Background: The mTOR signaling pathway is activated in most sarcomas. R, an oral mTOR inhibitor, demonstrated activity in phase I-II trials in advanced sarcomas following failure of prior CT. Methods: This trial is an international, double-blind study randomized 1:1 between R (40 mg orally for 5 days/week) vs. placebo (P) as maintenance therapy in pts with metastatic sarcoma (stratified soft-tissue vs bone; 1st vs, 2nd/3rd line prior CT) following stable disease or better response to prior CT. Primary endpoint is progression-free survival (PFS) based on independent radiological review (IRR). Secondary endpoints include overall survival (OS), best target lesion response, cancer-related symptoms, and safety and tolerability. Results: 711 pts were randomized from Jun ’07 to Jan ’10 and analyzed for efficacy. At data cut-off, 53 pts remained on blinded drug. Baseline characteristics were well balanced between the study arms. Analysis of 552 PFS events per IRR showed that R met the prespecified study endpoint with a statistically significant improvement in PFS compared to P (Hazard Ratio HR=0.72, P=0.0001, stratified log-rank). Median PFS improved by 21% (17.7 wks R vs. 14.6 wks P). Based on local site assessment of PFS, R demonstrated an improvement with HR=0.69 (P<0.0001) and a 52% gain in median (22.4 wks R vs. 14.7 wks P). PFS benefit was noted across all prespecified strata. Follow-up for OS is ongoing; results at data cut-off (313 OS events) indicate a trend favoring R (median OS: 88.0 wks R vs. 78.7 wks P; HR=0.92, 95% CI (0.74, 1.15)). While incidence of stomatitis (52%) and other adverse events was higher in pts receiving R, the overall safety profile was consistent with other mTOR inhibitors. Conclusions: This randomized trial of ridaforolimus met the primary endpoint of improved PFS in pts with metastatic soft-tissue or bone sarcomas to maintain benefit from prior standard CT. The rapid progression of metastatic sarcomas demonstrates the aggressive nature of these malignancies, and maintenance therapy with R will provide a new option for pts with this life-threatening disease.
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