Gefitinib

Gefitinib is an oral, selective EGFR TK inhibitor currently used in EGFR-mutant NSCLC patients and has activity against EGFR-expressing UC cell lines. Gefitinib was evaluated in a phase II trial in metastatic UC patients who did not respond to one prior chemotherapeutic regimen. In the 31 patients enrolled, the median PFS was 2 months with one confirmed partial response (PR). Pretreatment biopsies were required for retrospective evaluation of EGFR expression, although overexpression was not an inclusion criterion. The partial responder’s tumor harbored 2+ EGFR expression; 8 of 15 patients showed primary progression (2 to 3+ EGFR expression). No correlation was noted between EGFR staining and response; additionally, this study was designed before the observation that EGFR mutations correlate with gefitinib sensitivity in NSCLC.

The Cancer and Leukemia Group B conducted a multicenter phase II study (CALGB 90102) evaluating the addition of gefitinib (500 mg/d) to GC in untreated patients with advanced UC. All patients received 6 cycles of GC plus gefitinib, and those with objective responses or stable disease (SD) were continued on maintenance gefitinib until progression. An ORR of 42.6% was observed with 7 complete responses (CR) and 16 PRs. The median OS was 15.1 months; the median time to progression was 7.4 months. Grades 3 to 4 hematologic toxicity were seen in 22% patients (n = 12). Nonhematologic grade 3 toxicities included fatigue (20%), emesis (24%), diarrhea (14%), and rash (11%). Based on these results, the addition of gefitinib does not seem to improve response rate or survival compared with chemotherapy alone. Notably, patients were not screened for EGFR overexpression or mutation before trial enrollment.

Erlotinib

Erlotinib, another EGFR TK inhibitor, was tested in 20 patients with histologically confirmed muscle-invasive UC in the neoadjuvant setting for 4 weeks before radical cystectomy. Seven patients (35%) with clinical T2 disease had their disease downstaged to non-muscle-invasive bladder cancer, and 5 patients (25%) had no residual disease, comparing favorably with historical rates of less than pT2 disease after transurethral resection or neoadjuvant chemotherapy, although the lack of a comparator arm in this study limits the ability to draw definitive conclusions. Treatment was well tolerated with rash the most common side effect observed in 15 patients (75%). Five patients who achieved pT0 responses within the bladder exhibited the acneiform rash known to correlate with response to EGFR TK inhibition in NSCLC and colon cancers. Although patients were not preselected based on EGFR mutations or amplification, tumors are being retrospectively analyzed to define any molecular correlates with treatment response.

Lapatinib

Lapatinib, a dual TK inhibitor of EGFR and HER2, was evaluated as second-line therapy in 59 platinum-refractory locally advanced or metastatic UC patients with a primary endpoint of objective response rate greater than 10%. One patient achieved a PR; 18 (31%) patients displayed SD. Median time to disease progression and OS were 8.6 weeks and 17.9 weeks, respectively. Diarrhea, nausea, and vomiting were the most commonly reported toxicities. Seventeen of 19 patients who achieved SD or PR (89%) had EGFR and/or HER2 overexpressing tumors. The possible correlation between EGFR and HER2 expression and response to lapatinib therapy underscores the importance of prospective genetic sequencing as an eligibility criterion for targeted therapy studies.

Cetuximab

Cetuximab is an anti-EGFR monoclonal antibody FDA approved for the treatment of head and neck and colorectal cancers. A randomized phase II study gauged the efficacy of cetuximab with or without paclitaxel in patients with previously treated metastatic UC. Patients received weekly cetuximab alone or weekly paclitaxel plus cetuximab. The single-agent cetuximab arm was terminated after 9 of the first 11 patients exhibited progression at 8 weeks. Median PFS and OS were 7.6 weeks and 17 weeks, respectively, and no objective responses were observed. In contrast, 28 patients were enrolled onto the combination arm with a median PFS and OS of 16.4 weeks and 42 weeks, respectively. The ORR was 25% (3 CRs and 4 PRs). Notably, the most common treatment-related grade 3 to 4 adverse events were rash and hypomagnesemia. A comparator arm using single-agent chemotherapy was not incorporated into this study. Additionally, patients who received perioperative chemotherapy but not first-line therapy in the metastatic setting were also enrolled. Finally, patients were not preselected based on molecular predictors of response or resistance to cetuximab, such as EGFR overexpression or KRAS mutation, respectively.

A randomized phase II trial of GC with or without cetuximab was performed in advanced UC patients, with a primary endpoint of ORR. Patients were randomly assigned in a 1:2 fashion to GC alone or GC with cetuximab. Early in the study, gemcitabine was dose reduced by 20% to mitigate an observed increase in thromboembolic events with the 3-drug combination, resulting in decreased standard-of-care dose intensity. The ORR was 57.1% with GC and 61.4% with GC plus cetuximab. The median OS was 17.4 months with GC versus 14.3 months with GC plus cetuximab ( P = .43). A higher rate of grades 3 to 4 acneiform rash was seen with cetuximab.

