Phase 2 trial of sorafenib in patients with advanced urothelial cancer

A Trial of the Eastern Cooperative Oncology Group


  • This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.



There is no effective second-line systemic chemotherapy for patients with disease progression after cisplatin-based chemotherapy. A phase 2 trial of sorafenib was performed to determine the activity and toxicity of this agent in a multi-institutional setting in patients previously treated with 1 prior chemotherapy regimen.


Twenty-seven patients with advanced urothelial carcinoma were treated with sorafenib 400 mg orally twice daily continuously until progression or unacceptable toxicity.


There were no objective responses observed. The 4-month progression-free survival (PFS) rate was 9.5%; median overall survival of the group was 6.8 months. There were no therapy-related deaths, and common grade 3 toxicities included fatigue and hand-foot syndrome.


Although sorafenib as a single agent has minimal activity in patients with advanced urothelial cancer in the second-line setting, further investigation of tyrosine kinase inhibitors using different trial designs with PFS endpoints is warranted. Cancer 2009. © 2009 American Cancer Society.

Over the last 20 years, cisplatin-based chemotherapy has been established as the standard of care in the management of patients with advanced urothelial cancer. For the fit patient with preserved renal function, cisplatin-based multiagent chemotherapy with either gemcitabine + cisplatin (GC) or methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) is supported by randomized trial evidence of benefit.1, 2 Unfortunately only a relatively small percentage of patients are cured with either GC or M-VAC.3, 4

During the past 2 decades, a clinically evident stage migration5 has led to earlier appreciation of metastatic disease. Concomitantly, there has been an increased utilization of neoadjuvant and adjuvant chemotherapy, resulting in an increasing proportion of patients fit enough to be considered for second-line chemotherapy for metastatic disease. Recent phase 2 studies evaluating second-line chemotherapy have demonstrated objective response rates in the 10% to 25% range for a variety of single agents and combination regimens.6-8 Although patients with a reasonable performance status (PS) who develop progressive metastatic disease after front-line, platinum-based chemotherapy are frequently treated with salvage chemotherapy, this is done primarily with palliative intent, as there is no evidence that such therapy improves progression-free or overall survival.9

Urothelial cancer has a myriad of molecular targets that make it attractive for the investigation of novel agents; however, in contrast to the more common epithelial cancers, there have been limited efforts to evaluate novel agents in this disease. Although the epidermal growth factor receptor (EGFR) is frequently overexpressed in high-grade urothelial cancer, several small phase 2 trials of EGFR-targeted agents have failed to demonstrate meaningful activity.10, 11

Vascular endothelial growth factor (VEGF) binds to its cognate receptors, VEGFR1 and VEGFR2, to induce cell proliferation and migration. VEGF receptors are expressed on urothelial carcinomas, and there is both preclinical and some clinical evidence supporting the antitumor efficacy of targeting this pathway.12-14

Sorafenib is a multikinase inhibitor of VEGFR2, VEGFR3, and platelet-derived growth factor receptor-beta.15 Evidence from phase 3 trials of improvement in progression-free survival (PFS) for patients with clear renal cell carcinoma and hepatoma led to regulatory approval of sorafenib in these 2 relatively chemotherapy-resistant epithelial neoplasms.16, 17

Based on the need for more active agents and the overexpression of VEGF and VEGFR in many patients with advanced urothelial cancer, the Eastern Cooperative Oncology Group investigated sorafenib in patients with progressive advanced urothelial cancer after front-line chemotherapy.


Eligible patients had histologically confirmed transitional cell carcinoma (or mixed histologies containing a component of transitional cell carcinoma) of the urothelium with evidence of progressive, bidimensionally measurable regional or metastatic disease. Patients must have been disease-free from prior malignancies for at least 5 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at entry. Patients must have demonstrated progressive disease after 1 and only 1 prior systemic chemotherapy regimen administered in the metastatic setting. Prior perioperative therapy in either the neoadjuvant or adjuvant setting was permitted, provided that it was completed >12 months before the chemotherapy administered in the metastatic setting. Patients must have been at least 4 weeks out from major surgery. Adequate renal and hepatic function were required, with a serum creatinine <1.5 mg/dL, aspartate aminotransferase (AST) ≤2.5 mg/dL, and bilirubin ≤1.5 times the upper limit of normal. Adequate bone marrow reserve was mandated with a requirement for neutrophils ≥1500 mm3 and a platelet count ≥100,000/μL at entry. Patients requiring ongoing therapeutic anticoagulation or cytochrome p450 enzyme–inducing antiepileptic drugs, or having a history of a bleeding diathesis, were excluded.

Sorafenib was administered orally at a dose of 400 mg (2 tablets) orally twice daily for a total daily dose of 800 mg. One cycle consisted of 56 days of therapy. Patients were mandated to monitor and record their blood pressure weekly during Cycle 1, then every cycle. No dose escalation was permitted, dose modifications were mandated as follows: dose level 2, 400 mg/day; dose level 3, 400 mg every other day. Dose modifications were specified for myelosuppression and mandated for any grade 3 or 4 toxicity.

