, and monitoring of disease.

      Supplemental Online Material

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