Trastuzumab

HER2 overexpression has been linked to shorter time to recurrence and is found in both primary and metastatic lesions in UC. Micropapillary histology, an aggressive variant characterized by poor survival, also harbors a high rate of ERBB2 amplification. In a retrospective analysis of 80 UC specimens derived from radical cystectomies, 28% exhibited 2 to 3+ HER2 overexpression by immunohistochemistry (IHC). In 60 of these specimens, matched metastatic samples were available, and 2 to 3+ HER2 overexpression was observed in both lymph node (63%) and distant (86%) metastatic deposits. Based on these findings, a trial assessing the safety and efficacy of the humanized monoclonal anti-HER2 antibody, trastuzumab, in combination with carboplatin, gemcitabine, and paclitaxel in advanced UC patients was conducted, with cardiac toxicity as the primary endpoint. HER2 overexpression by IHC, gene amplification by fluorescence in situ hybridization (FISH), or elevated serum extracellular domain HER2 levels was a requirement for study participation. The median time to progression and OS were 9.3 and 14.1 months, respectively, and the ORR was 70%, with most responses occurring in HER2 IHC 3+ or FISH-amplified patients. Because this was not a randomized trial, the impact of trastuzumab addition to chemotherapy could not be assessed. Additionally, the concordance between IHC overexpression and FISH amplification seen in breast cancer was not observed in this sample set, suggesting that gene amplification does not necessarily correlate with HER2 protein levels in UC.

Although the bladder TCGA identified HER2 alterations in 9% of muscle-invasive specimens, the HER2 mutation rate was higher than that of any other cancer type sequenced. Stemming from these data, neratinib, an irreversible HER2 TK inhibitor, which has shown significant improvements in disease-free survival in HER2+ breast cancer, is currently being tested in UC through a novel basket trial design. Patients with EGFR mutations or amplifications and HER2 or HER3 mutations across multiple cancer types, including advanced UC, are being enrolled, with the primary objective of measuring 8-week ORR.

Dovitinib

Dovitinib (TKI258), an oral multitargeted receptor TK inhibitor of FGFR1-3, vascular endothelial growth factor receptor (VEGFR), and others was assessed in 44 patients with metastatic chemo-refractory UC at a dose of 500 mg/d on a 5-days-on/2-days-off schedule. The study included FGFR3 mutant and wild-type cases. None of the FGFR3 mutant patients responded; 1 PR was present in the wild-type cohort. The median PFS was 3 months in the mutant group and 1.8 months in the wild-type group. The drug was not carried into an expansion phase based on these results. A phase I study of BGJ398, a pan-FGFR inhibitor, in patients with metastatic FGFR-altered cancers, has shown promising results: 4 of 5 patients with FGFR3-mutant UC experienced tumor reductions (27%–48%), with hyperphosphatemia the most common adverse event noted.

Sunitinib

Sunitinib is a small-molecule multitargeted receptor TK inhibitor against VEGFR, platelet-derived growth factor receptor, and KIT, with activity in in vitro and in vivo UC models. In 77 patients with advanced, previously treated UC, sunitinib was assessed in 2 patient cohorts by dose and schedule: cohort A patients received 50 mg daily on a 4-week-on and 2-week-off regimen, whereas cohort B patients received 37.5 mg daily continuously. Three patients in cohort A and 1 in cohort B experienced a PR. Clinical regression or stable disease was observed in 33 of 77 patients (43%); the duration of regression ranged from 0.6 to 23.4 months. PFS (2.4 vs 2.3 months) and OS (7.1 vs 6.0 months) were comparable between cohorts A and B, respectively. Grades 3 to 4 toxicities were observed in 57 patients. Sunitinib did not achieve the threshold of ≥20% ORR (CR + PR) to be considered promising; however, antitumor responses were seen in some patients, indicating that anti-VEGF signaling may be therapeutically effective in a biomarker-guided context. Additionally, tumor necrosis resulted in decreased density of marker lesions but did not correlate with reduction in tumor diameter, implying that the Response Evaluation Criteria in Solid Tumors (RECIST) may not be the most accurate method to gauge responses to anti-angiogenic agents. In the metastatic and neoadjuvant (muscle invasive disease) settings, the combination of gemcitabine and cisplatin was assessed with sunitinib in 2 parallel phase II trials. Both studies were limited by severe toxicity requiring premature closure.

Another multicenter trial evaluated sunitinib as first-line treatment in cisplatin-ineligible metastatic UC patients. Of 38 patients, 3 (8%) evinced PRs and 19 (50%) exhibited stable disease. The median time to progression and OS were 4.8 months and 8.1 months, respectively, lower than the historical response rates observed with carboplatin-based chemotherapy. However, the 58% clinical benefit rate (PR+CR+SD) suggests activity in select patients. Notably, low pretreatment IL-8 levels correlated with improved time to progression. Additionally, patients with greater than 40 Hounsfield Unit enhancement within their tumors, a surrogate for high tumor vascularity on baseline contrast-enhanced computed tomography scans, were likelier to benefit from sunitinib.

