Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial
- Date: 14 Aug 2015
- Author: Yusuke Okuma
- Affiliation: Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital
- Link: Read the original article
- Topic: Lung and other thoracic tumours
Thymic malignancies, which comprise thymomas and thymic carcinomas, are categorized as rare cancers according to the definition of the RARECARE project (1). Recently, the ESMO committee proposed a position paper on rare cancers (2) and regarded the international collaboration of the International Thymic Malignancy Interest Group (ITMIG) as a model for research on rare cancers. (3)
Until publication of some recent results of clinical trials, there was insufficient evidence to support chemotherapy for advanced thymic malignancies because only a few retrospective studies with small numbers of patients or single arm phase II studies were available.
Therefore, the survival benefit of chemotherapy for advanced thymic carcinoma was uncertain. Also, the biological background was poorly understood. The National Comprehensive Cancer
Network (NCCN) guidelines recommend single-agent chemotherapy or enrolment in clinical trials for refractory thymic carcinoma (4). In addition, recent clinical trials have recommended distinguishing thymic carcinomas from thymomas, because they have different biological and clinical characteristics.
Thomas et al. published "Phase II Trial of Sunitinib in Patients with Recurrent Thymoma and Thymic carcinoma" in Lancet Oncology (5). The authors concluded that sunitinib is active, having a 26% response rate in patients with refractory thymic carcinomas previously treated with palliative-intent platinum-based chemotherapy. However, in this clinical trial thymomas did not respond to sunitinib. For rare cancers, response rates must be used as a surrogate end point for assessing the clinical benefit of chemotherapy. The reported response rate of 26% for refractory
thymic carcinoma is relatively good given that response rates in first-line settings are reportedly in 30-50% of the cases. (6) This phase II trial of sunitinib for refractory thymic carcinoma was the first study to show a positive outcome for refractory thymic carcinoma as no positive results have previously been reported. In the translational research part of this phase II trial, expression of programmed death-ligand 1 (PD-L1) in patients with thymic carcinoma after administration of sunitinib was identified; these results can be helpful in identifying potential immunotherapy for thymic carcinoma treatment [NCT02364076].
Results of recent trials of the following molecular targeted agents (MTAs) for refractory thymic malignancies were published in 2014-2015: belinostat (7), cixutumumab (8), everolimus (9), saracatinib (10), and milciclib (11). The rationale for these phase II studies is the retrospective finding of expression of biomarkers in archived specimens from small numbers of patients. In particular, c-Kit is overexpressed in 79% of thymic carcinomas and IGF-1R is detectable by immunohistochemistry in 70% of the cases. Setting up clinical trials based on biologically plausible hypothesis is a strategic approach, especially for rare cancers, as it reduces the proportion of negative trials. In a case series with documented clinical responses performed by Strobel et al. (12), thymic carcinoma was found to have enriched c-Kit expression and there was promising evidence for sunitinib having c-Kit inhibitor properties (13). A response rate of 26% for MTAs is not high in comparison with response rates achieved by EGFR-tyrosine kinase inhibitors and ALK-inhibitors in advanced non-small cell lung cancer, or other MTAs for other malignancies. However, when these rates are compared to the response rate of 22% for imatinib in gastrointestinal stromal tumors (GIST) and 38% for sunitinib in renal cell carcinomas, 26% in the second-line setting is acceptable as a treatment option. Sunitinib may offer hope for patients with refractory thymic carcinoma by means of symptom relief even if survival benefit remains uncertain. There are no published trials comparing sunitinib with best supportive care (IIa evidence level). The results of recent phase II trials with various MTAs suggest that belinostat and cixutumumab are the most promising treatment options for thymoma, whereas sunitinib and everolimus are the most encouraging therapies for thymic carcinoma. As for future directions, researchers must continue to investigate the potential predictive value of biomarkers to facilitate maximizing the effectiveness of targeted agents.
According to the European consensus position paper on rare cancers, the cost/efficacy threshold must be taken into account as it is for common cancers. If there is uncertainty regarding this issue, grants must be made available for performing the required trials. Some cytotoxic chemotherapy are reportedly cost-effective in patients with thymic carcinoma, resulting in moderate response rates. (14) Cytotoxic chemotherapy for refractory thymic malignancies is currently being investigated empirically with a limited rationale and poor patient selection. In the era of MTAs and translational approaches, the issue of cost and efficacy in thymic malignancies must continue to be examined.
- Is evidence from small series on retrospective data enough to justify chemotherapy for rare cancers?
- Is a response rate of 30% acceptable from the view of cost/efficacy?
- RARE CANCERS EUROPE. In.
- Casali PG, Bruzzi P, Bogaerts J, et al. Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO 2015;26(2):300-06.
- ITMIG Definitions and Policies. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 2011;6(7 Suppl 3):S1689-S755.
- Ettinger DS, Riely GJ, Akerley W, et al. Thymomas and thymic carcinomas: Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network: JNCCN 2013;11(5):562-76.
- Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. The lancet oncology 2015;16(2):177-86.
- Okuma Y, Saito M, Hosomi Y, et al. Key components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy. Journal of cancer research and clinical oncology 2015;141(2):323-31.
- Thomas A, Rajan A, Szabo E, et al. A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study. Clinical cancer research: an official journal of the American Association for Cancer Research 2014;20(21):5392-402.
- Rajan A, Carter CA, Berman A, et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. The lancet oncology 2014;15(2):191-200.
- Zucali PA, De Pas TM, Palmieri G, et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. ASCO Meeting Abstracts 2014;32(15_suppl):7527.
- Gubens MA, Burns M, Perkins SM, et al. A phase II study of saracatinib (AZD0530), a Src inhibitor, administered orally daily to patients with advanced thymic malignancies. Lung cancer 2015;89(1):57-60.
- Besse B, Garassino MC, Rajan A, et al. A phase II study of milciclib (PHA-848125AC) in patients (pts) with thymic carcinoma (TC). ASCO Meeting Abstracts 2014;32(15_suppl):7526.
- Strobel P, Bargou R, Wolff A, et al. Sunitinib in metastatic thymic carcinomas: laboratory findings and initial clinical experience. British journal of cancer 2010;103(2):196-200.
- Rossi V, Donini M, Sergio P, et al. When a thymic carcinoma "becomes" a GIST. Lung cancer 2013;80(1):106-8.
- Okuma Y, Hosomi Y, Takahashi S, et al. Response to cytotoxic chemotherapy in patients previously treated with palliative-intent chemotherapy for advanced thymic carcinoma. Clinical lung cancer 2015;16(3):221-7.
The author have no conflict of interest to declare.
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.