Axitinib for the management of metastatic renal cell carcinoma

Abstract

In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5 mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2-6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advanced RCC previously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable non-cumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95% CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95% CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6). In the three studies, the most common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients. An observed association between diastolic blood pressure ≥90 mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second-line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm.

Figures

Fig 1

Axitinib drug design. Reproduced from Hu-Lowe et al.,[32] with permission.

Table I

IC50 for selected targeted agents. Reproduced from Bellmunt et al.,[33] with permission

Fig. 2

Relative potency of targeted agents in metastatic renal cell carcinoma (mRCC).[,,–45] IC50 = concentration that produces 50% inhibition; VEGFR = vascular endothelial growth factor receptor. Reproduced from Bellmunt et al.,[33] with permission.

Fig 3

Quantitative representation of tumor initial area under the curve (IAUC) values mapped over the tumor region Ktrans, volume transfer constant. Reproduced from Liu et al.,[55] with permission.

Table II

Summary of efficacy findings in key phase II studies [n (%)]

Fig. 4

Tumor responses from phase II trials of axitinib in patients with metastatic renal cell carcinoma (mRCC). Each bar represents one patient. Maximum percentage reduction in tumor size of target lesions by Response Evaluation Criteria In Solid Tumors (RECIST).[-100% = complete response; -30% = partial response; n = 48]. Reproduced from (a) Rini et al.[57] and (b) Rixe et al.,[56] with permissionbid = twice daily; CR = complete response; PR = partial response.

Table III

Common adverse events reported in phase II clinical trials[56,57]

Fig 5

Probability of a partial response with maximum diastolic blood pressure (DBP). Reproduced from Rixe et al.,[62] with permission.

Fig. 6

Study schema for AGILE 1051.[65] bid = twice daily; ECOG PS = Eastern Cooperative Oncology Group Performance Status; mRCC = metastatic renal cell carcinoma; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria In Solid Tumors.