Sorafenib

Sorafenib, another oral multitargeted receptor TK inhibitor against Raf and VEGFRs has also been evaluated in UC in 2 phase II trials: one in treatment-naïve metastatic disease and another in chemo-refractory patients. Neither study found any objective responses. A randomized phase II trial in the first-line metastatic setting combined sorafenib or placebo with GC. There were no significant differences in ORR or median PFS or OS between the 2 arms; diarrhea and hand-foot syndrome were more common with sorafenib therapy.

Pazopanib

Pazopanib is an oral multitargeted receptor TK inhibitor against VEGFR-1, -2, and -3; platelet-derived growth factor receptor–α and –β; and KIT. This drug was FDA approved for first-line treatment of clear cell RCC. A phase II study assessed the efficacy of pazopanib, 800 mg daily, in patients with chemorefractory UC. Twenty-one (51%) of 41 patients received pazopanib as third-line or further treatment, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Seven patients had a confirmed PR (17.1%). The median PFS and OS were 2.6 and 4.7 months, respectively. Grade 3 toxicities were observed in 12 (29%) patients, including 2 cases each of gastrointestinal and vaginal fistulization; all 4 patients reinitiated therapy. One additional patient died of a duodenal fistula. Patients who had fistulas also had bulky disease that responded significantly. On multivariate analysis, the presence of liver metastases, upper tract primary disease, and ECOG performance status were significantly associated with OS. When measured 4 weeks after treatment, IL-8 levels ≥87 pg/mL correlated with inferior OS (4.2 months vs 6.7 months for patients whose 4-week IL-8 levels were <87 pg/mL). The study investigators postulated that elevations in IL-8 levels within 4 weeks of treatment may reflect a resistance mechanism to anti-angiogenic therapy, thereby serving as an early predictive marker of lack of efficacy.

Vandetanib

Vandetanib, a dual VEGFR and EGFR inhibitor, was assessed in a randomized, phase II study with docetaxel in patients with advanced UC whose disease had progressed on platinum-based chemotherapy. One hundred forty-two patients were randomly assigned to vandetanib, 100 mg daily plus docetaxel, or docetaxel plus placebo. The primary endpoint of this study was to compare PFS between the 2 arms. The median PFS was 2.56 months for docetaxel plus vandetanib versus 1.58 months for docetaxel plus placebo with an HR of 1.02 (95% CI, 0.69 to 1.49; P = .9). Response rates and OS were not different between the arms with a higher rate of toxicity in the combination arm including rash/photosensitivity (11% vs 0%) and diarrhea (7% vs 0%). When a validated prognostic model in patients whose disease progressed on platinum-based chemotherapy comprising Hgb less than 10 g/dL, ECOG PS greater than 0, and the presence of liver metastases was applied to the study population, all 3 parameters were significantly associated with a risk of death.

Bevacizumab

Bevacizumab is a recombinant humanized monoclonal antibody against circulating VEGF and has displayed improvements in clinical outcomes when combined with chemotherapy in advanced RCC, NSCLC, colorectal cancer, and glioblastoma multiforme. The Hoosier Oncology Group designed a phase II trial of GC plus bevacizumab (dosed at 15 mg/kg every 3 weeks) in chemotherapy-naive patients with metastatic or unresectable UC. After 8 cycles of combination therapy, bevacizumab was continued for a total of 12 months. Because of a higher-than-expected thromboembolic rate, the gemcitabine dose was reduced from 1250 to 1000 mg/m ² . Deep vein thrombosis and pulmonary embolism events were subsequently significantly lower (8% after vs 41% before dose reduction; P = .023). Grades 3 to 4 hematologic toxicities included neutropenia, anemia, and thrombocytopenia. Nonhematologic grades 3 to 5 toxicities included hypertension (5%), proteinuria (2%), hemorrhage (7%), and cardiac toxicity (7%). Eight patients (19%) experienced a CR and 23 patients (53%) a PR. The median PFS and OS were 8.2 months and 19.1 months, respectively.

Bevacizumab was also evaluated in cisplatin-ineligible patients in a phase II study of gemcitabine, carboplatin, and bevacizumab, 15 mg/kg every 3 weeks. Patients received an initial dose of bevacizumab, 10 mg/kg, 2 weeks before the first dose of chemotherapy to enhance tumor penetration by cytotoxic agents. After a maximum of 6 cycles of chemotherapy, bevacizumab was continued for a total of 18 cycles as tolerated. The dose of carboplatin was reduced from an area under the curve of 5 to 4.5 after 13 patients were enrolled because of excess hematologic toxicities at the higher dose. An objective response was seen in 23 (49%) patients (3 complete; 20 partial), and 11 (23%) had SD. The median PFS was 6.5 months. The most common grade 3 to 4 toxicity was neutropenia (31%), whereas thromboembolic events were the most common nonhematologic grade 3 to 4 toxicities (20%). The median OS was 13.9 months, superior to that of other studies of patients treated with carboplatin plus gemcitabine alone. Additionally, 28 patients continued on maintenance bevacizumab after completing 6 cycles of chemotherapy, and 9 displayed shrinkage of target sites on monotherapy, suggesting that VEGF axis inhibition alone is effective in select patients.

Given these promising results, a phase III randomized trial (CALGB 90601) of GC with or without bevacizumab in the first-line metastatic setting is ongoing.