Despite recent advances in the management of a wide variety of solid tumors, the outcomes for patients with metastatic urothelial carcinoma (MUC) remain extremely poor. Cisplatin-based combination chemotherapy remains the standard of care for first-line systemic treatment of MUC, and for more than 20 years there have been no other US Food and Drug Administration–approved treatment options available for these patients. Finally there appears to be hope on the horizon, with an ever-increasing number of precisely targeted agents being developed for use in MUC, resulting in improved survival rates. These targeted agents have now entered the cancer treatment arena, a direct result of a greater understanding of the genetic background of MUC. In this review article, we summarize the current state of development of these targeted agents, used either alone or in combination with traditional chemotherapy in MUC. Our discussion focuses on the most promising novel agents, including therapies targeting receptors for fibroblast growth factor and endothelial growth factor; antiangiogenesis agents (bevacizumab); tyrosine kinase inhibitors (cabozantinib); and immune checkpoint inhibitors that target proteins in the immune checkpoint–regulation pathway (anti–programmed death 1 and anti–programmed death ligand 1).
Introduction
At diagnosis, 25% to 30% of bladder cancer patients will present with muscle-invasive bladder cancer (MIBC), with approximately 25% of those patients already harboring occult lymph node metastases. Approximately 5% will present with distant metastatic urothelial carcinoma (MUC).[1] Unfortunately, the 5-year survival rate in patients with locally advanced or metastatic disease is only around 15%.[2] Cisplatin-based chemotherapy has a proven survival benefit, both in patients who are treated neoadjuvantly for locally advanced disease and in those with metastases. Standard first-line regimens for locally advanced/metastatic disease include combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), and doublet therapy with gemcitabine plus cisplatin (GC). Despite an objective overall response rate (ORR) of greater than 50% to cisplatin-based therapy, the duration of response is approximately 7 months and the median survival time is 15 months.[3] Toxicity can be significant in this population of patients. Patients who do not respond to initial cisplatin-based therapy, or who develop a relapse after initial chemotherapy, respond poorly to subsequent treatments. The median survival time in these refractory patients is approximately 9 months.[4]
A clearer understanding of molecular targets and immunologic characteristics of urothelial tumor cells has resulted in new therapeutic leads that may help optimize first- and second-line therapy, evaluate new combination approaches, and elucidate the role of maintenance therapy after initial response. This article will review select novel targets and approaches relevant to urothelial cancer.
Therapeutic Leads: The Cancer Genome Atlas
The Cancer Genome Atlas (TCGA) Research Network is a multi-institutional, comprehensive, widespread effort developed by the National Cancer Institute to collect specimens of a broad range of cancer types, in the hope of analyzing the genetics and molecular biology of tumor subtypes, in order to identify common mutations and targets for treatment. Upon initiation of the project in 2006, researchers sought to identify genomic changes in more than 20 different types of human cancer, including bladder cancer. A decade later, many targeted drugs are being used to treat other types of cancer. Similarly, the focus of research in advanced urothelial cancer is now shifting away from chemotherapy and toward targeted therapies.
TCGA recently published a comprehensive integrated study of 131 chemotherapy-naive high-grade MIBCs.[5] Mutations in 32 genes have now been identified and found to be statistically significant in the development and disease course of bladder cancer. These genomic alterations—including changes impacting the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and receptor tyrosine kinase (RTK)/RAS pathways, ERBB2 (human epidermal growth factor receptor 2 [HER2]), ERBB3, and fibroblast growth factor receptor 3 (FGFR3)—have potential therapeutic implications.[6] Using data from the International Genomics Consortium to identify specific topics in need of future study may prove beneficial in constructing new trials involving agents that target these genes. Summarized in this article are studies that have evaluated therapeutic agents aimed at targets identified by TCGA. (Table 1 lists select clinical trials of targeted therapy agents in advanced bladder cancer, and Table 2 highlights some studies of checkpoint inhibitors in this disease setting.)
Anti–PI3K/AKT/mTOR Therapy
The serine/threonine protein kinase mTOR is part of the PI3K/AKT/mTOR pathway, which plays a critical role in cell growth, angiogenesis, protein synthesis, and cell survival. Mutations, copy number alterations, and RNA expression changes affecting the PI3K/AKT/mTOR pathway are commonly found in various malignancies, including bladder cancer.[7] Data from Memorial Sloan Kettering Cancer Center showed mutations or copy number gains/losses of genes in the PI3K/AKT/mTOR pathway, including PIK3CA, PIK3R1, TSC1, PTEN, and the AKT3 isoforms in 26 of 95 patients (27%) with high-grade MIBC. These genetic alterations were associated with a trend toward longer time to recurrence (hazard ratio [HR], 0.53; P = .08).[8] In a single-arm, nonrandomized, phase II trial, treatment with the oral mTOR inhibitor everolimus yielded two partial responses (PRs) and a median survival time of 8.3 months in patients with MUC refractory to up to four cytotoxic chemotherapy regimens.[9] In another single-institution phase II study, everolimus showed antitumor activity in only a small number of patients with advanced bladder cancer.[10] In these studies, patients were unselected. However, enrichment of the patient population with genetic alterations, such as a TSC1 mutation[11] or mTOR-activating mutations (E2419K and E2014K),[12] may increase the observed levels of sensitivity to mTOR inhibitors. In a phase I trial of pazopanib combined with everolimus, a complete response (CR) of 14 months was observed for a patient who had mutations of both E2419K and E2014K.[12] Several trials of the mTOR inhibitors sirolimus, temsirolimus, and everolimus are currently accruing patients with advanced bladder cancer in order to assess these agents either in combination with a standard chemotherapy regimen or as monotherapy.
