The timely review by Drs. Cheetham and Petrylak in this issue of ONCOLOGY highlights emerging agents for the therapy of advanced urothelial carcinoma. Since the development of first-line cisplatin-based combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) almost 3 decades ago, there have not been major advances in the treatment of this disease. Indeed, in an underpowered phase III trial, outcomes of treatment with the gemcitabine-cisplatin (GC) doublet were similar to those achieved with MVAC, with a reported median overall survival (OS) of 14 to 15 months for both regimens. In some countries, vinflunine remains the only commercially approved agent for salvage therapy of urothelial carcinoma (with approval based on the results of a phase III trial), although outcomes appear dismal (with a reported median OS of about 6 months) and are similar to outcomes observed with taxanes in this disease setting.[4-6]
Fortunately, recent data suggest that the systemic therapy of advanced urothelial carcinoma may be on the verge of a renaissance. Chief among the emerging treatments are antiangiogenic agents and inhibitors of the T-cell checkpoint molecules programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1). The vascular endothelial growth factor (VEGF) inhibitor bevacizumab demonstrated promising outcomes in a nonrandomized phase II trial, which led to a US Intergroup phase III placebo-controlled trial investigating the impact of adding bevacizumab to GC. More recently, ramucirumab, a VEGF receptor (VEGFR)-2 monoclonal antibody, extended progression-free survival when combined with second-line docetaxel in a randomized phase II trial. The phase III RANGE trial has been launched to confirm the improvement in outcomes when ramucirumab is used in combination with docetaxel as second-line therapy in urothelial cancer. It is worth noting that VEGFR tyrosine kinase inhibitors (TKIs), administered either alone (pazopanib, sunitinib) or in combination with chemotherapy (sorafenib, vandetanib), have not demonstrated significant benefits in randomized phase II trials.[9-12] Nintedanib, a TKI that targets VEGF and fibroblast growth factor receptors (FGFRs), is being investigated in combination with GC in a randomized phase II trial in the neoadjuvant setting. Cabozantinib, a TKI targeting VEGFRs and MET, appears active in a preliminary study; treatment with a regimen including this agent was associated with an increase of PD-1 expression in Tregs, suggesting that its combination with PD-1 inhibitors may be worth exploring.In addition, regorafenib, a TKI that inhibits the angiopoietin– tyrosine kinase 2 axis and FGFR1 in addition to VEGFRs, is being investigated in the salvage setting in a phase II trial.
Immunotherapy with T-cell checkpoint inhibitors has yielded benefits in a wide spectrum of malignancies, including urothelial carcinoma. Both PD-1 and PD-L1 inhibitors have demonstrated activity, especially durable responses, in patients with advanced urothelial carcinoma previously treated with platinum-based chemotherapy. Moreover, these agents offer the promise of precision medicine: phase II data indicate at least a numerically higher response rate in tumors with higher expression of PD-L1 in immune cells when using atezolizumab, a PD-L1 inhibitor.[14,15] Indeed, atezolizumab was approved by the US Food and Drug Administration (FDA) on May 18, 2016, based on the phase II IMvigor trial, which enrolled 310 patients who had progressed during or following platinum-containing chemotherapy. The overall response rate was 14.8% and the duration of responses ranged from 2.1+ to 13.8+ months. Patients with PD-L1 expression in > 5% and < 5% of tumor infiltrating immune cells demonstrated response rates of 26% and 9.5%, respectively. Pembrolizumab, a PD-1 inhibitor, has also produced durable responses and a median OS of approximately 1 year in patients with tumors expressing PD-L1 in > 1% of their tumor cells or immune cells. Both pembrolizumab and atezolizumab are under investigation as salvage therapy in phase III trials, in comparison with conventional vinflunine or taxanes.
Additionally, several inhibitors of PD-1 and PD-L1 are being evaluated in the first-line setting in cisplatin-ineligible patients with advanced urothelial carcinoma. A newer PD-L1 inhibitor, durvalumab, is undergoing phase III evaluation in the first-line setting in the DANUBE trial. This three-arm trial allows both cisplatin-eligible and -ineligible patients: gemcitabine plus platinum is administered in the control arm (with the platinum being cisplatin or carboplatin) vs durvalumab alone vs durvalumab plus the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor tremelimumab. Finally, atezolizumab, nivolumab, and pembrolizumab are also undergoing phase III evaluation in the adjuvant context following radical cystectomy with or without prior neoadjuvant chemotherapy for muscle-invasive urothelial cancer. The trial evaluating adjuvant atezolizumab selects for PD-L1–expressing tumors, while the other two trials do not require the presence of a biomarker.
