Sunitinib (Sutent, Pfizer) has shown activity in the second-line treatment of thymic cancer, a disease where numerous other agents have been tested and failed. The results come from the first clinical trial of sunitinib in heavily pretreated patients with thymic epithelial tumors, published online on January 13 in Lancet Oncology.
"Sunitinib has significantly more activity than other drugs tested in this disease and will likely become standard second-line treatment in thymic carcinoma," said senior author Giuseppe Giaccone, MD, PhD, professor of medical oncology and pharmacology at Georgetown University in Washington, DC. "First-line treatment with sunitinib warrants investigation, [and] combination with immune checkpoint inhibitors might be of interest," he told Medscape Medical News.
Although rare, thymic epithelial tumors are the most common type of tumors to arise in the mediastinum. Thymic epithelial tumors are separated into thymomas and thymic carcinomas, which are more aggressive than thymomas. Standard treatment consists of surgery, and platinum-based chemotherapy is used palliatively upon recurrence.
No standard therapies exist for patients whose cancer progresses after platinum-based chemotherapy. A number of drugs have been tried in this tumor type, but most have failed.
Sunitinib is a tyrosine kinase inhibitor already marketed for a number of cancers, including gastrointestinal stromal tumors, renal cell carcinoma, and pancreatic neuroendocrine tumors. Sunitinib has many targets, and no one knows how it really works, according to Dr Giaccone. One of its major mechanisms is the inhibition of angiogenesis, which can be challenging to study in humans, he continued.
"In our studies, we were not able to determine what the action of the drug is in thymic carcinoma," Dr Giaccone reported. "There are no biomarkers that can be used to predict response."
In an accompanying comment, Alexander Marx, MD, and Cleo-Aron Weis, MD, both from the Institute of Pathology at Heidelberg University in Germany, highlight the need to identify more effective combination treatments and biomarkers that can predict response to sunitinib in thymic carcinoma.
Several unknowns still exist, they point out, including the broad range of histology types in thymic epithelial tumors, the molecular and cellular targets of sunitinib, and the mechanisms by which sunitinib acts on thymic carcinoma.
Nevertheless, the study "represent[s] major progress" in the treatment of thymic epithelial tumors, according to Drs Marx and Weis.
"The finding that sunitinib has high activity in a substantial subset of patients with thymic carcinoma and a satisfactory safety profile will certainly change current clinical management of refractory thymic carcinoma and, eventually, of thymic carcinoma in neoadjuvant settings if biomarkers become available," they emphasize.
Study Details
The open-label phase 2 trial was conducted at two centers in the United States from May 2012 to October 2013. Participants had histologically confirmed thymic epithelial tumors and disease progression after at least one round of platinum-containing chemotherapy. They received oral sunitinib 50 mg twice daily in 6-week cycles (4 weeks on treatment, 2 weeks off treatment), until disease progression or unacceptable toxicity.
The analysis involved 40 participants (24 with thymic carcinoma and 16 with thymoma), with a mean follow-up of 17 months. After the thymoma group was found to have insufficient response to sunitinib, enrolment in this group was closed.
Of the 24 participants with thymic carcinoma, 91% achieved disease control, six (26) achieved a partial response, nine (39%) experienced tumor shrinkage, 15 (65%) achieved stable disease, and two (9%) experienced disease progression. The median duration of response was 16.4 months (range, 1.4 - 16.4 months).
Overall 1-year survival estimates were 78% (95% confidence interval, 58.0 - 90.4) for thymic carcinoma.
"This level of activity warrants its use in this subtype of thymic carcinoma," Dr Giaccone said.
Of the 16 patients with thymoma, 81% achieved disease control, and the overall 1-year survival estimate was 86%.
Analyses of blood lymphocytes, serum endothelial and tumor cells, and the genetic characteristics of thymic carcinoma cells failed to identify biomarkers predictive of response to sunitinib.
Grade 3/4 adverse events occurred in 70% of patients. There were five reports (13%) of decreased left-ventricular fraction, three (8%) of which were grade 3 events. One patient with thymoma died of cardiac arrest caused by ventricular fibrillation, which was thought to be related to treatment, but that patient also had a history of atrioventricular block, coronary artery bypass graft surgery, and pacemaker placement, the researchers note.
They point out that cardiac risk factors are related to cardiac tumor involvement and treatment for thymic epithelial tumors, and they advise careful monitoring of cardiac function with sunitinib use in these patients.
The Cancer Therapy Evaluation Program funded the study and distributed sunitinib, which was provided by Pfizer. Dr Giaccone, Dr Marx, and Dr Weis have disclosed no relevant financial relationships.
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