Abstract: Cabozantinib is an oral tyrosine-kinase inhibitor whose targets include VEGFR, MET, and AXL. Cabozantinib is approved for the treatment of patients with advanced clear-cell renal-cell carcinoma (RCC) who have received prior antiangiogenic therapy. In the pivotal Phase III trial of second-line RCC, cabozantinib was associated with a significant improvement in overall survival, progression-free survival, and antitumor response compared with everolimus. Adverse events (AEs) were common for patients receiving cabozantinib, but were effectively managed with supportive care and dose modifications, as discontinuations of cabozantinib due to an AE were infrequent. This article reviews the management of the more common AEs associated with cabozantinib based on findings from the pivotal study, clinical practice guidelines, and the authors’ real-world clinical experience, with support from published literature. We focus on hypertension, palmar–plantar erythrodysesthesia, diarrhea, nausea, vomiting, decreased appetite, fatigue, and stomatitis. Effective management of these AEs involves a multimodal strategy that includes patient education, prophylactic and supportive care, and dose modifications. Effective AE management can allow patients to maintain antitumor activity with cabozantinib while mitigating the impact on quality of life.

Keywords: cabozantinib, adverse-event management, renal-cell carcinoma, targeted therapy, tyrosine-kinase inhibitors  


In the US, an estimated 64,000 new cases of kidney cancer will be diagnosed in 2017, primarily composed of clear-cell renal-cell carcinoma (RCC).1 Until as recently as 2006, treatments for advanced RCC were limited to cytokines, including IFNα and IL2. These therapies were associated with considerable toxicity and showed limited efficacy.2 This led to the development of therapies, including tyrosine-kinase inhibitors (TKIs), that target the VEGF pathway, which drives angiogenesis and tumor growth.3–5 Clinical studies have demonstrated that sequential use of VEGF-pathway inhibitors is a feasible and effective approach to treatment,6–8 and is supported in treatment guidelines.9–11

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In 2016, the TKI cabozantinib was approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of patients with advanced clear-cell RCC who have received prior antiangiogenic therapy, and became a preferred second-line option for RCC in US and European treatment guidelines.9–13 Cabozantinib maintains VEGF-pathway inhibition but also targets MET and AXL, receptor tyrosine kinases that are overexpressed in RCC14–16 and have been shown to promote tumor-cell survival and resistance to VEGF-pathway inhibition.17–20 Approval of cabozantinib in RCC was based on efficacy and safety results from the Phase III METEOR study, where it improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) compared with everolimus in patients who had received prior antiangiogenic therapy.7,8 The safety and tolerability profile of cabozantinib was manageable: the majority of patients required dose modifications, but treatment discontinuations due to adverse events (AEs) were infrequent.

Given the recent approval of cabozantinib for RCC, it is timely to discuss strategies to manage the more common AEs associated with cabozantinib. In this article, we review the clinical outcomes from the pivotal Phase III METEOR trial7,8 and provide practical guidance to prepare patients for cabozantinib therapy. We propose management approaches for the more common AEs based on guidelines from cancer organizations, the literature on managing AEs associated with TKIs, and our own clinical experience.