Multiple other agents appear to have activity at least in selected patients. Tumor tissue genomic analyses suggest a variety of potential therapeutic targets in epidermal growth factor receptor (EGFR)/human epidermal growth factor receptors 2 and 3 (HER2/HER3), the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, the mitogen-activated protein kinase pathway, and pathways regulating the G1/S phase of the cell cycle.[17,18] Indeed, a subset of patients with tumors harboring TSC1 and mTOR mutations demonstrated deep responses to everolimus.[19,20] However, trastuzumab in combination with GC for HER2-overexpressing metastatic urothelial carcinoma and lapatinib alone as maintenance therapy following first-line chemotherapy in HER2- or EGFR-expressing metastatic urothelial carcinoma did not improve outcomes.[21,22] In contrast, inhibition of both EGFR and HER2 by afatinib appeared preliminarily active in patients bearing tumors with HER2 or HER3 mutations or amplifications, which has led to a larger phase II trial in selected patients. Alterations in FGFR, including FGFR3 mutations, FGFR3-TACC3 translocations, and FGFR2 alterations have been associated with responses to potent FGFR inhibitors.[24,25] However, dovitinib, an older, less potent FGFR TKI, did not exhibit significant activity in patients with somatic FGFR3 mutations, suggesting that both the target and the drug are important. Palbociclib, a cyclin-dependent kinase (CDK)4/6 inhibitor approved for breast cancer, is being rationally evaluated in a molecularly selected population with intact RB and either CDK inhibitor 2A–negative tumors or cyclin D1 protein overexpression on immunohistochemistry. Trials evaluating epigenetic modifiers such as histone deacetylase inhibitors are underway, given the enrichment of these targets in urothelial carcinoma. Furthermore, tubulin-inhibiting cytotoxic chemotherapy may continue to play a role, as suggested by the activity demonstrated by eribulin and nanoparticle albumin-bound (nab)-paclitaxel.[27,28] Since these novel tubulin inhibitors do not require corticosteroid premedication, they may be particularly conducive to partnering with immunotherapeutics.
Novel trial strategies—including neoadjuvant approaches, regimens for use in the setting of bacillus Calmette Guérin–resistant non–muscle-invasive bladder cancer, and basket and umbrella trial designs—should be exploited to accelerate advances for molecularly defined subsets. Brief therapy of a few weeks in the neoadjuvant setting, assessing a small number of patients, may provide evidence for the presence or absence of biologic activity, before larger trials are launched. Additionally, the identification of intrinsic subtypes based on gene expression profiling may have implications for developing precision medicine.[30,31] Preliminarily, the basal subtype appears to be more chemosensitive; the luminal subtype harbors FGFR, HER2, and HER3 targets; and the mesenchymal/claudin-low subtype appears enriched for T-cell checkpoint targets.
Thus, the next decade promises to bring multiple advances to the clinic. As novel agents are explored as single agents or in combination with existing conventional therapy, rational combinations of biologic agents should also be vigorously explored, to make greater advances in the management of this molecularly heterogeneous malignancy. In particular, the combination of PD-L1 inhibition and CTLA-4 inhibition is already being evaluated in the previously described phase III first-line DANUBE trial, and evaluation of inhibition of PD-L1 (with atezolizumab) and VEGF (with bevacizumab) is planned in a first-line phase II trial for cisplatin-ineligible patients. When developing new regimens, it is critical to remember that many patients in the target population are elderly, and they frequently have multiple comorbidities, renal dysfunction, and poor performance status, which warrants the development of highly tolerable regimens. A highly collaborative international effort is necessary to achieve major advances, given the history of slow accrual to clinical trials and of incomplete trials, especially in the adjuvant setting.
Financial Disclosure: Dr. Sonpavde receives research support from Bayer, Celgene, Merck, Onyx, and Pfizer; and he serves on the advisory boards of, and as a consultant to, Agensys, Argos, Bayer, Genentech, Merck, Novartis, Pfizer, and Sanofi.
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