Agents Targeting Epidermal Growth Factor Receptor (EGFR)
The 170-kDa transmembrane receptor tyrosine kinase EGFR is a member of the ErbB family of type-1 receptor tyrosine kinases. In addition to EGFR, this receptor family includes the human epidermal growth factor receptors HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). EGFR is expressed in a variety of human epithelial tumors, including lung and bladder cancer. EGFR signaling has been shown to regulate the cell proliferation, apoptosis, angiogenesis, invasion, and tumor metastasis observed in preclinical models of transitional cell carcinoma (TCC) of the bladder.[13] This signaling pathway is expressed in about two-thirds of specimens of nonmetastatic MIBC; correlates with primary tumor stage; and is associated in some studies with tumor recurrence, progression, and patient survival.[14] Strong EGFR immunostaining patterns were observed in the majority of bladder cancer metastases (13 of 20) in one study.[15] Higher levels of EGFR appear to correlate with the basal-like histologic subgroup of bladder cancer. Therefore, the EGFR pathway represents a potential therapeutic target in urothelial carcinoma, either through antibodies that bind to the receptor or by the use of small molecules that target the tyrosine kinase.
Gefitinib
The rationale for the investigation of gefitinib in bladder cancer was based on the investigation of EGFR targeting by cetuximab (C225) in the early 2000s; cetuximab inhibited angiogenesis in mouse models of TCC, and this activity was enhanced by paclitaxel.[16] Gefitinib, an orally active selective EGFR tyrosine kinase inhibitor (TKI), has demonstrated antitumor activity synergistic with that of platinum and other chemotherapeutic agents in a variety of cell lines and human tumor xenograft models. In multiple studies, antitumor activity has been seen at all levels of EGFR expression, but has been greatest against tumors with the highest degree of EGFR expression. In EGFR-expressing human bladder cancer cell lines, gefitinib has inhibited extracellular signal-regulated kinase and AKT phosphorylation, as well as EGFR phosphorylation.
The Southwest Oncology Group evaluated gefitinib administered as a single agent in patients with MUC in whom prior platinum-based chemotherapy had failed.[17] Among the 31 patients treated, 1 patient demonstrated a PR in a lung metastasis and 2 patients had stable disease. At first evaluation, 81% of patients demonstrated progressive disease. The median survival time was 3 months.
A phase II trial (Cancer and Leukemia Group B 90102) sought to determine the efficacy of GC and gefitinib in patients with advanced urothelial carcinoma.[18] Patients with previously untreated measurable disease were treated with cisplatin at a dosage of 70 mg/m2 on day 1 and gemcitabine at 1,000 mg/m2 on days 1 and 8, given every 3 weeks concurrent with gefitinib at 500 mg/day orally for 6 cycles. Maintenance gefitinib at 500 mg/day was continued for patients with responding or stable disease. A total of 54 of 58 patients were assessable. There were 12 patients (22%) with node-only disease, and 25 (46%) had an Eastern Cooperative Oncology Group performance status of 0. There were 23 objective responses, for an ORR of 42.6% (95% CI, 29.2%–56.8%). The median survival time was 15.1 months (95% CI, 11.1–21.7 months) and the median time to progression was 7.4 months (95% CI, 5.6–9.2 months). However, the addition of gefitinib did not appear to improve the response rate or survival outcomes in comparison with historical controls of patients treated just with cisplatin plus gemcitabine.
Erlotinib
Treatment with the EGFR TKI erlotinib has been studied in a variety of tumor types. In a phase II open-label trial of this agent given prior to radical cystectomy for MIBC, 20 patients were treated with 4 weeks of adjuvant erlotinib; 60% were downstaged to pT1 or less, suggesting single-agent activity with EGFR inhibitors in this disease setting.[19] A similar trial at the University of Texas MD Anderson Cancer Center is assessing the rate of complete pathologic response after 3 to 5 weeks of erlotinib therapy in patients with MIBC.[20]
Despite high levels of expression of EGFR in patients with MUC, the aforementioned results with the TKIs have been disappointing, and may be related to the paucity of EGFR mutations in bladder cancer specimens. In patients treated with EGFR TKIs for advanced lung cancer, point mutations at exons 19 and 21 of the EGFR gene’s ATP-dependent tyrosine kinase domain are associated with response. Chaux et al[21] found that mutations of these exons were not detected in micro-dissected paraffin sections obtained from 19 urothelial tumors, despite immunohistochemical expression in 74% of the examined cases. Thus, alterations associated with TKI response have not been detected in urothelial carcinoma.
