Cixutumumab Combined With Temsirolimus Shows Activity in Refractory Ewing’s Sarcoma

CHICAGO-A combination of cixutumumab, a type 1 insulin-like growth factor receptor (IGF-1R) inhibitor, and temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, showed evidence of activity in refractory Ewing’s sarcoma (EWS) tumors as well as small-round-cell tumors in a phase I multicenter clinical study (AACR2012 abstract LB-124/CCR-12-0061). Findings were reported by lead investigator Aung Naing, MD, assistant professor in the department of investigational cancer therapeutics, division of cancer medicine, at the University of Texas MD Anderson Cancer Center in Houston. Results were reported simultaneously in the AACR journal Clinical Cancer Research.

MRI showing Ewing's sarcoma of the left hip.

“EWS is the second most common bone malignancy striking children, adolescents and young adults in the prime of their lives,” said Dr. Naing. “More treatment options are needed for this disease because relapse is quite frequent.” He said earlier studies of IGF-1R inhibitors and mTOR inhibitors as monotherapy for the EWS “family of tumors” produced variable outcomes.

Dr. Naing and his colleagues evaluated a subset of 20 patients, including 17 with EWS and 3 with desmoplastic small-round-cell tumors (DSRCT), who were treated as part of an expansion cohort from a phase I study of cixutumumab and temsirolimus. All patients had been pretreated heavily before enrolling in the study.

Researchers assigned patients to 4-week cycles of 6 mg/kg cixutumumab and 25 mg to 37.5 mg of temsirolimus. At median follow-up of 8.9 months, they observed prolonged stable disease lasting more than 6 months and 2 complete responses in 29% of the patients with EWS. Tumor regression of over 20% occurred in 5 EWS patients (100%, 100%, 27%, 23%, 23%) with time to treatment failure lasting 22, 2+, 15, 18, and 8 months, respectively. Biopsy samples of one patient, taken at the time of emergence of resistance to a different IGF-1R inhibitor, demonstrated upregulation of mTOR pathway proteins, as determined by morphoproteomic analysis of the resistant tumor. “The patient achieved a complete response with a time to treatment failure of 22 months on our trial,” said Dr. Naing, which provides “strong evidence for synergy between mTOR and IGF-1R antagonists.”

Another patient with EWS had a partial response with prior IGF-1R treatment and then had a mixed response with the combination treatment: “remarkable regression in three lung modules … but progression in a fourth lesion.” Morphoproteomic analysis of this patient’s resistant tumor demonstrated upregulation of mTOR and ERK/MEK signals. The latter, said Dr. Naing, suggests the possibility that a combination of IGFR/mTOR and MEK inhibitors may warrant investigation to determine if it can reverse resistance.

Four responders developed grade 3 mucositis, myelosuppression, or hyperglycemia which investigators said were “well controlled” with supportive therapy while maintaining drug dose.

“This study demonstrated early evidence that this combination can be considered for patients with relapsed and recurrent diseases,” said Dr. Naing. “Further studies in larger numbers of patients with EWS and DSRCT, as well as additional investigation into underlying resistance mechanisms in individual patients, are needed.”

Further commenting on the findings, Dr. Naing told CancerNetwork, “Since we have seen prolonged stable disease and complete response in this heavily pretreated patient population, our collaborators in sarcoma are planning to conduct a trial with a larger patient population and earlier in the course of their diseases.”

The MD Anderson researchers were joined by investigators from the Karmanos Cancer Institute, Detroit, Michigan, and from the Cancer Therapy Evaluation Program (CTEP) and National Cancer Institute, Rockville, Maryland.