Ridaforolimus Delayed Tumor Progression in Patients with Previously Treated Metastatic Sarcoma  


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“Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy,” according to results of an international phase III trial. The large randomized placebo-controlled phase III trial evaluated the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Aberrant mTOR signaling is common in sarcomas and other malignancies and ridaforolimus has demonstrated clinical activity against sarcomas and other solid tumors in phase I and II trials. 

Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus at 40 mg (four 10-mg tablets) or matching placebo administered orally once per day for 5 days every week. The mean age was 52.0 years for the 347 patients receiving ridaforolimus vs 50.6 years for the 364 patients receiving placebo arm. “Approximately 90% of patients had soft tissue sarcomas, with the other 10% having bone sarcomas, and approximately 73% of patients had high-grade tumors, with only 5% having low-grade tumors,” the researchers reported. “More than 60% of patients had lung metastases, followed by liver and bone metastases. Almost 40% of patients in the ridaforolimus and placebo arms had received > two lines of prior therapy.”

Study Results

Independent review found that treatment with ridaforolimus “led to a modest, although significant, improvement” in progression-free survival, the primary endpoint of the study, compared with placebo (hazard ratio [HR] = 0.72; 95% confidence interval [CI] = 0.61–0.85; P = .001). The median progression-free survival was 17.7 weeks for those receiving ridaforolimus vs 14.6 weeks for those receiving placebo. This represented a 28% reduction in the risk of progression or death. “Ridaforolimus induced a mean 1.3% decrease in target lesion size vs a 10.3% increase with placebo (P < .001),” the researchers reported. The median overall survival was 90.6 weeks with ridaforolimus vs 85.3 weeks with placebo (HR = 0.93; 95% CI = 0.78–1.12; P = .46). 

“Despite the proportional benefit, because of the faster rate of disease progression in this study population, the absolute magnitude of [progression-free survival] improvement with ridaforolimus was relatively modest,” the authors wrote. “This small, but nonetheless statistically significant, difference in [progression-free survival] with ridaforolimus did not translate into a significant difference in [overall survival]. It is important to note that this trial was not powered to detect differences in [overall survival]; additionally, the statistical plan was based on a predicted [overall survival] duration of 12 months in the placebo population, and the longer-than-expected survival in the placebo arm reduced the power of the study to detect any differences in [overall survival].”

The toxicities observed with ridaforolimus were “as expected with mTOR inhibition,” the investigators noted. Adverse events that occurred more commonly with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 adverse events were reported by 64.1% of patients receiving ridaforolimus vs 25.6% of those receiving placebo.

The investigators argued that combination therapy with ridaforolimus and inhibitors of other intracellular compensatory signaling pathways “may lead to even more substantial benefit by preventing compensatory cellular mechanisms, which likely minimized the inhibitory action of ridaforolimus.” ■

Demetri GD, et al: J Clin Oncol 31:2485-2492, 2013.



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