Efficacy of axitinib rechallenge in metastatic renal cell carcinoma

Abstract

DOI: 10.1111/iju.14529 Establishment of rechallenge treatment will result in increasing available regimens for late-line treatment in therapeutic strategies of mRCC. Recently, immune checkpoint inhibitors plus axitinib, which was shown to have a survival benefit in a randomized clinical trial, has been recommended as a first-line regimen in sequential therapy for mRCC. Thus, the utility of reAxi is of considerable interest. In the present study, we describe the clinical outcomes, including the therapeutic efficacy and toxicity of re-Axi. A total of 11 patients who were treated with axitinib in a rechallenge setting at Kobe University Hospital, Kobe, Japan, between May 2015 and December 2019 were enrolled. The induction dose of re-Axi was decided in consideration of the safety profile in i-Axi and performance status at the induction. Patients who tolerated the initial dose then progressed to dose escalation at the discretion of the treating physician. Dose reduction was used to manage uncontrollable toxicity. In both i-Axi and re-Axi, axitinib was administered orally in 4-week cycles until disease progression, unacceptable AEs or death. The treatment response to axitinib was evaluated by computed tomography at least once every 12 weeks and was classified according to the Response Evaluation Criteria In Solid Tumors 1.1. AEs were evaluated based on the Common Terminology Criteria for Adverse Events version 4.0. We used the Kaplan– Meier method to estimate PFS and overall survival. The study design was approved by the Research Ethics Committee of our institution (No. B190324), which was carried out in accordance with the Declaration of Helsinki. Informed consent to participate in the present study was obtained from all patients. The clinical characteristics of the 11 patients are summarized in Table S1. Re-Axi were administered at the fourth-line or later in all cases (maximum: seventh). As shown in Figure 1a, all patients who received i-Axi (PR, n = 5; and SD, n = 6) and 10 patients who received re-Axi (PR, n = 5; and SD, n = 5) showed a clinical benefit. Notably, although cases 2, 4, 8 and 9 showed SD with i-Axi, they achieved PR with re-Axi. The median PFS value with i-Axi and re-Axi were 11.7 months (95% CI 4.6–40.0; Fig. 1b) and 13.3 months (95% CI 6.9–not reached; Fig. 1c), and the median overall survival values with re-Axi were 21.8 months (95% CI 6.9–not reached; Fig. 1d), respectively. AEs of grade ≥3 are shown in Table S2. Although dose reduction was required due to AEs in nine of 11 patients with iAxi, none required any dose reduction, and AEs of grade ≥3 were observed in just four patients with re-AXi. Rechallenge of targeted therapy has been shown to be feasible in previous reports. Sunitinib, an anti-vascular endothelial growth factor receptor inhibitor, has been the most thoroughly examined agent for rechallenge treatment. In the REchallenge with SUnitinib in MEtastatic RCC Study, sunitinib rechallenge had an objective response rate of 15% and a median PFS of 7.9 months. Munarriz et al. reported that the objective response rate and median PFS of sunitinib rechallenge were 27.2% and 6.2 months, respectively. Although the efficacy of re-Axi remains unclear, some case reports and our cases with re-Axi showed a comparable efficacy to aforementioned the sunitinib rechallenge, suggesting that axitinib might be suitable in the rechallenge setting, like sunitinib. The safety of re-Axi was shown to be favorable in the present study. As re-Axi was able to be started at a tolerable dose based on the AE profile during i-Axi, none required dose reduction due to AEs, suggesting that predictable toxicity might be an advantage in rechallenge treatment. Similarly, rechallenge with other vascular endothelial growth factor receptor inhibitors, including sorafenib and sunitinib, has been reported to be well tolerated. However, given that axitinib is less likely to be associated with AEs than other targeted therapies in the initial administration, axitinib might be most suitable as a regimen for rechallenge treatment among targeted therapies in terms of tolerability. The study was a preliminary case series including a small number of patients with a relatively short follow-up duration. In addition, the treatment course between i-Axi and re-Axi varied among cases. Further prospective, large-scale studies will be required to validate the present results.