Two targeted therapies—the IGF-IR inhibitor cixutumumab and the mTOR inhibitor temsirolimus—seem safe and effective in shrinking tumors in patients with treatment-resistant Ewing sarcoma and a related condition.

IGF-IR and mTOR inhibitor treatment considered safe, with manageable side effects

A pair of targeted therapies—an insulin-like growth factor I receptor (IGF-IR) inhibitor, Lilly's cixutumumab, and Pfizer's mTOR inhibitor, temsirolimus—may be effective in shrinking tumors in patients with treatment-resistant Ewing sarcoma (EWS) or desmoplastic small–round cell tumors (DSRCT), a related condition. That was the conclusion of a phase I trial by researchers from The University of Texas MD Anderson Cancer Center presented at the American Association for Cancer Research Annual Meeting 2012 in Chicago on March 31.

The researchers treated 20 patients with refractory disease—17 with EWS and 3 with DSRCT—with cixutumumab (6 mg/kg) and temsirolimus (25 to 37.5 mg) by i.v. infusion each week in 4-week cycles. According to principal investigator Aung Naing, MD, assistant professor in MD Anderson's Department of Investigational Cancer Therapeutics, the drugs affect molecular pathways that cause cell proliferation and survival, abnormal blood vessel growth, and resistance to chemotherapy and radiotherapy.

Seven of the 20 patients responded to the combination and had stable disease for more than 5 months. Two achieved a complete response, one for 27 months. Five of the responders have EWS and saw their tumors shrink by more than 20%. The median follow-up was 8.9 months.

The most common side effects were thrombocytopenia, mucositis, myleosuppression, high cholesterol, and hyperglycemia, which were manageable with supportive therapy.

A rare bone malignancy, EWS strikes about 500 children, adolescents, and young adults every year. Although relapse is relatively common, survival rates have steadily improved in patients who are diagnosed early; about 65% to 70% of patients now live at least 5 years. But if the disease has already metastasized at the time of diagnosis, the prognosis is poor.

The researchers were particularly encouraged by the findings because all of the patients had failed to benefit from several previous therapies. “They had been heavily, heavily pretreated and were quite resistant to most other treatments,” said Naing. He noted that when the 2 drugs had been used as single agents, treatment results were mixed.

As part of the trial, the researchers performed next-generation sequencing on tumor samples from 2 patients. They found that each patient's cancer took a different route to resistance. In the next phase of their work, the researchers will look at resistance mechanisms in individual patients in greater detail.

Joseph Ludwig, MD, assistant professor in MD Anderson's Department of Sarcoma Medical Oncology, said that the team aims to launch a phase II study of the combination therapy in untreated patients. One of their challenges is to convince drug companies to fund it and other research. “With so few Ewing sarcoma patients, they just see that there's little market for these drugs,” he explained.