Efficacy and Safety of Axitinib as First-Line Therapy in Japanese Patients with Metastatic Renal Cell Carcinoma


Previous study reported that patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib for metastatic renal cell carcinoma (mRCC). In this study, we reviewed our experience of axitinib as a first-line therapy for mRCC in Japanese patients, focusing on its efficacy and safety. We retrospectively assessed 26 patients treated with axitinib as a first-line therapy for mRCC from July 2010 to July 2014 at Chiba Cancer Center and Kinki University Hospital. Observation period was 24.6 ± 18.3 months. The objective response rate was 50.0%, and the median progression-free survival was 27.5 months. Overall survival was not estimable. Common grade 3 adverse events were hypertension in 19 patients and proteinuria in 5 patients. Axitinib demonstrated significant efficacy as a first-line therapy in Japanese patients with mRCC. Careful monitoring and management of the adverse effects may help to control its toxicities.

Share and Cite:

Namekawa, T. , Fukasawa, S. , Komaru, A. , Kobayashi, M. , Ohzeki, T. , Sato, Y. , Rii, J. , Uemura, H. , Ichikawa, T. and Ueda, T. (2015) Efficacy and Safety of Axitinib as First-Line Therapy in Japanese Patients with Metastatic Renal Cell Carcinoma. Journal of Cancer Therapy, 6, 670-678. doi: 10.4236/jct.2015.68074.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Rini, B.I. (2009) Metastatic Renal Cell Carcinoma: Many Treatment Options, One Patient. Journal of Clinical Oncology, 27, 3225-3234.
[2] Motzer, R.J., Hutson, T.E., Tomczak, P., Michaelson, M.D., Bukowski, R.M., Rixe, O., Oudard, S., Negrier, S., Szczylik, C., Kim, S.T., Chen, I., Bycott, P.W., Baum, C.M. and Figlin, R.A. (2007) Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma. New England Journal of Medicine, 356, 115-124.
[3] Escudier, B., Eisen, T., Stadler, W.M., Szczylik, C., Oudard, S., Siebels, M., Negrier, S., Chevreau, C., Solska, E., Desai, A.A., Rolland, F., Demkow, T., Hutson, T.E., Gore, M., Freeman, S., Schwartz, B., Shan, M., Simantov, R. and Bukowski, R.M. (2007) Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma. New England Journal of Medicine, 356, 125-134.
[4] Rini, B.I., Escudier, B., Tomczak, P., Kaprin, A., Szczylik, C., Hutson, T.E., Michaelson, M.D., Gorbunova, V.A., Gore, M.E., Rusakov, I.G., Negrier, S., Ou, Y.-C., Castellano, D., Lim, H.Y., Uemura, H., Tarazi, J., Cella, D., Chen, C., Rosbrook, B., Kim, S. and Motzer, R.J. (2011) Comparative Effectiveness of Axitinib versus Sorafenib in Advanced Renal Cell Carcinoma (AXIS): A Randomised Phase 3 Trial. The Lancet, 37, 1931-1939.
[5] Hu-Lowe, D.D., Zou, H.Y., Grazzini, M.L., Hallin, M.E., Wickman, G.R., Amundson, K., Chen, J.H., Rewolinski, D.A., Yamazaki, S., Wu, E.Y., McTigue, M.A., Murray, B.W., Kania, R.S., O’Connor, P., Shalinsky, D.R. and Bender, S.L. (2008) Nonclinical Antiangiogenesis and Antitumor Activities of Axitinib (AG-013736), an Oral, Potent, and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases 1, 2, 3. Clinical Cancer Research, 14, 7272-7283.
[6] Rixe, O., Bukowski, R.M., Michaelson, M.D., Wilding, G., Hudes, G.R., Bolte, O., Motzer, R.J., Bycott, P., Liau, K.F., Freddo, J., Trask, P.C., Kim, S. and Rini, B.I. (2007) Axitinib Treatment in Patients with Cytokine-Refractory Metastatic Renal-Cell Cancer: A Phase II Study. Lancet Oncology, 8, 975-984.
[7] Rini, B.I., Wilding, G., Hudes, G., Stadler, W.M., Kim, S., Tarazi, J., Rosbrook, B., Trask, P.C., Wood, L. and Dutcher, J.P. (2009) Phase II Study of Axitinib in Sorafenib-Refractory Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology, 27, 4462-4468.
