Feasibly of axitinib as first-line therapy for advanced or metastatic renal cell carcinoma: a single-institution experience in Japan

Till 2005, the standard of care was limited to cytokine therapy, including interferon-alpha (IFN-α) and/or interleukin-2, and these treatments were frequently associated with limited efficacy and high toxicity [18]. A better understanding of the molecular mechanisms that target angiogenesis by direct inhibition of VEGF or mTOR has led to improved treatment options for RCC. Clinical trials using novel targeted agents, including TKIs or mTORs, have been evaluated in large randomized controlled studies conducted in both the first- and second-line setting [19]. Of these, sunitinib demonstrated superior efficacy to IFN-α as first-line mRCC therapy, with a median PFS of 11 versus 5 months (P < 0.001), respectively, in a randomized phase III trial [4]. Sunitinib is currently regarded as the reference standard of care for the first-line treatment of mRCC.

Several studies have reported widely variable rates and grades of sunitinib-related AEs [6,8,9,20]. The rates of incidence for the most common grade 3/4 AEs that require dose discontinuation and/or reduction, including hand-foot syndrome (HFS), stomatitis, and hypertension were similar to the rates reported in previous trials [21,22]. However, differences in ethnicity-based treatment tolerance may have also played a role. Miyake et al. reported that the rates of incidence of AEs ≥ grade 3 in a phase III clinical trial and a phase II Japanese clinical trial were 61% and 95%, respectively [9]. Similarly, ad hoc analyses indicate that several AEs occur at a significantly higher rate in Asian patients relative to Caucasian patients; for example, HFS occurred in 70% of Asian patients compared with 28% of Caucasian patients (P < 0.001) [8]. Although the standard sunitinib schedule involves four weeks of treatment and two weeks of rest, a modified schedule of sunitinib treatment, with two weeks of treatment and one week of rest, was associated with significantly decreased toxicity [23].

Common AEs of axitinib include diarrhea, hypertension, fatigue, anorexia and weight loss. The safety profile of axitinib is generally manageable with standard medical intervention [24]. In the AXIS study, discontinuation rates due to treatment-related AEs were 4% in the axitinib arm and 8% in the sorafenib arm, while dose interruptions and reductions were required in 77% and 31% of axitinib recipients [25]. The AXIS study protocol allowed for dose escalation in the absence of hypertension or grade 2 AEs, which may have been partially responsible for the subsequent increase in dose-reduction rate [26].

In this study, the treatment-naïve cRCC patients had a relatively longer PFS without axitinib dose titration, compared with other clinical trials. Rini et al. reported that in treatment-naïve mRCC patients who initially tolerated axitinib at a dose of 5 mg twice daily, a significantly higher proportion achieved an objective response with axitinib dose titration than with placebo titration [27]. Furthermore, based on the results from a phase 3 trial evaluating axitinib versus sorafenib in treatment-naïve patients with mRCC, the median PFS was 10.1 months with axitinib and 6.5 months with sorafenib (P = 0.038) [13]. In addition, median PFS was 13.7 months with axitinib and 6.6 months with sorafenib in patients with ECOG PS 0 (P = 0.022) [13]. In this study, the differences in PFS were not significant between all risk groups, according to the MSKCC risk stratification. Although brief exposure to higher axitinib doses may achieve immediate tumor shrinkage, a substantial proportion of patients may subsequently be forced to lower axitinib doses, which may lead to lower rates of long term disease control.

The current study has several limitations. First, it is a retrospective study, with an inherent potential for bias. Second, a relatively small number of patients were enrolled in this study, and the follow-up period was relatively short. In this study, the number of enrolled patients was relatively high age compared with other randomized trials [13,27]. AEs were also effectively managed with medications or axitinib dose reduction in this study. Although a large proportion of patients in other randomized control studies were recruited from North America and Western Europe, some patients were recruited from Asia, but the number was not large enough. Therefore, axitinib as first-line therapy may provide a treatment option for selected Japanese patients with locally advanced or mRCC.