Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial

Abstract

Summary Background No standard therapy exists for refractory or relapsed, advanced thymic epithelial tumors (TETs). We investigated the efficacy of cixutumumab, a fully human, IgG1 monoclonal antibody targeting the insulin-like growth factor-1 receptor, in TETs after failure of prior chemotherapy. Methods In this multicentre, open-label, phase 2 trial we enrolled patients aged 18 years or older with histologically confirmed recurrent or refractory TETs, who had progressed after at least one prior platinum-containing chemotherapy regimen, had Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease and adequate organ function. Eligible patients received cixutumumab (20 mg/kg, intravenous) every three weeks until disease progression or development of intolerable toxicity. The primary endpoint was response rate, analyzed on an intention-to-treat basis. Multiple pharmacodynamic studies were performed. This trial has completed enrollment and is registered with ClinicalTrials.gov, number NCT00965250. Findings Between August 25, 2009, and March 27, 2012, 49 patients were enrolled (37 thymomas; 12 thymic carcinomas) and received a median of six cycles of cixutumumab (range 1–46). At final analysis median potential follow-up was 24 months (IQR 17·3–36·9). In the thymoma cohort five (14%) of 37 patients (95% CI 5–29%) achieved a partial response, 28 had stable disease and four had progressive disease. Corresponding numbers for the thymic carcinoma cohort were zero of 12 patients (95% CI 0–26%), five and seven. The most common grade 3–4 adverse events in both cohorts combined were hyperglycemia (5 [10%] of 49 patients), lipase elevation (3 [6%]), weight loss, tumor pain, and hyperuricemia (2 each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions (five new-onset) during treatment, the most common of which was pure red cell aplasia. Two (4%) of 49 treated patients died while on study. One case was attributed to disease progression and the other to disease–related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Interpretation Cixutumumab monotherapy is well tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Funding Division of Cancer Treatment and Diagnosis, National Cancer Institute/National Institutes of Health and ImClone Systems.

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes

“…45 In advanced stage refractory disease, KIT mutations have exclusively been reported to occur in thymic carcinomas, but their potential role as biomarkers needs further studies; meanwhile, targeting angiogenesis using multikinase inhibitors is of higher relevance in carcinomas irrespective of their KIT mutational status. 46 By contrast, the histone deacetylase inhibitor, belinostat, 47 the insulin-like growth factor 1 receptor-targeting antibody, cixutumumab, 48 and somatostatin analogues 49 are more effective in thymomas. The importance of diagnosing NUT carcinoma results from the ineffectiveness of conventional chemotherapeutic regimens and availability of promising new targeted agents.…”

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

“…There is, however, evidence of activity in heavily pre-treated Ewing sarcoma (EWS), other types of sarcomas, and neuroendocrine tumors, although data in the latter are conflicting [32,39–44]. In addition, IGF-1R antibodies were recently reported to have single agent activity in recurrent ovarian cancer and relapsed thymoma, although thymoma treatment was associated with the development of autoimmune conditions including red cell aplasia [45,46]. Activity in EWS and childhood sarcomas may be a consequence of functional interactions between oncogenic fusion proteins (EWS-FLI1 and related fusion partners) and the IGF pathway [47–50].…”

FDG PET/CT Manifestation of Rare Widespread Metastatic Chemoradiation-Refractory Thymic Squamous Cell Carcinoma

“…Metastatic thymic SCC has poor prognosis and usually requires multimodality treatment including surgery, radiation therapy, and chemotherapy. [4][5][6] Extrathoracic metastasis in patients with thymic carcinoma is very rare, around 3% to 6%. 5,7 In a review of 35 cases of extrathoracic thymic metastases, 7 only 2 cases demonstrated extrathoracic skeletal muscle metastases.…”