Before study entry, all patients underwent physical examination and had their ECOG performance status and weight documented. There also were pretherapy complete blood count (CBC) and differential, serum creatinine, blood urea nitrogen, AST, bilirubin, and computed tomograms of chest, abdomen, and pelvis. A CBC and the above chemistries were repeated on the first day of each subsequent therapy cycle. Tumor measurements were performed with each cycle of therapy.

Each site was required to have approval of this clinical trial by a local human investigations committee in accord with an assurance filed with and approved by the Department of Health and Human Services. All patients provided written informed consent before registration onto this study.

Tumor responses were analyzed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. National Cancer Institute common toxicity criteria (Common Terminology Criteria for Adverse Events v. 3) were used to analyze toxicity. Patients with objective responses or stable disease were continued on therapy until development of unacceptable toxicity.

The primary goal of this study was to evaluate the 4-month PFS rate in patients treated with sorafenib. If this treatment showed evidence of at least a 50% PFS rate at 4 months, it would be considered as a promising therapy for further study. A PFS rate of 30% or less would not be of interest. This cohort used a 2-stage design, with 4-month PFS rate as the primary endpoint. At the initial stage, 20 eligible patients were to be entered, and accrual was to be suspended. The first-stage stopping rule was based on response rates. Responses were assessed using RECIST. If no objective response was observed in the first 20 eligible patients, the trial would be terminated. On the basis of this stopping rule, the probability of terminating the study early was 0.54 if the true underlying response rate was 3% and 0.04 if the true rate was 15%. If 1 or more responses were observed in the first 20 eligible patients, the study was to accrue an additional 19 eligible patients for a total of 39 eligible patients. If 16 or more patients were alive and progression-free at 4 months among the 39 eligible patients, the treatment would be considered worthy of further consideration in this population.

Descriptive statistics were used to analyze the characteristics of the patients at study entry. Exact binomial confidence intervals were computed for response rates. The method of Kaplan and Meier was used to characterize overall survival and PFS.18 Overall survival was computed from the time of registration to death. PFS was computed from the time of registration to death or progression, whichever occurred first. Patients who were still alive and progression free were censored at the date of last disease assessment.


From October of 2005 through October of 2006, 27 patients from 14 ECOG institutions were entered into the study and were evaluable for toxicity. Five of these patients were classified as ineligible and were only included in toxicity evaluations, 2 patients had ineligible lab values for entry, 1 had a second cancer, and 2 were enrolled before the 4-week interval from prior systemic therapy.

Patient Characteristics

All 22 eligible patients had tumors that were histologically pure or predominantly transitional cell carcinoma. Patients ranged in age from 37 to 81 years, with a median of 66 years. Most patients were white (95%) and men (64%). With respect to ECOG PS, 36% patients were fully active (PS 0), and 64% had PS 1. Fifteen (68%) patients had bladder as the site of tumor. By using the risk factor status defined by Bajorin, 3 (14%) patients had 0 risk factors, and 19 (86%) had 1 risk factor.19 All 22 patients had been treated with multiagent cytotoxic systemic chemotherapy, 17 (77%) patients had undergone surgery with therapeutic intent, and 6 (27%) had prior radiation therapy (Table 1).

Table 1. Baseline Patient Characteristics
CharacteristicsNo. of Patients (%)
  • ECOG indicates Eastern Cooperative Oncology Group; MSK, Memorial Sloan-Kettering Cancer Center.

  • *


Age, y, median [range]66 [37-81]
 Men14 (64)
 Women8 (36)
ECOG performance status 
 08 (36)
 114 (64)
Sites of metastases 
 Distant nodes8 (36)
 Liver10 (46)
 Bone9 (41)
 Lung14 (64)
Prognostic factors (MSK)* 
 03 (14)
 119 (86)

Response Assessment

No response was observed among eligible patients. Three (14%) patients had stable disease, and 9 (41%) had progression as their best overall response. Ten other patients were deemed unevaluable for response, and 6 patients had at least 1 follow-up assessment; however, they were not performed within the mandated time frame. The remainder did not have follow-up imaging before death or removal from study either from clinical deterioration or therapy-related toxicity. Fifteen (68%) patients went off treatment because of disease progression, and 4 (18%) because of excessive toxicity. Thirteen (59%) patients received only 1 cycle of protocol therapy, 8 (36%) received 2 cycles, and 1 (5%) received 4 cycles. Median number of cycles administered was 1 (range, 1-4).

Among the 22 eligible patients, 18 (82%) had progressed and died as of March 5, 2008. Figure 1 shows PFS. The 4-month PFS rate based on the Kaplan-Meier method was 11.0% (90% confidence interval [CI], 0%-23.0%). Median PFS was 2.2 months (90% CI, 1.8-3.7 months). Median survival was 6.8 months (90% CI, 5.7-8.5 months) (Fig. 2).

