Consecutive targeted therapy in patients with metastatic kidney cancer

Every year, more than 200 thousand new cases of renal cell carcinoma (RCC) are registered worldwide. 25% of patients at primary examination are diagnosed with metastatic RCC (mRCC), and 20--40% of patients after radical surgery later demonstrate cancer progression and metastases. Thus, the incidence of locally advanced mRCC remains high. Tyrosine kinase inhibitors demonstrated efficacy in the treatment of mRCC in randomized trials comparing investigational drug with cytokine therapy or placebo. The randomized phase 3 AHIS trial was among the first studies directly comparing targeted therapies in which the efficacy of axitinib was directly compared with that of sorafenib in patients with mRCC which progressed after 1-line systemic therapy. 723 patients with mRCC were included in the trial who were randomized 1:1 to receive axitinib (n = 361) and sorafenib (n = 362). 389 (54%) patients earlier received sunitinib, 251 (35%) - cytokines, 59 (8%) - bevacizumab, and 24 (3%) - temsirolimus. The overall median survival was 20.1 months for the axitinib group and 19.2 months for the sorafenib group (p = 0.374). Median progression-free survival in the total population was significantly longer in the axitinib group compared to the sorafenib group (6.7 and 4.7 months, р < 0.0001) (р < 0.0001). After a detailed analysis, high incidence of arterial hypertension (17%) induced by axitinib proved to be a reliable predictor of the effectiveness of targeted therapy. Median overall survival in patients who developed hypertension 12 weeks after randomization and had diastolic blood pressure (BP) ≥ 90 mm Hg was significantly longer than in patients with diastolic blood pressure <90 mm Hg: 20.7 vs. 12.9 monthsin the axitinib group (p = 0.0116) and 20.2 vs 14.8 months in the sorafenib group (р = 0.0020). Axitinib is one of the first targeted therapies that demonstrated efficacy in a comparison with another targeted therapy - sorafenib - in the randomized phase 3 AXIS trial in patients with mRCC which progressed after 1-line systemic therapy. Axitinib, compared with sorafenib, significantly increased median progression-free survival regardless of the first-line therapy (cytokine or tyrosine kinase inhibitor therapy, p <0.0001). Axitinib has a satisfactory safety profile, and hypertension induced by the use of axitinib is valid marker of the effectiveness of targeted therapy. Compliance with guidelines for optimizing axitinib dosage and management of hypertension in patients with mRCC helps to achieve the best survival rates.

метастатический почечно-клеточный рак, таргетная терапия, ингибиторы ангиогенеза, акситиниб, metastatic renal cell carcinoma, targeted therapy, angiogenesis inhibitors, axitinib

1. Escudier B, Eisen T, Stadler W et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 2007, 356: 125-134.

2. Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med, 2007, 356: 2271-2281.

3. 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.

4. Escudier B, Pluzanska A, Koralewski, P et al. 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.

5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer [v.2014]. Доступно по адресу http://www.nccn.org/.

6. Ljungberg B, Bensalah K, Bex A, Canfield S, Dabestani S, Hofmann F, Hora M, Kuczyk MA et al. Guidelines on renal cell cancer. European Association of Urology 2014. Доступно по адресу http//www.uroweb.org/.

7. Rini BI, Rixe O, Bukowski RM, et al. AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC). J Clin Oncol, 2005, 23: Abstr 4509.

8. Sonpavde G, Hutson TE, Rini BI. Axitinib for renal cell carcinoma. Expert Opin Investig Drugs, 2008, 17: 741-48.

9. O'Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003; 101: 3597-605.

10. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther, 2003, 2: 471-78.

11. Flaherty KT. Sorafenib in renal cell carcinoma. Clin Cancer Res, 2007, 13: 747-52.

12. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol, 2007, 8: 975-84.

13. Motzer RJ, De la Motte Rouge T, Harzstark AL, et al. Axitinib second-line therapy for metastatic renal cell carcinoma (mRCC): 5-year (yr) overall survival (OS) data from a phase 2 trial. J Clin Oncol, 2011, 29: 4547.

14. Tomita Y, Uemura H, Fujimoto H, et al. Key predictive factors of axitinib (AG-013736)-induced proteinuria and effi cacy: a Japanese phase II study in patients with cytokine-refractory metastatic renal cell cancer (mRCC). Ann Oncol, 2010, 21(8): 902.

15. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol, 2009, 27: 4462-68.

16. Rini BI, Escudier B, Tomczak P, et al. Comparative eff ectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet, 2011, 378: 1931-39.