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).
Agents Targeting the FGFR
TO PUT THAT INTO CONTEXT
Matthew D. Galsky, MD
Icahn School of Medicine at Mount Sinai, New York, New York
New Hope for Patients With Advanced Urothelial Cancer
There has been a paucity of new drugs developed for the treatment of metastatic urothelial cancer, with no drugs approved for this indication by the US Food and Drug Administration (FDA) in more than 30 years. This lack of progress likely has myriad causes, including a poor understanding of the pathogenesis and heterogeneity of the disease, a patient demographic characterized by older age and smoking-related comorbidities, and inadequate interest on the part of industry. However, after decades without substantial progress, a series of advances in both the laboratory and the clinic in the past few years have begun to change the outlook for patients with advanced urothelial cancer.
How Have Targeted Approaches Changed Diagnosis and Treatment?
Several factors underlie recent advances in the management of urothelial cancer; these include comprehensive efforts to define the molecular pathogenesis of urothelial cancer, and the introduction of novel therapies directed at targets that range from tumor angiogenesis, to activating somatic mutations in growth factor receptors, to adaptive immune resistance. Antibodies directed against the immune checkpoint inhibitors programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have demonstrated durable responses in a subset of patients with platinum-resistant urothelial cancer. Now, with the recent FDA approval of the PD-L1 inhibitor atezolizumab, this drug class represents the first to gain regulatory approval in this disease setting. Small-molecule inhibitors of mutated FGFR3 (fibroblast growth factor receptor 3) have demonstrated single-agent responses in the clinic, finally validating mutant FGFR3 as a relevant therapeutic target in this disease. With the increasing availability of these tools in the clinic, it will be incumbent upon the bladder cancer research community to begin to focus not only on developing new drugs but also on developing new therapies. Questions regarding when to optimally employ these newer agents, in which patients, and in which sequences and combinations will only be determined through iterative cycles of bench-to-bedside research.
Financial Disclosure: Dr. Galsky receives research funding from Bristol-Myers Squibb, Merck, and Novartis; and he serves on the advisory boards of Merck and Novartis.
Mutations of the FGFR3 gene are prevalent in both non-MIBC and MIBC. The multikinase inhibitor dovitinib targets FGFR3 kinase. This agent was evaluated in patients with platinum-refractory metastatic disease as part of a phase II trial enrolling 44 patients and using a two-stage design. Median PFS was 3 months. Because of a lack of treatment response in the first stage and because most patients did not receive more than 6 months of therapy, patients were not recruited for the second stage of the trial. It is not clear why dovitinib lacked activity. Possible reasons include lack of target inhibition due to low drug potency (much more potent FGFR3 inhibitors, including BGJ398 and JNJ-42756493, are now available and have shown activity in humans) or inadequate selection of patients (since activating translocations and FGFR3 expression were not quantified and may better identify responders). It is also possible that the profile of kinases inhibited by dovitinib is not optimal for effectiveness.
Vascular endothelial growth factor (VEGF)
The VEGF family binds with high affinity to three tyrosine kinase receptors (VEGFR-1, VEGFR-2, and VEGFR-3), mediating normal and pathogenic angiogenesis in various cancers, mostly through interaction with VEGFR-2. VEGF is important in the pathophysiology of urothelial cancer. It is often overexpressed in bladder cancer. A high level of VEGF in both serum and urine is correlated with tumor progression, a higher recurrence rate,[29, 30] and poor survival. VEGFR-2 is expressed in 50% of urothelial carcinomas, and expression is significantly higher in MIBC than in non-MIBC.
Inoue et al evaluated the prognostic value of tumor VEGF expression in patients with MIBC treated with neoadjuvant MVAC chemotherapy and radical cystectomy. They examined VEGF expression before and after neoadjuvant chemotherapy, along with basic fibroblast growth factor and interleukin-8 expression and microvessel density by immunohistochemistry in biopsy specimens from 55 patients with MIBC. VEGF expression and microvessel density in pretreated biopsy samples showed a correlation with disease recurrence (P = .032 and P = .015, respectively). VEGF appears to be a rational therapeutic target. Various VEGF-targeting agents are currently being evaluated in MIBC. Although targeting angiogenesis by way of VEGF is a promising strategy in urothelial carcinoma, the results with TKIs that target VEGFRs have not been encouraging.
