Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers.
[en] BACKGROUND: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. PATIENTS AND METHODS: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. RESULTS: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. CONCLUSIONS: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.
Disciplines :
Oncology
Author, co-author :
Seront, E.
Rottey, S.
Sautois, Brieuc ; Université de Liège > Département des sciences cliniques > Département des sciences cliniques
Kerger, J.
D'Hondt, L. A.
Verschaeve, V.
Canon, J.-L.
Dopchie, C.
Vandenbulcke, J. M.
Whenham, N.
Goeminne, J. C.
Clausse, M.
Verhoeven, D.
Glorieux, P.
Branders, S.
Dupont, P; Université de Liège > HEC-Ecole de gestion : UER > UER Opérations
Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers.
American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society 2011.
Bajorin DF, Dodd PM, Mazundar M et al. Long term survival in metastatic transitional cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999; 17: 3173-3181.
Saxman SB, Propert KJ, Einhorn LH et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1997; 15: 2564-2569.
von der Maase H, Sengelov L, Roberts JT et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23: 4602-4608.
Bellmunt J, Theodore C, Demkov T et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009; 27: 4454-4461.
Garcia JA, Danielpour D. Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol Cancer Ther 2008; 7: 1347-1354.
Chen M, Cassidy A, Gu J et al. Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk. Carcinogenesis 2009; 30: 2047-2052.
Aveyard JS, Skilleter A, Habuchi T et al. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 1999; 80: 904-908.
Saal LH, Johansson P, Holm K et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA 2007; 104: 7564-7569.
Knowles MA, Platt FM, Ross RL et al. Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer. Cancer Metastasis Rev 2009; 28: 305-316.
Platt FM, Hurst CD, Tayler CF et al. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res 2009; 15: 6008-6017.
Qian CN, Furge KA, Knol J et al. Activation of the PI3K/Akt pathway induces urothelial carcinoma of the renal pelvis: identification in human tumors and confirmation in animal models. Cancer Res 2009; 69: 8256-8264.
Wu W, Shu X, Hovsepyan H et al. VEGF receptor expression and signalling in human bladder tumors. Oncogene 2003; 22: 3361-3370.
Yang CC, Chu KC, Yeh WM. The expression of vascular endothelial growth factor in transitional cell carcinoma of urinary bladder is correlated with cancer progression. Urol Oncol 2004; 22: 1-6.
Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372: 449-456.
Yao JC, Shah MH, Ito T et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514-523.
Krueger DA, Care MM, Holland K et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363: 1801-1811.
Fechner G, Classen K, Schmidt D et al. Rapamycin inhibits in vitro growth release of angiogenetic factors in human bladder cancer. Urology 2009; 73: 665-668.
Mansure JJ, Nassim R, Chevalier S et al. Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer. Cancer Biol Ther 2009; 8: 2339-2347.
Chiong E, Lee IL, Dadbin A et al. Effects of mTOR inhibitor everolimus (RAD001) on bladder cancer cells. Clin Cancer Res 2011; 17: 2863-2873.
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1-10.
Bellmunt J, Choueiri TK, Fougeray R et al. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol 2010; 28: 1850-1855.
Beer TM, Goldman B, Nichols CR et al. Southwest Oncology Group phase II study of irinotecan in patients with advanced transitional cell carcinoma of the urothelium that progressed after platinum based chemotherapy. Clin Genitourin Cancer 2008; 6: 36-39.
Winquist E, Vokes E, Moore MJ et al. A phase II study of oxaliplatin in urothelial cancer. Urol Oncol 2005; 23: 150-154.
Witte RS, Manola J, Burch PA et al. Topotecan in previously treated advanced urothelial carcinoma: an ECOG phase II trial. Invest New Drugs 1998; 16: 191-195.
Lorusso V, Pollera CF, Antimi M et al. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer. Eur J Cancer 1998; 34: 1208-1212.
Vaughn DJ, Broome CM, Hussain M et al. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol 2002; 20: 937-940.
McCaffrey JA, Hilton S, Mazumdar M et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol 1997; 15: 1853-1857.
Dreicer R, Li S, Manola J et al. Phase 2 trial of epothilone B analog BMS-247550 (ixabepilone) in advanced carcinoma of the urothelium (E3800): a trial of the Eastern Cooperative Oncology Group. Cancer 2007; 110: 759-763.
Sweeney CJ, Roth BJ, Kabbinavar FF et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 2006; 24: 3451-3457.
Wulfing C, Machiels JP, Richel DJ et al. A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer 2009; 115: 2881-2890.
Twardowski P, Stadler W, Frankel P et al. Phase II study of aflibercept (VEGFTrap) in patients (pts) with recurrent or metastatic transitional cell carcinoma (TCC) of the urothelium: A California Cancer Consortium trial. J Clin Oncol 2009; 27: 15s. (Abstr e16030).
Dreicer R, Li H, Stein M et al. Phase 2 trial of sorafenib in patients with advanced urothelial cancer: a trial of the Eastern Cooperative Oncology Group. Cancer 2009; 115: 4090-4095.
Gallagher DJ, Milowsky MI, Gerst SR et al. Phase II study of sunitinib in patients with metastatic urothelial cancer. J Clin Oncol 2010; 28: 1373-1379.
Necchi A, Nicolai N, Guglielmi A et al. Phase II study of pazopanib monotherapy for patients with relapsed/refractory urothelial cancer. Presented at the 35th European Society for Medical Oncology (ESMO) Congress. Milan, Italy, October 8-12, 2010.
Milowsky MI, Regazzi AM, Garcia-Grossman IR et al. Final results of a phase II study of everolimus (RAD001) in metastatic transitional cell carcinoma (TCC) of the urothelium. J Clin Oncol 2011; 29: 15s. (Abstr 4606).
Milowsky MI, Regazzi AM, Garcia-Grossman IR et al. Phase II study of everolimus (RAD001) in metastatic transitional cell carcinoma (TCC) of the urothelium. J Clin Oncol 2011; 29: 7s. (Abstr 245).
Satoh N, Yamada Y, Kinugasa Y et al. Angiopoietin-1 alters tumor growth by stabilizing blood vessels or by promoting angiogenesis. Cancer Sci 2008; 99: 2373-2379.
Oka N, Yamamoto Y, Takahashi M et al. Expression of angiopoietin-1 and -2, and its clinical significance in human bladder cancer. BJU Int 2005; 95: 660-663.
Rosa AI, Gonçalves J, Cortes L et al. The angiogenic factor angiopoietin-1 is a proneurogenic peptide on subventricular zone stem/progenitor cells. J Neurosci 2010; 30: 4573-4584.
Takahashi N, Kawanishi-Tabata R, Haba A et al. Association of serum endoglin with metastasis in patients with colorectal, breast, and other solid tumors, and suppressive effect of chemotherapy on the serum endoglin. Clin Cancer Res 2001; 7: 524-532.
Neshat MS, Mellinghoff IK, Tran C et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001; 98: 10314-10319.
Cho D, Signoretti S, Dabora S et al. Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2007; 5: 379-385.
Oza AM, Elit L, Tsao MS et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC clinical trial group. J Clin Oncol 2011; 29: 3278-3285.
Ellard SL, Clemons M, Gelmon KA et al. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 2009; 27: 4536-4541.
Weigelt B, Warne PH, Downward J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 2011; 30: 3222-3233.
Cloughesy TF, Yoshimoto K, Ngiemphu P et al. Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 2008; 5: e8.
Wan X, Harkavy B, Shen N et al. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 2007; 26: 1932-1940.