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

Abstract

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).

Figure 1. Waterfall plots of tumour responses to sunitinib

Responses in patients with (A) thymic carcinoma and (B) thymoma. Of three patients with thymoma who had progressive disease, two came off treatment because of the appearance of new lesions and one stopped treatment owing to a 20% increase in tumour size. All three had progressive disease at the first restaging timepoint.

Figure 2. Survival in patients with thymoma and thymic carcinoma

(A) Progression-free survival and (B) overall survival.

Figure 3. Survival according to predictive biomarkers

(A) Overall survival in the total study population of patients with either no increases (ie, reductions or no changes) or increases in the proportion of apoptotic circulating endothelial cells among nucleated cells on day 1 of cycle three. (B) Overall survival of patients with thymic carcinoma with either no increases (ie, reductions or no changes) or increases in the proportion of circulating endothelial progenitor cells among nucleated viable cells on day 1 of cycle three. (C) Overall survival of patients with ten or more circulating tumour cells (CTCs) per 10 mL of peripheral blood at baseline, and of those with less than ten cells. (D) Overall survival of patients with ten or more CTCs per 10 mL of peripheral blood on day 1 of cycle two, and of those with less than ten cells.

Figure 4. Changes in immune subsets with sunitinib in thymic epithelial tumours

(A) Relative changes in peripheral blood Treg PD-1 expression before treatment, on day 1 of cycle two, and on day 1 of cycle three. (B) Overall survival of patients either with decreases or with no changes or increases in Treg PD-1 expression on day 1 of cycle three. (C) Relative changes in CTLA4 expression on peripheral blood CD8+ T cells before treatment, on day 1 of cycle two, and on day 1 of cycle three. (D) Overall survival of patients with a high (ie, above th e median) increase in CD8+ T-cell CTLA4 expression on day 1 of cycle two, and of those with a low (ie, below the median) increase in CTLA4 expression.