Trial of Ridaforolimus in Sarcoma Patients Meets Primary Endpoint of Improved Progression-Free Survival

CHICAGO—The results of the Phase 3, placebo-controlled SUCCEED trial, which evaluated the oral mTOR inhibitor ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy (CT), have shown that the primary endpoint of progression-free survival (PFS) has been met to maintain the benefit of prior CT, as reported by Sant Chawla, MD, of the Sarcoma Oncology Center, Santa Monica, CA, and colleagues at the American Society of Clinical Oncology's 2011 Annual Meeting. With the rapid progression of metastatic sarcomas demonstrating the aggressive nature of these malignancies, Dr. Chawla stated that “maintenance therapy with ridaforolimus will provide a new option for patients with these life-threatening diseases.”

The SUCCEED (Sarcoma Multi-Center Clinical Evaluation of the Efficacy of Ridaforolimus) trial is an international, double-blind study randomized 1:1 between ridaforolimus 40mg for five days per week and placebo as maintenance therapy in patients with metastatic sarcoma. Inclusion criteria include confirmed diagnosis of metastatic soft-tissue or bone sarcoma, ongoing favorable outcome after a minimum of four cycles of prior chemotherapy for metastatic disease, ECOG performance status of 0 or 1, age ≥13 years, adequate organ and bone marrow function, and completed prior chemotherapy with last dose received at least 3 and up to 12 weeks prior to randomization.

The 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. While 711 patients were randomized from 2007 to 2010 and analyzed for efficacy, 53 patients remained on blinded drug at data cut-off.

Analysis of 552 PFS events per IRR showed that ridaforolimus met the prespecified study endpoint with a statistically significant improvement in PFS compared to placebo (P=0.0001). Median PFS improved by 21% (ridaforolimus 17.7 weeks vs. placebo 14.6 weeks). Based on local site assessment of PFS, ridaforolimus demonstrated an improvement with a hazard ratio (HR) of 0.69 (P<0.0001) and a 52% gain in median PFS (ridaforolimus 22.4 weeks vs. placebo 14.7 weeks). PFS benefit was noted across all prespecified strata. Follow-up for OS is ongoing; results at data cut-off (386 OS events) indicate a trend favoring ridaforolimus (median OS: ridaforolimus 21.4 months vs. placebo 19.2 months; HR=88; P=0.2256). Survival was similar for both arms, HR=0.94 (P=0.6152), following disease progression and demonstrated that ridaforolimus did not adversely impact survival.

Tumor response, as measured by clinical benefit rate, was also improved in a greater number of patients treated with ridaforolimus (40.6% vs. 28.6%; P=0.0009). Data further demonstrated that ridaforolimus inhibits tumor growth; mean best target lesion response was -1.3% for ridaforolimus compared with +10.3% for placebo; P<0.0001.

While the incidence of stomatitis (61% vs. 18%), thrombocytopenia (34% vs. 4%), rash (28% vs. 6%). and other adverse events (infections, fatigue, and diarrhea) were higher in patients receiving ridaforolimus, the overall safety profile was consistent with other mTOR inhibitors.

The pathway called mTOR – mammalian target of rapamycin--plays a central role in signaling caused by mitogens such as growth factors to regulate translation but is dysregulated in certain forms of cancer, such as sarcomas. Ridaforolimus has demonstrated activity in Phase 1 and 2 trials in advanced sarcomas following failure of prior CT.

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