Clinical Experience of Rapamycin Inhibitors in the Treatment of Other Solid Tumors
Subependymal giant-cell astrocytoma (SEGA) results from mutations in the TSC1 or TSC2 genes, whose products are major regulatory proteins linked to the activation of the mTOR pathway. A recent phase II trial of everolimus in children and adults with SEGAs showed signi?cant reduction in tumor volume in a majority of the patients with decreased occurrence of seizures. Notably, the drug was well tolerated even with prolonged treatment, suggesting that it may be an attractive alternative to surgical resection in selective cases. On the contrary, a phase II trial with temsirolimus in patients with recurrent glioblastoma multiforme (GBM) did not show ef?cacy.
There has been also substantial interest towards the development of mTOR inhibitors for the treatment of sarcomas. Temsirolimus has failed to demonstrate meaningful activity as monotherapy in these tumors, as evidenced by a phase II trial in which PFS was only 2 months. Everolimus, on the contrary, may have synergistic activity with imatinib mesylate in gastrointestinal stromal tumors (GIST). Phase I/II data of this combination in patients who progressed with imatinib mesylate alone showed a modest improvement in progression-free survival (PFS). A phase II trial with ridaforolimus in 216 patients with advanced sarcoma was carried out. Patients enrolled included osteosarcoma, leiomyosarcoma, liposarcoma and other soft tissue sarcomas. In several cases stable disease was attained, with amedian survival of 40 weeks, and outcomes were similar between the four histologic subtypes.
Besides brain tumors and sarcomas, mTOR inhibition has been studied in various other solid tumors, including gastrointestinal, prostate, and head and neck cancers. The combination of bevacizumab and everolimus exhibited clinical activity in patients with metastatic colorectal cancer, despite previous progression on a bevacizumab-based regimen. There is also preliminary evidence from a study in patients with hepatocellular carcinoma suggesting that everolimus may be moderately active in stabilizing disease progression. Other trials combining mTOR inhibitors with sorafenib or bevacizumab in patients with hepatocellular carcinoma are ongoing. The combination of bicalutamide and everolimus appears to have promising antitumor activity and an acceptable toxicity pro?le in castrate-resistant prostate cancer, whereas various trials with rapalogs are being conducted for either the treatment of advanced prostate cancer or in the neo-adjuvant setting.
References
   Adriaensen ME, et al. Eur J Neurol 2009; 16: 691-696.
   Krueger DA, et al. N Engl J Med 2010; 363: 1801-1811.
   Dumez H. J Clin Oncol 2008; 26: abstract 10519.
   Altomare I, et al. J Clin Oncol 2010; 28(15Suppl): abstract 3535.
   Chen L, et al. J Clin Oncol 2009; 27 (15Suppl): abstract 4587.
   Kelley RK, et al. J Clin Oncol 2011; 29: (4Suppl): abstract 296.
   Pan C, et al. J Clin Oncol 2010; 28 (AUY922): e15131.
   Phase Ib/II evaluation of RAD001 with docetaxel and bevacizumab in
   patients with metastatic androgen independent cancer (Panobinostat).
Related Posts
Clinical Experience of Rapamycin Inhibitors in the Treatment of Breast Cancer
Posts Related to Clinical Experience of Rapamycin Inhibitors in the Treatment of Other Solid Tumors
   Clinical Experience of Rapamycin Inhibitors in the Treatment of Breast Cancer
   Clinical trials have evaluated the ef?cacy of rapalogs with endocrine therapy as neoadjuvant treatment, as well as the role of rapalogs in the treatment of ...
   Clinical Experience of Rapamycin Inhibitors in the Treatment of Lung Cancer and Pancreatic Neuroendocrine Tumors
   There have been phase I and II clinical trials to assess the clinical ef?cacy of everolimus in lung cancer. A phase I study of everolimus ...
   Clinical Experience of Rapamycin Inhibitors in the Treatment of Renal Cell Carcinoma
   Both temsirolimus and everolimus have been approved for the treatment of advanced renal cell cancer (RCC). In a randomized control trial, temsirolimus was compared to ...
There has been also substantial interest towards the development of mTOR inhibitors for the treatment of sarcomas. Temsirolimus has failed to demonstrate meaningful activity as monotherapy in these tumors, as evidenced by a phase II trial in which PFS was only 2 months. Everolimus, on the contrary, may have synergistic activity with imatinib mesylate in gastrointestinal stromal tumors (GIST). Phase I/II data of this combination in patients who progressed with imatinib mesylate alone showed a modest improvement in progression-free survival (PFS). A phase II trial with ridaforolimus in 216 patients with advanced sarcoma was carried out. Patients enrolled included osteosarcoma, leiomyosarcoma, liposarcoma and other soft tissue sarcomas. In several cases stable disease was attained, with amedian survival of 40 weeks, and outcomes were similar between the four histologic subtypes.
Besides brain tumors and sarcomas, mTOR inhibition has been studied in various other solid tumors, including gastrointestinal, prostate, and head and neck cancers. The combination of bevacizumab and everolimus exhibited clinical activity in patients with metastatic colorectal cancer, despite previous progression on a bevacizumab-based regimen. There is also preliminary evidence from a study in patients with hepatocellular carcinoma suggesting that everolimus may be moderately active in stabilizing disease progression. Other trials combining mTOR inhibitors with sorafenib or bevacizumab in patients with hepatocellular carcinoma are ongoing. The combination of bicalutamide and everolimus appears to have promising antitumor activity and an acceptable toxicity pro?le in castrate-resistant prostate cancer, whereas various trials with rapalogs are being conducted for either the treatment of advanced prostate cancer or in the neo-adjuvant setting.
References
   Adriaensen ME, et al. Eur J Neurol 2009; 16: 691-696.
   Krueger DA, et al. N Engl J Med 2010; 363: 1801-1811.
   Dumez H. J Clin Oncol 2008; 26: abstract 10519.
   Altomare I, et al. J Clin Oncol 2010; 28(15Suppl): abstract 3535.
   Chen L, et al. J Clin Oncol 2009; 27 (15Suppl): abstract 4587.
   Kelley RK, et al. J Clin Oncol 2011; 29: (4Suppl): abstract 296.
   Pan C, et al. J Clin Oncol 2010; 28 (AUY922): e15131.
   Phase Ib/II evaluation of RAD001 with docetaxel and bevacizumab in
   patients with metastatic androgen independent cancer (Panobinostat).
Related Posts
Clinical Experience of Rapamycin Inhibitors in the Treatment of Breast Cancer
Posts Related to Clinical Experience of Rapamycin Inhibitors in the Treatment of Other Solid Tumors
   Clinical Experience of Rapamycin Inhibitors in the Treatment of Breast Cancer
   Clinical trials have evaluated the ef?cacy of rapalogs with endocrine therapy as neoadjuvant treatment, as well as the role of rapalogs in the treatment of ...
   Clinical Experience of Rapamycin Inhibitors in the Treatment of Lung Cancer and Pancreatic Neuroendocrine Tumors
   There have been phase I and II clinical trials to assess the clinical ef?cacy of everolimus in lung cancer. A phase I study of everolimus ...
   Clinical Experience of Rapamycin Inhibitors in the Treatment of Renal Cell Carcinoma
   Both temsirolimus and everolimus have been approved for the treatment of advanced renal cell cancer (RCC). In a randomized control trial, temsirolimus was compared to ...