[8] Ueda, T., Uemura, H., Tomita, Y., Tsukamoto, T., Kanayama, H., Shinohara, N., Tarazi, J., Chen, C., Kim, S., Ozono, S., Naito, S. and Akaza, H. (2013) Efficacy and Safety of Axitinib versus Sorafenib in Metastatic Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 3 AXIS Trial. Japanese Journal of Clinical Oncology, 43, 616-628.
[9] Hutson, T.E., Lesovoy, V., Al-Shukri, S., Stus, V.P., Lipatov, O.N., Bair, A.H., Rosbrook, B., Chen, C., Kim, S. and Vogelzang, N.J. (2013) Axitinib versus Sorafenib as First-Line Therapy in Patients with Metastatic Renal-Cell Carcinoma: A Randomised Open-Label Phase 3 Trial. Lancet Oncology, 14, 1287-1294.
[10] Rini, B.I., Melichar, B., Ueda, T., Grünwald, V., Fishman, M.N., Arranz, J.A., Bair, A.H., Pithavala, Y.K., Andrews, G.I., Pavlov, D., Kim, S. and Jonasch, E. (2013) Axitinib with or without Dose Titration for First-Line Metastatic Renal-Cell Carcinoma: A Randomised Double-Blind Phase 2 Trial. Lancet Oncology, 14, 1233-1242.
[11] Motzer, R.J., Bacik, J., Murphy, B.A., Russo, P. and Mazumdar, M. (2002) Interferon-Alfa as a Comparative Treatment for Clinical Trials of New Therapies against Advanced Renal Cell Carcinoma. Journal of Clinical Oncology, 20, 289-296.
[12] Therasse, P., Arbuck, S.G., Eisenhauer, E.A., Wanders, J., Kaplan, R.S., Rubinstein, L., Verweij, J., Van Glabbeke, M., van Oosterom, A.T., Christian, M.C. and Gwyther, S.G. (2000) New Guidelines to Evaluate the Response to Treatment in Solid Tumors. The Journal of the National Cancer Institute, 92, 205-216.
[13] National Cancer Institute (2009) Common Terminology Criteria for Adverse Events (Version 4). National Cancer Institute.
[14] Tomita, Y., Uemura, H., Fujimoto, H., Kanayama, H.O., Shinohara, N., Nakazawa, H., Imai, K., Umeyama, Y., Ozono, S., Naito, S. and Akaza, H., Japan Axitinib Phase II Study Group (2011) Key Predictive Factors of Axitinib (AG-013736)-Induced Proteinuria and Efficacy: A Phase II Study in Japanese Patients with Cytokine-Refractory Metastatic Renal Cell Carcinoma. European Journal of Cancer, 47, 2592-2602.
[15] National Comprehensive Cancer Network (2015) NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. National Comprehensive Cancer Network.
[16] Ljungberg, B., Bensalah, K., Bex, A., Canfield, S., Dabestani, S., Hofmann, F., Hora, M., Kuczyk, M.A., Lam, T., Marconi, L., Merseburger, A.S., Mulders, P.F.A., Staehler, M. and Volpe, A. (2013) Guidelines on Renal Cell Carcinoma. European Association of Urology.
[17] Tomita, Y., Shinohara, N., Yuasa, T., Fujimoto, H., Niwakawa, M., Mugiya, S., Miki, T., Uemura, H., Nonomura, N., Takahashi, M., Hasegawa, Y., Agata, N., Houk, B., Naito, S. and Akaza, H. (2010) Overall Survival and Updated Results from a Phase II Study of Sunitinib in Japanese Patients with Metastatic Renal Cell Carcinoma. Japanese Journal of Clinical Oncology, 40, 1166-1172.
[18] Atkinson, B.J., Kalra, S., Wang, X., Bathala, T., Corn, P., Tannir, N.M. and Jonasch, E. (2014) Clinical Outcomes for Patients with Metastatic Renal Cell Carcinoma Treated with Alternative Sunitinib Schedules. The Journal of Urology, 191, 611-618.
