Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients after Benefit from Prior Chemotherapy

Purpose Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients and Methods Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. Results A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Conclusion Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.