Bevacizumab is a monoclonal antibody targeting VEGF-A. Bevacizumab combinations have been evaluated as first-line therapy in MUC. The Hoosier Oncology Group treated 43 chemotherapy-naive patients with MUC and reported a 72% ORR, with 19% of patients attaining a CR. The median OS was 19.1 months. Of note, grade 3 or higher vascular events, such as deep venous thrombosis or pulmonary embolism, were observed in 21% of patients. This was postulated to be due to the initial 1,250-mg/m2 dose of gemcitabine. In another phase II study of chemotherapy-naive cisplatin-ineligible patients with metastatic disease, whose expected survival time was approximately 9 months, bevacizumab combined with GC and carboplatin led to a 63% response rate and an OS of 13.9 months. Both of these studies showed better results than might be expected compared with historical controls. Given these encouraging results, a phase III trial of GC with and without bevacizumab as first-line treatment was launched as an intergroup study led by the Alliance cooperative group (ClinicalTrials.gov identifier: NCT00942331). In the metastatic setting, a phase II trial of bevacizumab with GC as neoadjuvant therapy followed by adjuvant paclitaxel has completed accrual (ClinicalTrials.gov identifier: NCT00268450). The results of these studies are pending.
Bevacizumab has also been investigated in the neoadjuvant setting. In two phase II trials, it was combined with either GC or dose-dense MVAC, resulting in pathologic response rates of 31% and 53%, respectively, with downstaging to less than stage T2. The combination of bevacizumab plus GC was associated with postoperative complications in some patients (5 of 12 [42%]), including enterovesical fistula, delayed wound healing, prolonged ileus, and pelvic abscess.
Aflibercept (also known as VEGF-Trap) is a recombinant fusion protein that binds and neutralizes multiple VEGF isoforms. A small phase II study evaluated this agent in 22 patients with measurable, metastatic, or locally advanced urothelial cancer previously treated with 1 platinum-containing regimen. One PR was reported. Median PFS was 2.79 months (95% CI, 1.74–3.88 months). Aflibercept was well tolerated, with toxicities similar to those seen with other VEGF pathway inhibitors. However, it was demonstrated to have limited single-agent activity in patients with platinum-pretreated urothelial carcinoma.
The fully humanized immunoglobulin (Ig)G1 monoclonal antibody ramucirumab blocks the binding of VEGF to VEGFR-2. It is approved as a single agent or in combination with paclitaxel or docetaxel for gastric cancer. In vitro, ramucirumab chemosensitizes bladder cancer cell lines to docetaxel. A randomized phase II trial compared docetaxel at 75 mg/m2 (n = 45) intravenously (IV) vs ramucirumab at a dose of 10 mg/kg IV in combination with the same dose and schedule of docetaxel (n = 46). These urothelial cancer patients were required to demonstrate progression within 12 months of administration of treatment with platinum-based regimens for metastatic disease, or neoadjuvant/adjuvant therapy. The addition of ramucirumab to docetaxel met the prespecified efficacy endpoint for prolonging PFS in second-line treatment for patients with locally advanced disease or MUC. PFS was significantly longer in the combination arm compared with docetaxel alone (median PFS, 5.4 months [95% CI, 3.1–6.9 months] vs 2.8 months [95% CI, 1.9–3.6 months]; stratified HR, 0.389 [95% CI, 0.235–0.643]; P = .0002). OS, a secondary endpoint, was not significantly different between the two arms. The most common grade ≥ 3 adverse events were neutropenia, fatigue, febrile neutropenia, and anemia. Patients in a third study arm, treated with the VEGFR-1–directed antibody icrucumab plus docetaxel, demonstrated a worse overall median PFS (1.6 months). To further confirm these observations, RANGE (ClinicalTrials.gov identifier: NCT02426125), a phase III study, is comparing docetaxel vs ramucirumab plus docetaxel.
Sunitinib, an oral inhibitor of multiple tyrosine kinase receptors, including VEGFR, has shown synergistic antitumor effects with both cisplatin and gemcitabine in preclinical models of urothelial cancer. Sunitinib monotherapy produced mixed effects in patients with advanced urothelial cancers, when administered either as a first-line therapy for patients who were not candidates for cisplatin-based chemotherapy (because of renal impairment) or as second-line therapy after chemotherapy.
In trials in which sunitinib was combined with GC for either first-line metastatic or neoadjuvant treatment of patients with urothelial cancer, high rates of toxicity and intolerability were a major issue. Sunitinib, given as maintenance therapy in a randomized phase II trial to patients who had achieved stable disease or a PR or CR after 4 to 6 cycles of chemotherapy, did not improve 6-month PFS compared with placebo. Because of these disappointing results, there are no ongoing trials of sunitinib for MUC.
MET/Hepatocyte Growth Factor 1 (HGF1) Inhibition
The TKI cabozantinib primarily targets VEGFR-2 and c-MET (also known as MET or HGF1), which might be potential targets in urothelial carcinoma. Cabozantinib is being studied in an ongoing phase II trial as second-line treatment of MUC. In a preliminary report of 25 patients with refractory urothelial cancer treated with 60 mg of oral cabozantinib daily, PRs were demonstrated in 14% of patients, and another 38% had stable disease. Grade 3 toxicities included fatigue and mucositis. Of note, myeloid-derived stem cells and regulatory T cells (Tregs) were evaluated in patients whose urothelial cancer was treated with cabozantinib; patients with low Tregs at baseline had an improved PR rate (P = .014), PFS (P = .059), and OS (P = .071). Tregs decreased with cabozantinib treatment (P = .015). Overall, programmed death 1 (PD-1) expression in Tregs increased after cabozantinib (P = .011).