Cetuximab
The anti-EGFR monoclonal antibody cetuximab is approved for treatment of non–small-cell lung cancer (NSCLC), head and neck cancer, and colorectal cancers. Cetuximab monotherapy has preclinical activity in bladder tumor models. Although it has modest antitumor effects when used as a single agent in this setting, enhanced tumor effects were revealed when cetuximab was combined with the second-line agent paclitaxel.[16]
A randomized, noncomparative, phase II study aimed to evaluate the efficacy of cetuximab with or without paclitaxel in the second-line setting in bladder cancer.[22] A total of 39 patients were randomly assigned to 4-week cycles of cetuximab at 250 mg/m2 with or without paclitaxel at 80 mg/m2 per week. The arm assessing single-agent cetuximab closed after 9 of the first 11 patients had progressed by 8 weeks. However, there appeared to be some synergy between anti-EGFR monoclonal antibodies and taxanes. Cetuximab may well augment paclitaxel antitumor activity; in the combination arm (which accrued 28 patients) there was a 25% response rate, with 12 patients having progression-free survival (PFS) beyond 16 weeks. However, in small studies such as this one, the data must be interpreted with caution, since the median PFS and overall survival (OS) times observed (16.4 and 42 weeks, respectively) were very modest and within the range reported for other agents in this disease setting. Other trials currently evaluating cetuximab include TUXEDO (Cancer Research UK trial number CRUK/09/021), a phase II trial in the United Kingdom of cetuximab administered concurrently with chemoradiation therapy (using either mitomycin-C and 5-fluorouracil or cisplatin) in MIBC.
Panitumumab
A phase I, multicenter, open-label study sequentially enrolled 86 patients with advanced refractory solid tumors, to receive the EGFR antibody panitumumab (given at 6 mg/kg every 2 weeks or 9 mg/kg every 3 weeks).[23] Objective responses were reported in four patients (5%) with colon, rectal, esophageal, and bladder cancers. The results suggested that panitumumab administered at 9 mg/kg every 3 weeks appeared to be safe, and studies using this dosing schedule are ongoing. Further evaluation of panitumumab in urothelial carcinoma was planned in a randomized, multicenter, phase II study by the German Association of Urological Oncology ([AUO] trial AB 34/09) comparing GC in combination with panitumumab vs GC as first-line therapy for patients with locally advanced/metastatic urothelial carcinoma. Unfortunately, this study was terminated due to insufficient recruitment.
Agents Targeting HER2
The second member of the EGFR family, HER2, plays an important role in the pathogenesis of urothelial carcinoma. Several studies have reported HER2 protein overexpression rates of 5% to 80% in bladder cancer. Lae et al analyzed 1,005 MIBC tissue samples for overexpression of HER2 and HER2 gene amplification.[24] HER2 protein overexpression was found in 11.4% of tissue samples. HER2 gene amplification was found in 5.1% of MIBC. A study evaluating 80 cystectomy and lymph node dissection specimens found 28% of cystectomy cases (22 of 80) were HER2-positive and 53% (17 of 32) had positive lymph nodes.
Trastuzumab
In a phase II trial, the anti-HER2 humanized monoclonal antibody trastuzumab was used in combination with paclitaxel, gemcitabine, and carboplatin to treat patients with advanced HER2-positive bladder cancer. The regimen produced a 70% response rate, including CRs, in patients with metastatic disease.[25] Trastuzumab administered concurrently with paclitaxel chemoradiation treatment is being evaluated in patients with MIBC who have undergone transurethral resection of bladder tumor and are not candidates for radical cystectomy.
A study investigating trastuzumab combined with standard GC doublet chemotherapy for bladder cancer in the first-line setting closed enrollment early (ClinicalTrials.gov identifier: NCT02006667). Another study investigating single-agent trastuzumab in the second-line setting (ClinicalTrials.gov identifier: NCT02013765) closed early because of recruitment difficulties.
Lapatinib
The dual EGFR and HER2 TKI lapatinib is also being studied in combination with chemotherapy for MUC. Although single-agent treatment with lapatinib in unselected patients with platinum-refractory MUC yielded only a 1.7% ORR, it led to markedly worse OS in those with low copy numbers of EGFR and HER2, compared with patients who had high overexpression of EGFR and/or HER2.[26] This subgroup analysis reinforces the concept of selecting appropriate patients for targeted therapies.
Importantly, 18% of patients in the postoperative treatment group (no chemoradiation prior to surgery) who were determined preoperatively to have T3 or T4 disease or lymph-node metastasis were found to actually have T1 or T2 or node-negative tumors on pathologic examination of the resected specimen. This important observation clearly highlights the limitations of preoperative staging at the time the study was performed, and perhaps the potential for overtreatment of some patients. The finding underscores the need for accurate staging so as to avoid unnecessary treatment of patients with early-stage tumors.
A recently completed phase II/III trial (n = 223) comparing maintenance lapatinib vs placebo after first-line chemotherapy in patients with locally advanced or metastatic bladder cancer found no difference in OS or PFS, even in HER2-positive patients.[27] A phase I trial that combined lapatinib with GC has recently been completed (ClinicalTrials.gov identifier: NCT00623064).
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