Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

BMC Cancer

Jun Guo²  Yiran Huang⁴  Xu Zhang¹  Fangjian Zhou³  Yinghao Sun⁸  Shukui Qin⁶  Zhangqun Ye⁹  Hui Wang⁵  Annette Jappe⁷  Patrick Straub⁷  Nicoletta Pirotta⁷  Sven Gogov⁷ 

[1] The General Hospital of PLA, Beijing, China

[2] Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Beijing, 100142, China

[3] Sun Yat-sen University Cancer Center, Guangzhou, China

[4] Shanghai Renji Hospital, Shanghai, China

[5] Beijing Novartis Pharma Company, Ltd., Beijing, China

[6] Nanjing Bayi Hospital, Yanggongjing, Nanjing, China

[7] Novartis Pharma AG, Basel, Switzerland

[8] Shanghai Changhai Hospital, Yangpu District, China

[9] Wuhan Tongji Hospital, Wuhan, China

关键词: Sorafenib;    Sunitinib;    Renal cell cancer;    mTOR inhibitor;    Everolimus;    Asian;   

Others  :  1079854
DOI  :  10.1186/1471-2407-13-136

 received in 2012-09-18, accepted in 2013-03-11,  发布年份 2013

【 摘 要 】

Background

In China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC.

Methods

An open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011.

Results

A total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response.

Conclusions

Safety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical benefit to Chinese patients with anti-VEGF-refractory mRCC.

Trial registration

clinicaltrials.gov, NCT01152801

【 授权许可】

   
2013 Guo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 7 .

Figure 2.

【 参考文献 】

• [1]American Cancer Society: Cancer Facts and Figures 2012. Atlanta, GA: American Cancer Society; 2012:1-66.
• [2]International Agency for Research on Cancer: Globocan 2008 fast stats. China; [http://globocan.iarc.fr/factsheet.asp webcite]
• [3]Yang L, Parkin DM, Ferlay J, Li L, Chen Y: Estimates of cancer incidence in China for 2000 and projections for 2005. Cancer Epidemiol Biomarkers Prev 2005, 14:243-250.
• [4]Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 2005, 353:2477-2490.
• [5]Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N, for the AVOREN Trial Investigators: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007, 370:2103-2111.
• [6]Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, for the TARGET Study Group: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125-134.
• [7]Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356:115-124.
• [8]Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ: Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol 2010, 28:2137-2143.
• [9]Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE: Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010, 28:1061-1068.
• [10]Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A: Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010, 116:4256-4265.
• [11]Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011, 378:1931-1939.
• [12]National Comprehensive Cancer Network, Inc: The NCCN Clinical Practice Guidelines in Oncology™ for Kidney Cancer V.2.2012. [http://www.nccn.org webcite]
• [13]Escudier B, Kataja V: Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012, 23:vii65-vii71.
• [14]Ljungberg B, Cowan NC, Hanbury DC, Hora M, Kuczyk MA, Merseburger AS, Patard JJ, Mulders PF, Sinescu IC: EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol 2010, 58:398-406.
• [15]de Reijke TM, Bellmunt J, van Poppel H, Marreaud S, Aapro M: EORTC-GU group expert opinion on metastatic renal cell cancer. Eur J Cancer 2009, 45:765-773.
• [16]Bjornsti MA, Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004, 4:335-348.
• [17]Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT: Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995, 270:815-822.
• [18]Lebwohl D, Thomas G, Lane HA, O’Reilly T, Escudier B, Yao JC, Pavel M, Franz D, Berg W, Baladi J-F, Stewart J, Motzer RJ: Research and innovation in the development of everolimus for oncology. Expert Opin Drug Discov 2011, 6:323-338.
• [19]Husseinzadeh HD, Garcia JA: Therapeutic rationale for mTOR inhibition in advanced renal cell carcinoma. Curr Clin Pharmacol 2011, 6:214-221.
• [20]Tanaka C, O’Reilly T, Kovarik JM, Shand N, Hazell K, Judson I, Raymond E, Zumstein-Mecker S, Stephan C, Boulay A, Hattenberger M, Thomas G, Lane HA: Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008, 26:1596-1602.
• [21]Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Cajal S, Jones S, Vidal L, Shand N, Macarulla T, Ramos FJ, Dimitrijevic S, Zoellner U, Tang P, Stumm M, Lane HA, Lebwohl D, Baselga J: Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008, 26:1603-1610.
• [22]Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP: A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 2009, 115:2438-2446.
• [23]Jac J, Giessinger S, Khan M, Willis J, Chiang S, Amato R: A phase II trial of RAD001 in patients with metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol 2007, 25(Suppl):5107.
• [24]Stein A, Wang W, Carter AA, Chiparus O, Hollaender N, Kim H, Motzer RJ, Sarr C: Dynamic tumor modeling of the dose–response relationship for everolimus in metastatic renal cell carcinoma using data form the phase 3 RECORD-1 trial. BMC Cancer 2012., 12 BioMed Central Full Text
• [25]Stein A, Carter A, Hollaender N, Motzer R, Sarr C: Quantifying the effect of everolimus on both tumor growth and new metastases in metastatic renal cell carcinoma (RCC): a dynamic tumor model of the RECORD-1 phase III trial. J Clin Oncol 2011., 29(Suppl)abstr 4602. Presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3–7; Chicago, Illinois
• [26]Xu B, Wu Y, Shen L, Ye D, Jappe A, Cherfi A, Wang H, Yuan R: Two dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors. J Hematold Oncol 2011, 4:3. BioMed Central Full Text
• [27]Cancer Therapy Evaluation Program: Common Terminology Criteria for Adverse Events V3.0 (CTCAE). [http://ctep.cancer.gov webcite]
• [28]Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A, for the RECORD-1 Study Group: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008, 372:449-456.
• [29]Porta C, Ostanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, Creel P, Dickow B, Fischer P, Gornell SS, Meloni F, Motzer RJ: Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 2011, 47:1287-1298.
• [30]Ravaud A: Treatment-associated adverse event management in the advanced renal cell carcinoma patient treated with targeted therapies. Oncologist 2011, 16(suppl 2):32-44.
• [31]White DA, Camus P, Endo M, Escudier B, Calvo E, Akaza H, Uemura H, Kpamegan E, Kay A, Robson M, Ravaud A, Motzer RJ: Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 2010, 182:396-403.
• [32]Tsukamoto T, Shinohara N, Tsuchiya N, Hamamoto Y, Maruoka M, Fujimoto H, Niwakawa M, Uemura H, Usami M, Terai A, Kanayama HO, Sumiyoshi Y, Eto M, Akaza H: Phase III trial of everolimus in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from RECORD-1. Jpn J Clin Oncol 2011, 41:17-24.