Cabazitaxel is a taxane that exhibits preclinical antitumor activity in both docetaxel-sensitive and -resistant tumors. A survival benefit has been demonstrated with cabazitaxel use in metastatic castration-resistant prostate cancer. Modest antitumor activity has been demonstrated with other taxanes, such as paclitaxel and docetaxel, with responses ranging between 6% and 20%. In cisplatin- and gemcitabine-refractory cell lines, cabazitaxel demonstrated less cross-reactivity than standard agents such as pemetrexed, methotrexate, oxaliplatin, and paclitaxel. These preclinical data justify further evaluation of cabazitaxel in urothelial carcinoma. The National Cancer Institute evaluated cabazitaxel (ClinicalTrials.gov identifier: NCT01437488), initially dosed at 20 mg/m2, then escalated to 25 mg/m2 at the investigator’s discretion, and administered with growth factor support. No responses were observed in 14 patients, with 1 patient dying from refractory hypoxia. Therefore, further evaluation of cabazitaxel as a single agent in the treatment of urothelial carcinoma is unwarranted. Cabazitaxel had limited clinical activity in platinum-refractory MUC and was associated with toxicity (fatigue, diarrhea, anemia, nausea, neuropathy, increased creatinine levels, lightheadedness, and hypophosphatemia). Unfortunately, the study did not proceed to the second stage; it was closed early, due to lack of treatment efficacy. An ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT01616875) is evaluating the efficacy of neoadjuvant cisplatin combined with cabazitaxel.
Eribulin is a novel synthetic antimicrotubule agent that binds to the vinca domain of tubulin and inhibits the polymerization of tubulin. It is an analog of halichondrin B, originally isolated from the sea sponge. This agent demonstrates improved survival over physician’s-choice chemotherapy in breast cancer patients who have received prior treatment. In an extended phase II trial by The California/Pittsburgh Cancer Consortium, eribulin was administered at 1.8 mg/m2 on days 1 and 8 of a 21-day cycle to 150 patients with advanced urothelial cancer who had received prior platinum-based therapy. In developing the study, a response rate of 20% or higher was deemed by the authors to be of clinical importance; an ORR of 34.7% was reported. The median PFS and OS were 4.1 and 9.5 months, respectively. There was no significant increase in neuropathy or hematologic toxicity in patients who were tubulin-naive compared with patients who were tubulin-exposed. Several trials are in development for the use of eribulin in patients with advanced urothelial cancer and renal dysfunction (ClinicalTrials.gov identifier: NCT00365157).
Antibodies for Immune Therapy: Immune Checkpoint Inhibitors
Immune therapy focusing on novel agents that target proteins in the immune checkpoint regulation pathway (especially PD-1 and its ligand, programmed death ligand 1 [PD-L1]) has produced a survival benefit in a variety of solid tumors, including metastatic lung cancer and renal cancer. Immune therapy is also emerging as a promising new treatment in bladder cancer, with significant potential demonstrated in preclinical models and early clinical trials (see Table 2).
The monoclonal antibody ipilimumab targets cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4). CTLA-4 is a potent immune checkpoint molecule that downregulates T-cell activation after binding to antigen-presenting cells. Ipilimumab first demonstrated clinical activity and improved clinical outcomes in patients with metastatic melanoma. To evaluate its efficacy in urothelial cancer, the Hoosier Oncology Group treated 36 chemotherapy-naive MUC patients with ipilimumab in combination with GC. Patients were initially treated with 2 cycles of GC followed by 4 cycles of GC/ipilimumab, followed by ipilimumab maintenance administered every 3 months. The observed mean survival time of 14.6 months was no different from that of historical controls, but it was achieved at the cost of additional immune-related toxicities such as diarrhea (in 8% of patients), colitis (6%), and rash (6%). Treatment with ipilimumab was associated with an increased number of CD4+ and CD8+ T cells.
