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Correspondence: Address to Manish Kohli, MD, Division of Hematology and Medical Oncology, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
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.
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Credit Statement: Mayo Clinic College of Medicine and Science designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.
MOC Credit Statement: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 MOC point in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
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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Date of Release: 10/1/2017
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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).
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.
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.
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.
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.
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.
Regardless of study-specific terminology, several common biological trends have emerged (Figure 1).
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),
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.
Basal tumors are associated with squamous or sarcomatoid differentiation, advanced-stage or metastatic disease at presentation, and a more aggressive clinical course.
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.
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).
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
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.
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.
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%).
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.
One consequence of this sequence variation burden is the formation of sequence variation-associated neoantigens—peptides displayed on the tumor cell surface.
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.
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.
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.
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.
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.
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.
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
Regimen
No. of patients
Overall response rate (%), P value
Median OS (mo), P value
Better tolerated
Highlight
Reference, year
Metastatic: first-line treatment
Cisplatin vs MVAC
126 120
12 39
P<.001
8.2 12.5
P<.001
Cisplatin
Established combination chemotherapy as superior to single agent
A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
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.
Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.
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.
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.
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.
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).
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.
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.
with evidence of improvement in survival compared with single-agent cisplatin and combination chemotherapy with cisplatin, cyclophosphamide, and doxorubicin.
Phase III comparison of cisplatin alone versus cisplatin, doxorubicin and cyclophosphamide in the treatment of bladder (urothelial) cancer: a Southeastern Cancer Study Group trial.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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 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
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.
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%
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.
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.
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.
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].
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.
Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation: the National Cancer Institute of Canada Clinical Trials Group.
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.
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).
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,
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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).
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.
A retrospective analysis of 8 trials using taxane-based combination chemotherapy found that doublets may improve survival compared with taxane monotherapy.
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.
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.
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),
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.
Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
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].
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.
Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
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].
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.
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.
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.
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
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.
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.
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.
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.
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.
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.
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].
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,
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.
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.
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.
Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: preliminary results from the phase 2 KEYNOTE-052 study.
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)
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.
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.
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%).
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.
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.
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.
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.
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).
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 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).
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 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%.
A randomized placebo-controlled neoadjuvant nintedanib (FGFR inhibitor) or placebo with gemcitabine and cisplatin for patients with invasive bladder cancer
2
Pathologic CR
ISRCTN56349930/NEOBLADE
Adjuvant
A study of atezolizumab vs observation as adjuvant therapy in participants with high-risk muscle-invasive UC after resection
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)
Nivolumab in combination with ipilimumab compared with standard of care chemotherapy (gemcitabine plus cisplatin or carboplatin) in inoperable or metastatic UC
Nintedanib (FGFR inhibitor) in patients with advanced FGFR3-mutated, FGFR3-overexpressed, or FGFR3–wild type UC in whom platinum-based chemotherapy failed
B-701 (FGFR3 monoclonal antibody) plus docetaxel vs placebo plus docetaxel in the treatment of locally advanced or metastatic, relapsed or refractory UC
Palbociclib in patients with metastatic UC with cyclin-dependent kinase inhibitor 2A loss and positive retinoblastoma expression after failure of first-line therapy
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.
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.
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%.
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
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.
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.
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.
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.
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.
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.
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).
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.
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).
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.
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.
Low T-cell receptor diversity, high somatic mutation burden, and high neoantigen load as predictors of clinical outcome in muscle-invasive bladder cancer.
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.
A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
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.
Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.
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.
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.
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.
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).
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.
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.
Phase III comparison of cisplatin alone versus cisplatin, doxorubicin and cyclophosphamide in the treatment of bladder (urothelial) cancer: a Southeastern Cancer Study Group trial.
Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group.
Guideline on muscle-invasive and metastatic bladder cancer (European Association of Urology Guideline): American Society of Clinical Oncology clinical practice guideline endorsement.
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.
Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience.
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.
Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.
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].
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].
Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation: the National Cancer Institute of Canada Clinical Trials Group.
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].
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.
Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
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].
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
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.
Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: preliminary results from the phase 2 KEYNOTE-052 study.
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].
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.
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.
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.
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].
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