Figure 1.

Progression-free survival is shown.

Figure 2.

Overall survival is shown.


Toxicity from sorafenib was similar to that seen in a renal cancer population. There were no therapy-related deaths. Two patients experienced grade 4 pulmonary embolism (7.0%). Common grade 3 toxicities included fatigue and hand-foot reaction, each occurring in 5 (19%) patients.


Despite the availability of several conventional cytotoxic drugs with antitumor activity in patients with disease progression after platinum-based chemotherapy, there remains limited evidence that any single agent or combination regimen improves patient outcome.9 Bellmunt and colleagues recently reported the results of a phase 3 trial comparing vinflunine (a microtubule inhibitor) plus best supportive care versus best supportive care alone in patients with advanced urothelial cancer whose disease had progressed after platinum-based chemotherapy.20 Therapy was relatively well tolerated, and although there was a median 2-month survival advantage (6.9 vs 4.6 months), favoring the vinflunine arm, this difference had not yet achieved statistical significance at the time of its initial report.

There have been a small number of small phase 2 trials of targeted agents in advanced urothelial cancer, all but 1 in the salvage setting.

The potential for synergy between trastuzumab and active chemotherapeutic agents such as paclitaxel and carboplatin in advanced urothelial cancer, and reports of HER-2/neu expression in urothelial cancers ranging from approximately 10% to 80%, led Hussain and colleagues to conduct a multicenter phase 2 trial of trastuzumab in combination with paclitaxel, carboplatin, and gemcitabine. Eligible patients were required to have locally recurrent or metastatic disease, without prior chemotherapy for metastatic disease. As the primary endpoint of the study was cardiac toxicity, patients were mandated to have an ejection fraction >50% and no evidence of ischemic heart disease. HER-2/neu overexpression by either immunohistochemistry, fluorescence in situ hybridization, or elevated serum HER-2/neu electron-capture detection was required. Forty-four of 57 HER-2/neu–positive patients received protocol therapy. Myelosuppression was the most common grade 3 and 4 toxicity, with 23% of patients manifesting grade 1 to 3 cardiac toxicity. There were 2 therapy-related deaths. Thirty-one (70%) of 44 patients responded (5 complete and 26 partial), and 25 (57%) of 44 were confirmed responses. Median survival was 14.1 months.21

The EGFR is overexpressed in high-grade urothelial cancers, and the availability of a variety of EGFR-targeting agents made this an attractive target.22 In a phase 2 trial of gefitinib in the second-line setting, Southwest Oncology Group investigators observed only 1 (3%) partial response in 29 enrolled patients.23 A Cancer and Leukaemia Group B study of cisplatin + fixed dose rate gemcitabine + gefitinib was stopped early secondary to unacceptable therapy-related toxicity primarily from the fixed dose gemcitabine, and therefore the value of adding gefitinib to the regimen was unevaluable.11

Wulfing et al conducted a phase 2 trial of lapatinib (reversible dual inhibitor of ErbB1 and ErbB2 tyrosine kinases) in patients with locally advanced or metastatic urothelial cancer after progression on a cisplatin-based regimen. Eligible patients were required to manifest expression by immunohistochemistry of either HER-1 or HER-2. Although therapy was well tolerated, only 1 of 59 enrolled patients demonstrated an objective response to therapy.10 Unlike other epithelial cancers in which EGFR domain mutations are relatively well understood, there are limited data in urothelial cancer, and additional studies using monoclonal antibodies in combination with chemotherapy are planned.

Investigators at Memorial Sloan-Kettering Cancer Center conducted a single-institution phase 2 trial of sunitinib in patients with advanced disease progressing on front-line chemotherapy for advanced disease. Sunitinib was administered in conventional 6-week cycles, 50 mg/day × 4 weeks, with 2 weeks off. Forty-five patients were enrolled, and toxicity was as would be expected with this agent, although 1 patient died of therapy-related complications. Of 41 evaluable patients, 3 achieved a confirmed partial response, with an additional 11 patients achieving stable disease. Further follow-up will be needed to define time to disease progression and survival. An additional cohort of patients have been enrolled to study a continuous 37.5-mg dosing schedule.24

The current study demonstrates that sorafenib at 400 mg twice per day has no clinically meaningful activity in patients with advanced urothelial cancer after front-line chemotherapy. In retrospect, given the evolving understanding of sorafenib's level of activity in advanced renal cancer, it is not surprising that most patients manifested early disease progression. Given the aggressive nature of advanced urothelial cancer, only an agent or combination of agents with the ability to produce rapid objective responses will likely demonstrate obvious clinical activity in this setting. Testing agents like sorafenib in other settings of advanced urothelial cancer, that is, as maintenance therapy after an objective response to conventional cytotoxic drugs using disease-free progression as a primary endpoint, may provide a better assessment of this class of agents in this disease.

Conflict of Interest Disclosures

This study was supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, and CA21076 and by the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services.