Elsevier

Gynecologic Oncology

Volume 134, Issue 2, August 2014, Pages 274-280
Gynecologic Oncology

A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: A study of the Princess Margaret, Chicago and California Consortia

https://doi.org/10.1016/j.ygyno.2014.05.016Get rights and content

Highlights

  • Sunitinib showed encouraging activity and interestingly prolonged disease control for several patients with recurrent endometrial cancer.

  • Toxicities were frequently observed but manageable.

  • Targeting the angiogenesis pathway seems to be a promising strategy in this disease where options are currently limited.

Abstract

Objective

Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC.

Methods

We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50 mg daily administered on a 4 weeks on–2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate.

Results

34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar–plantar erythrodysesthesia, diarrhea and hematologic.

Conclusion

Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.

Introduction

Endometrial cancer (EC) is the most common gynecological cancer in western countries [1]. More than 90% of cases occur in women older than 50 years of age, with a median age at diagnosis of 63. Although the majority of EC cases are diagnosed when disease is localized to the uterus, up to 25% of cases will recur and the outcome for women with advanced or metastatic EC remains poor. The 5-year relative survival rate for those with regional and distant metastases is decreased to 16.9%. In this setting, the current options are limited to platinum and/or taxane-based chemotherapy and hormonal therapy [2]. The choice or sequence of these agents generally depends on tumor and patient factors. The combination of cytotoxic chemotherapy has shown significant activity for advanced disease with response rates ranging from 31% to 81% and a median survival of approximately 1 year, but the response tends to be lower in heavily pretreated patients [3]. A recent phase III non-inferiority trial of first-line chemotherapy with carboplatin and paclitaxel for metastatic or recurrent EC suggests that this regimen be considered the treatment of choice based on its efficacy and reduced toxicity [4]. However treatment options in patients having failed initial systemic therapy are limited and results are generally disappointing [5]. Hormonal therapy is usually recommended for patients whose tumors express estrogen or progesteron receptors [6]. Progestational agents have demonstrated efficacy in patients with advanced or recurrent EC with response rates of ~ 20% reported in patients with hormone-positive disease [6]. Response rates are much lower (≤ 12%) in patients with hormone-negative and poorly differentiated tumors. Once these initial therapies have been delivered, no set standard of care has been established [7], [8], [9], [10]. Indeed, patients requiring second line therapy for recurrent EC have limited options with modest response rates usually no higher than 15% [11]. As such, there is a recognized need for improvement of therapy for recurrent or metastatic EC.

Vascular endothelial growth factor (VEGF) is a key driver of angiogenesis and has been recognized as a potentially important mechanism of tumor growth, survival and metastasis in EC [12], [13]. VEGF overexpression has been consistently demonstrated in EC, and the degree of expression correlates with poor outcome in many reports [14], [15], [16], [17], [18]. Inhibition of this pathway has been widely studied and shown to be biologically active in many neoplastic diseases such as kidney, colon, lung and ovarian carcinomas [19], [20], [21], [22], [23]. VEGF inhibition however has not been as extensively studied in EC. Bevacizumab, a recombinant humanized monoclonal antibody against VEGF-A, is the most commonly studied anti-angiogenic agent. One study has reported a 13.5% response rate with bevacizumab when given to 52 patients treated in second or third line for advanced or metastatic EC. Median progression free survival (PFS) was 4.2 months [24]. These data compare favorably with other phase II data of second line systemic treatments in this population.

Sunitinib, an orally available, small molecule multi-targeted receptor tyrosine kinase inhibitor is a potent inhibitor of the VEGF receptors (VEGFR-1, -2, and -3) as well as of other major tyrosine kinase receptors including platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), ret proto-oncogene, and fms-like tyrosine kinase 3 (FLT3) [25]. Since sunitinib has affinity for multiple VEGF receptors, it is seen as an attractive antiangiogenic agent. This molecule has been found to be highly effective in renal cell carcinoma (RCC), GIST and pancreatic neuro-endocrine tumors [22], [26], [27]. Sunitinib has been shown to be tolerable and active both on an intermittent schedule (50 mg daily for four weeks followed by a two week drug holiday) and as a continuous oral daily dose of 37.5 mg [28].

In this phase II study, we aimed to assess preliminary efficacy of sunitinib as single agent in patients with advanced or metastatic EC.

Section snippets

Patient population

Patients with histologically or cytologically confirmed metastatic or recurrent EC or carcinosarcoma treated with at most one line of prior chemotherapy for advanced disease were eligible. Inclusion criteria also included: age ≥ 18 years, performance status ≤ 2, life expectancy > 3 months and adequate organ function including demonstration of normal left ventricular ejection fraction (LVEF). In cases where patients had received prior systemic therapy, demonstration of progression on or after therapy

Results

Between April 2007 and December 2009, 34 women from 15 centers were enrolled on this study. The histologic subtypes were endometrioid for 25 patients (73%) and serous for 6 patients and 3 had carcinosarcoma. One patient with endometrioid EC never received sunitinib as she withdrew consent prior to receiving the first dose. The efficacy and toxicity analysis is based on all of the 33 patients who received at least one dose of the study drug. Patient characteristics are shown in Table 1.

At the

Discussion

Sunitinib met the pre-set activity threshold for this trial with a response rate of 18% and an encouraging disease control rate at six months of 30%.

Although most patients progressed rapidly on sunitinib therapy as represented by the relatively short median PFS of three months, there was a subset of patients who derived prolonged benefit from this therapy. This is illustrated by the 30% of patients who were free of progression at six months and the 21% of patients that remained progression free

Conflict of interest statement

None for all the authors.

Acknowledgments

We acknowledge Robert Halford for their constant support for the realization of this study.

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