[19] Ohzeki, T., Fukasawa, S., Komaru, A., Namekawa, T., Sato, Y., Takagi, K., Kobayashi, M., Uemura, H., Ichikawa, T. and Ueda, T. (2014) Efficacy of Traditional and Alternative Sunitinib Treatment Schedules in Japanese Patients with Metastatic Renal Cell Carcinoma. International Journal of Urology, 21, 1065-1068.
[20] Kondo, T., Takagi, T., Kobayashi, H., Iizuka, J., Nozaki, T., Hashimoto, Y., Ikezawa, E., Yoshida, K., Omae, K. and Tanabe, K. (2014) Superior Tolerability of Altered Dosing Schedule of Sunitinib with 2-Weeks-On and 1-Week-Off in Patients with Metastatic Renal Cell Carcinoma—Comparison to Standard Dosing Schedule of 4-Weeks-On and 2-Weeks-Off. Japanese Journal of Clinical Oncology, 44, 270-277.
[21] Seidel, C., Busch, J., Weikert, S., Steffens, S., Fenner, M., Ganser, A., Grunwald, V. (2012) Progression Free Survival of First Line Vascular Endothelial Growth Factor-Targeted Therapy Is an Important Prognostic Parameter in Patients with Metastatic Renal Cell Carcinoma. European Journal of Cancer, 48, 1023-1030.
[22] Rini, B.I., Cohen, D.P., Lu, D.R., Chen, I., Hariharan, S., Gore, M.E., Figlin, R.A., Baum, M.S. and Motzer, R.J. (2011) Hypertension as a Biomarker of Efficacy in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib. Journal of the National Cancer Institute, 103, 763-773.
[23] Rautiola, J., Donskov, F., Peltola, K., Joensuu, H. and Bono, P. (2014) Sunitinib-Induced Hypertension, Neutropenia and Thrombocytopenia as Predictors of Good Prognosis in Metastatic Renal Cell Carcinoma Patients. BJU International. (Epub ahead of print)
[24] Izzedine, H., Massard, C., Spano, J.P., Goldwasser, F., Khayat, D. and Soria, J.C. (2010) VEGF Signalling Inhibition-Induced Proteinuria: Mechanisms, Significance and Management. European Journal of Cancer, 46, 439-448.
[25] Gunduz, F., Kuru, O. and Senturk, U.K. (2003) Effect of Nitric Oxide on Exercise-Induced Proteinuria in Rats. Journal of Applied Physiology, 95, 1867-1872.
[26] Schrijvers, B.F., Flyvbjerg, A. and De Vriese, A.S. (2004) The Role of Vascular Endothelial Growth Factor (VEGF) in Renal Pathophysiology. Kidney International, 65, 2003-2017.
[27] Kamba, T., Tam, B.Y., Hashizume, H., Haskell, A., Sennino, B., Mancuso, M.R., Norberg, S.M., O’Brien, S.M., Davis, R.B., Gowen, L.C., Anderson, K.D., Thurston, G., Joho, S., Springer, M.L., Kuo, C.J. and McDonald, D.M. (2006) VEGF-Dependent Plasticity of Fenestrated Capillaries in the Normal Adult Microvasculature. American Journal of Physiology Heart and Circulatory Physiology, 290, H560-H576.
[28] Garovic, V.D., Wagner, S.J., Petrovic, L.M., Gray, C.E., Hall, P., Sugimoto, H., Kalluri, R. and Grande, J.P. (2007) Glomerular Expression of Nephrin and Synaptopodin, but Not Podocin, Is Decreased in Kidney Sections from Women with Preeclampsia. Nephrology, Dialysis, Transplantation, 22, 1136-1143.
[29] Pithavala, Y.K., Tortorici, M., Toh, M., Garrett, M., Hee, B., Kuruganti, U., Ni, G. and Klamerus, K.J. (2010) Effect of Rifampin on the Pharmacokinetics of Axitinib (AG-013736) in Japanese and Caucasian Healthy Volunteers. Cancer Chemotherapy and Pharmacology, 65, 563-570.
[30] Fujiwara, Y., Kiyota, N., Chayahara, N., Suzuki, A., Umeyama, Y., Mukohara, T. and Minami, H. (2012) Management of Axitinib (AG-013736)-Induced Fatigue and Thyroid Dysfunction, and Predictive Biomarkers of Axitinib Exposure: Results from Phase I Studies in Japanese Patients. Investigational New Drugs, 30, 1055-1064.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.