Axitinib in the successive targeted therapy of patients with metastatic kidney cancer

Background. There is a global increase in the incidence of renal cell carcinoma (RCC); more than 200 thousand new cases are recorded
every year. Despite the high (40–60 %) detection rate for localized RCC, the incidence of locally advanced and metastatic RCC (mRCC)
remains high. Tyrosine kinase inhibitors, such as sorafenib, sunitinib, bevacizumab, and pazopanib, versus cytokine therapy or placebo
demonstrated their efficacy in the treatment of mRCC during randomized trials. A randomized Phase III AXIS trial evaluating the efficacy of axitinib in direct comparison with sorafenib in patients with progressive mRCC during first-line systemic therapy has become one of the first studies comparatively investigating the targeted drugs.

Subjects and methods. The trial enrolled 723 patients with mRCC from 175 centers in 22 countries in the period September 2008 to July 2010. The patients were randomized 1:1 to either axitinib (n = 361) or sorafenib (n = 362). Of them, 389 (54 %) patients had previously received sunitinib, 251 (35 %) cytokines, 59 (8 %) bevazisumab, and 24 (3 %) temsirolimus.

Results. Median overall survival (OS) was 20.1 months (95 % confidence (CI) 16.7–23.4) in the axitinib group and 19.2 months (CI 17.5–22.3) in the sorafenib group (odds ratio (OR) 0.969; 95 % CI 0.800–1.174; p = 0.374). According to the investigator assessments, median progression-free survival was 8.3 months (95 % CI 6.7–9.2) in the patients who took axitinib and 5.7 months (CI 4.7–6.5) in those who received sorafenib (OR 0.656; 95 % CI 0.552–0.779; p < 0.0001). The most common grade III adverse reactions related to axitinib included hypertension (n = 60 (17 %)), diarrhea (n = 40 (11 %)), and fatigability (n = 37 (10 %)). The grade III adverse reactions associated with sorafenib included palmoplanar syndrome (n = 61 (17 %)), hypertension (n = 43 (12 %)), and diarrhea (n = 27 (8 %)). A detailed analysis
showed that the high registration rate of axitinib-induced hypertension was a significant prognostic factor of the efficiency of targeted therapy. Median OS in patients with hypertension developing within 12 weeks after randomization and a diastolic blood pressure (BP) ≥ 90 mm Hg was significantly longer than in those with a diastolic BP of < 90 mm Hg: 20.7 months (95 % CI 18.4–24.6) versus 12.9 months (CI 10.1–20.4) in the axitinib group (р = 0.0116) and 20.2 months (95 % CI 17.1–32.0) versus 14.8 months (95 % CI 12.0–17.7) in the sorafenib group (р = 0.0020). During a multivariate analysis, the prognostic factors associated with short-term OS included a previous treatment option (cytokines or sunitinib), ECOG somatic status = 1; a less than 1‑year interval from diagnosis to treatment initiation in the AXIS trial; more than
one metastatic focus; hepatic metastases; skeletal metastases; a hemoglobin level below the lower limit of the normal range; a corrected calcium level of > 10 mg / dl; a lactate dehydrogenase level 1.5‑fold above the upper limit of the normal range, and alkaline phosphatase or neutrophil levels greater than the upper limit of the normal range.

Conclusion. Axitinib is one of the first targeted drugs, which has demonstrated its efficacy in direct comparison with the other targeted agent sorafenib within the framework of the randomized Phase III AXIS trial in patients with progressive mRCC during first-line systemic therapy. Axitinib versus sorafenib significantly increased median progression-free survival rates in the general population of patients and in those who had previously received therapy with cytokines or sunitinib (p < 0.0001). Axitinib has a satisfactory toxicity profile and the high registration rate of hypertension associated with the drug is a significant prognostic factor for the efficiency of targeted therapy, as shown by the detailed analysis. To comply with the guidelines for monitoring BP and correcting hypertension permits long-term and effective targeted axitinib therapy.

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