Atezolizumab (also known as MPDL3280A) is a high-affinity human anti–PD-L1 monoclonal IgG1 antibody. It has demonstrated clinical activity in melanoma, breast cancer, NSCLC, and renal cancer. In a phase I trial of second-line atezolizumab in TCC, tumor immune cell (IC) expression of PD-L1, but not tumor cell expression, correlated with outcome. IC 0, 1, 2, and 3 expression was defined as 0%, < 1%, 1% to 5%, 5% to 10%, and > 10% of immune cells expressing PD-L1. ORRs were 43% for patients with tumor immune cells expressing high levels of PD-L1 (IC 2/3), compared with 11% in patients whose tumor immune cells had low expression of IC (0/1). The median duration of response has not been reached, and is independent of PD-L1 status. The median PFS was 6 months in the IC 2/3 group compared with 1 month in the 0/1 group. The median survival in the IC 2/3 group has not yet been reached after a median of 14 months follow-up. The median survival in the IC 0/1 group was 8 months, similar to results with cytotoxic chemotherapy but with less toxicity. There were no treatment-related deaths on the study; 5% of patients had grade 3 or 4 immune-mediated toxicities, including elevated transaminase levels, increased bilirubin, and hypophysitis. Atezolizumab was granted breakthrough therapy designation status by the US Food and Drug Administration (FDA) in June 2014, and priority review for locally advanced bladder cancer or MUC in March 2016. On May 18, 2016, it was approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma.
Two trials have been designed to confirm the initial data: a large phase II study of platinum-experienced patients (IMvigor 210; ClinicalTrials.gov identifier: NCT02108652) and a phase III trial comparing atezolizumab vs chemotherapy in 767 platinum-refractory patients (IMvigor 211; ClinicalTrials.gov identifier: NCT02302807). IMvigor 210 treated 315 platinum-refractory urothelial cancer patients with atezolizumab at 1,200 mg IV every 3 weeks. The primary endpoint of IMvigor 210 was a response rate by Response Evaluation Criteria in Solid Tumors (RECIST) of > 10%, which was achieved in each of the prespecified immune cell groups. Twenty-seven percent of patients with IC 2/3, 18% of those with IC 1/2/3, and 15% of all patients had response rates > 10% by RECIST. The median PFS was 2.1 months, and PFS was similar in all immune cell groups. The median OS was 11.4 months in the IC 2/3 patients and 8.8 months in the IC 1/2/3 patients. For all patients, median survival time was 7.9 months. An exploratory analysis found that PD-L1 immune cell prevalence was highly enriched in the basal subtype of urothelial cancer, compared with the luminal subtype (60% vs 23%; P < .001); the median mutation load was significantly higher in responders than in nonresponders. The IMvigor 211 trial has completed accrual.
Pembrolizumab is an anti–PD-1 antibody that blocks interaction with both PD-L1 and PD-L2. In KEYNOTE-012, a phase Ib trial that selected for patients expressing PD-L1 in tumor cells, 33 patients with urothelial cancer (approximately 75% of whom had prior platinum-based therapy) received pembrolizumab every 2 weeks. The ORR was 27.6%, with 10.3% of patients demonstrating a PR. The mean duration of response has not yet been reached; the median PFS and OS were 2 months and 12.7 months, respectively. Immune-related side effects included colitis, myositis, rhabdomyolysis, rash, and uveitis (with 1 patient discontinuing treatment due to myositis and rhabdomyolysis). There were no treatment-related deaths. A re-analysis of the PD-L1 immunoreactivity demonstrated no objective responses when this marker was evaluated both in tumor cell samples and in tumor-associated inflammatory cells. Immune-related gene expression using NanoString Technologies’ nCounter Platform found that a 13-gene T-cell receptor signaling panel predicted clinical benefit as measured by tumor response; however, no correlation with survival was found.
The phase III KEYNOTE-045 trial, which has completed accrual, is comparing pembrolizumab vs treatment with paclitaxel, docetaxel, or vinflunine in patients with disease progression after platinum-based therapy (ClinicalTrials.gov identifier: NCT02256436). The phase II KEYNOTE-052 trial, currently recruiting patients, will investigate the efficacy of pembrolizumab in patients with advanced urothelial cancer or MUC who have not received any previous systemic therapy (unless it has been > 12 months since they completed neoadjuvant and adjuvant platinum-based chemotherapy) and who are ineligible for cisplatin-based therapy (ClinicalTrials.gov identifier: NCT02335424).
Advances have been made in targeted therapeutic and immunotherapeutic approaches to the treatment of MUC. Randomized clinical trials will define the role of antiangiogenesis therapy in combination with chemotherapy in both the first- and second-line settings. Identification of the dramatic activity of immunotherapy in urothelial cancer patients treated with immune checkpoint blockade is a significant advance in this disease; these response rates may be improved via refinement of the markers used to predict response, and by novel combinations of immune checkpoint inhibitors. The optimal sequences of immune therapy and targeted agents are yet to be defined.
Financial Disclosure: Dr. Petrylak receives grant support from Agensys, AstraZeneca, Eli Lilly, Merck, Novartis, OncoGeneX, Pfizer, Roche, and Sanofi. He receives consultant fees from all previously cited companies except Merck; and he is also a consultant to EMD Serono, Exelis, and Sanofi-Aventis. Dr. Cheetham has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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