New developments in mammalian target of rapamycin inhibitors for the treatment of sarcoma.
Bottom Line: The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase in the phosphatidylinositol 3-kinase/serine/threonine protein kinase Akt signaling pathway, has an important role in the regulation of protein synthesis, cell proliferation, angiogenesis, and metabolism.Alterations of the mTOR signaling pathway are common in malignancies, including several types of sarcoma.Rapamycin and its analogs (rapalogs) are effective anticancer agents in a broad range of preclinical models.
Affiliation: Division of Medical Hematology/Oncology, Northwestern University, Chicago, Illinois, USA. firstname.lastname@example.orgShow MeSH
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Mentions: On the basis of results from the phase 1 oral study in metastatic solid tumors and the phase 2 intravenous study in sarcoma, an oral formulation of ridaforolimus at a dose of 40 mg once daily 5 times per week was selected for testing in a large phase 3 study in patients with sarcoma. The Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus (SUCCEED) trial was designed to determine whether oral ridaforolimus can be used to maintain disease stability in the metastatic setting.101 The multicenter, multinational, double-blind, placebo-controlled, randomized, phase 3 trial was planned to evaluate 650 patients with metastatic sarcoma who have had favorable outcomes (eg, SD, PR, or CR) to first-line, second-line, or third-line chemotherapy. The primary outcome measure is PFS; secondary efficacy endpoints include OS, best target lesion response, improvement in symptoms, and safety and tolerability (Fig. .2).101 Top-line data recently presented from the SUCCEED trial demonstrate that treatment with oral ridaforolimus resulted in a 28% reduction (P = .0001) in the risk of progression compared with placebo (hazard ratio, 0.72) and a statistically significant 21% (3.1 week) improvement in median PFS (ridaforolimus vs placebo, 17.7 weeks vs 14.6 weeks).89 In a preliminary analysis based on 313 events, the median OS with ridaforolimus was 88.0 weeks versus 78.7 weeks in the placebo group. The incidence of stomatitis (52%) and other AEs was higher with ridaforolimus than with placebo; these findings were consistent with safety data reported for other mTOR inhibitors. Although additional data on secondary endpoints are pending, including updated OS data, these initial results for using ridaforolimus in the treatment of STS seem promising.
Affiliation: Division of Medical Hematology/Oncology, Northwestern University, Chicago, Illinois, USA. email@example.com