Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial

Summary

Background

No standard treatments are available for advanced thymic epithelial tumours after failure of platinum-based chemotherapy. We investigated the activity of sunitinib, an orally administered tyrosine kinase inhibitor.

Methods

Between May 15, 2012, and Oct 2, 2013, we did an open-label phase 2 trial in patients with histologically confirmed chemotherapy-refractory thymic epithelial tumours. Patients were eligible if they had disease progression after at least one previous regimen of platinum-containing chemotherapy, an Eastern Cooperative Oncology Group performance status of two or lower, measurable disease, and adequate organ function. Patients received 50 mg of sunitinib orally once a day, in 6-week cycles (ie, 4 weeks of treatment followed by 2 weeks without treatment), until tumour progression or unacceptable toxic effects arose. The primary endpoint was investigator-assessed best tumour response at any point, which we analysed separately in thymoma and thymic carcinoma cohorts. Patients who had received at least one cycle of treatment and had their disease reassessed were included in the analyses of response. The trial was registered with ClinicalTrials.gov, number NCT01621568.

Findings

41 patients were enrolled, 25 with thymic carcinoma and 16 with thymoma. One patient with thymic carcinoma was deemed ineligible after enrolment and did not receive protocol treatment. Of patients who received treatment, one individual with thymic carcinoma was not assessable because she died. Median follow-up on trial was 17 months (IQR 14·0–18·4). Of 23 assessable patients with thymic carcinoma, six (26%, 90% CI 12·1–45·3, 95% CI 10·2–48·4) had partial responses, 15 (65%, 95% CI 42·7–83·6) achieved stable disease, and two (9%, 1·1–28·0) had progressive disease. Of 16 patients with thymoma, one (6%, 95% CI 0·2–30·2) had a partial response, 12 (75%, 47·6–92·7) had stable disease, and three (19%, 4·1–45·7) had progressive disease. The most common grade 3 and 4 treatment-related adverse events were lymphocytopenia (eight [20%] of 40 patients), fatigue (eight [20%]), and oral mucositis (eight [20%]). Five (13%) patients had decreases in left-ventricular ejection fraction, of which three (8%) were grade 3 events. Three (8%) patients died during treatment, including one individual who died of cardiac arrest that was possibly treatment-related.

Interpretation

Sunitinib is active in previously treated patients with thymic carcinoma. Further studies are needed to identify potential biomarkers of activity.

Funding

National Cancer Institute (Cancer Therapy Evaluation Program).

Introduction

Thymic epithelial tumours are rare cancers, yet they are the most common tumours of the anterior mediastinum, accounting for 20% of all mediastinal cancers.¹ On the basis of morphological features and atypia of thymic epithelial cells and their relative proportion to lymphocytes, thymic epithelial tumours are classified as either thymomas (further subclassified into types A, AB, B1, B2, and B3) or thymic carcinomas.² Although thymomas and thymic carcinomas share the same neoplastic cell of origin, thymic carcinomas are more aggressive, are less responsive to chemotherapy, and have an increased likelihood of producing distant metastases. 10-year survival for B1 thymomas is 95%, whereas 5-year survival for thymic carcinomas is only 30–50%.³

Surgery is the mainstay of treatment for thymic epithelial tumours and is the only potentially curative option. Patients with unresectable disease and recurrence after radical surgery usually receive palliative chemotherapy. Studies of platinum-based regimens for thymic carcinoma have shown objective responses in 55–90% of patients and 5-year survival of 30–55%, although these studies had small numbers of patients with thymic carcinoma.4, 5 No standard treatments are available after failure of platinum-based chemotherapy. With its poor prognosis, the paucity of systemic treatments is particularly evident in thymic carcinoma, for which several targeted agents have yielded disappointing results.⁶

Sunitinib is an oral tyrosine kinase inhibitor, including VEGFR, KIT, and PDGFR.⁷ Although limited, available evidence suggests that angiogenesis has an important role in thymic epithelial tumours; VEGF is overexpressed in these cancers, and VEGF expression and microvessel density are associated with invasiveness and stage.8, 9 Higher serum concentrations of VEGF and b-FGF have been noted in patients with thymic carcinoma.¹⁰ Overexpression of KIT has been reported in about 80% of thymic carcinomas, and mutations in the gene encoding this receptor are noted in about 10% of these cancers.11, 12 PDGF and PDGFRα are also overexpressed in thymic epithelial cells.¹³ Anecdotal reports have suggested that drugs targeting VEGF, KIT, or PDGF might be efficacious in thymic epithelial tumours.¹⁴ Strobel and colleagues¹⁵ reported activation of multiple receptor tyrosine kinases and responses to sunitinib in three of four patients with thymic carcinoma. Immune dysfunction at several levels has been recorded in patients with thymic epithelial tumours, and abnormal immune surveillance might underlie tumorigenesis and progression of these cancers.¹⁶ Sunitinib has been reported to modulate immune cells to improve T-cell function and reverse immunosuppression.17, 18

We designed an open-label phase 2 study to investigate response to sunitinib in patients with thymic epithelial tumours who had progressive disease after at least one previous regimen of platinum-based chemotherapy. Taking into account the different biology and historically discrepant responses and survival of thymoma and thymic carcinoma, we enrolled patients with these tumour types in two separate cohorts.