Management of Adverse Events Associated with Cabozantinib Therapy in Renal Cell Carcinoma

This review reports on the safety profile of cabozantinib in patients with advanced renal cell carcinoma and offers guidance on the management of adverse events to maintain a positive balance between efficacy and safety of the product.

Abstract

Cabozantinib was recently approved for the treatment of advanced renal cell carcinoma (RCC) after treatment with vascular endothelial growth factor (VEGF)‐targeted therapy. Cabozantinib is a multikinase inhibitor targeting VEGF receptor (VEGFR) 2, mesenchymal‐epithelial transition receptor, and “anexelekto” receptor tyrosine kinase. A 60‐mg daily dose led to improved overall survival and progression‐free survival (PFS) versus everolimus in advanced RCC patients as a second‐ or later‐line treatment in the METEOR trial. Improved PFS with cabozantinib versus sunitinib has also been demonstrated in the first‐line setting in CABOSUN. However, cabozantinib, like other VEGFR inhibitors, is associated with toxicity that may affect the patient's quality of life. The most frequent adverse events (AEs) are diarrhea, fatigue, hypertension, hand‐foot syndrome, weight loss, nausea, and stomatitis. This article summarizes the safety profile of cabozantinib in RCC patients and offers guidance for the management of these AEs. We discuss the underlying mechanisms of these AEs and, based on our experiences with cabozantinib and other multikinase inhibitors, we present approaches to manage toxicity. Prophylactic and therapeutic solutions are available to help with the management of toxicity associated with cabozantinib, and adequate interventions can ensure optimum adherence and maximize patient outcomes.

Implications for Practice.

Cabozantinib leads to improved survival outcomes in renal cell carcinoma patients compared with everolimus. However, management of the adverse event profile is crucial to achieve optimum adherence and outcomes with the use of cabozantinib. This review aims to provide appropriate guidance that will minimize the impact of adverse events and help to maximize the utility of this agent in patients with advanced renal cell carcinoma.

Introduction

In clear‐cell renal cell carcinoma (RCC), a common finding is loss of function of the von Hippel‐Lindau tumor suppressor gene, which leads to the upregulation of hypoxia‐inducible factor‐responsive genes such as vascular endothelial growth factor (VEGF) [1], [2]. VEGF‐targeted and VEGF receptor (VEGFR)‐targeted agents block VEGFR receptor function and the downstream signaling pathway, which results in the inhibition of tumor angiogenesis [3]. Inhibiting this neovascularization via the VEGF signaling pathway results in tumor regression in animal models [4].

Several VEGF‐targeted and VEGFR‐targeted agents have been approved in a number of indications. However, targeting of the VEGF pathway can result in upregulation of mesenchymal‐epithelial transition factor (MET) expression, which may drive tumor invasiveness [5], [6], [7], [8], [9], [10]. The MET signaling pathway acts synergistically with VEGF to promote angiogenesis, tumor growth, and metastasis [9], [11], [12]. The anexelekto (AXL; meaning “uncontrolled”) gene is also upregulated in RCC and other cancers [13], and AXL may have a role in the development of secondary resistance to VEGF‐targeted agents [14]. High levels of AXL and MET expression in tumor tissue are associated with poor survival outcomes in RCC patients [15].

The knowledge of these pathways has led to the development of cabozantinib, a potent inhibitor of MET, VEGFR2 and AXL, with inhibitory concentration₅₀ values of 1.3, 0.035, and 7 nmol/L, respectively [5], [16], [17]. By targeting multiple pathways, cabozantinib blocks proliferation and metastatic escape pathways [18]. Simultaneous AXL and MET inhibition with cabozantinib overcame resistance induced by prolonged sunitinib therapy in preclinical models of metastatic RCC [15]. Moreover, cabozantinib inhibits other tyrosine kinases implicated in angiogenesis including FMS‐related tyrosine kinase 3 (FLT3) and stem cell growth factor receptor (KIT) [19], [20].

Cabozantinib has been assessed for efficacy in several solid tumors. In 2016, cabozantinib (tablet formulation) was approved in the U.S. for the treatment of patients with advanced RCC who have received prior antiangiogenic therapy. In the same year, cabozantinib received approval in the European Union (EU) for the treatment of advanced RCC in adults following prior VEGFR‐targeted therapy. Cabozantinib (capsule formulation) is also approved for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

Adverse events (AEs) associated with cabozantinib include diarrhea, fatigue, hypertension, dermatological manifestations such as hand‐foot syndrome (HFS), weight loss and decreased appetite, stomatitis, and nausea [21], [22], [23], [24], [25]. These AEs can have a negative impact on patients’ health‐related quality of life (HRQoL) and may require drug dose reductions or interruptions as a way to manage them [23], [25], [26].

The doses of cabozantinib studied in trials have differed depending on the indication. In this review, we discuss the safety profile of cabozantinib in patients with advanced RCC and offer guidance on the management of AEs to maintain a positive balance between efficacy and safety of the product. We focus this review on several of the most clinically relevant AEs such as diarrhea, fatigue, hypertension, and hand‐foot syndrome.

Methods

The PubMed database was searched in December 2016 using the following terms: “cabozantinib,” “XL184,” “XL 184,” “XL‐184,” and “BMS‐907351” without date limits or other limits applied to the search terms. We included publications reporting clinical trial data, pharmacokinetics, drug‐drug interactions, and safety data.

Results

From 352 unique references, 22 clinical trial publications that reported data on efficacy and safety, 14 publications on pharmacokinetics or drug interactions, and 6 miscellaneous reports on safety/toxicity were selected as being relevant for this review. Data from these publications are tabulated where relevant and discussed in clinical context. Recommendations were graded according to the Levels of Evidence developed by the Oxford Centre for Evidence‐Based Medicine (last updated March 2009) [27].

Overview of Clinical Trial Data

Pharmacokinetic Data.

Cabozantinib is available in two formulations: a capsule formulation (Cometriq [Exelixis, South San Francisco, CA], available as 20 and 80 mg) that is licensed for progressive metastatic MTC and a tablet formulation (Cabometyx [Exelixis, South San Francisco, CA], available as 20, 40, and 60 mg) that is approved for RCC [28]. The two formulations are not bioequivalent and therefore not interchangeable. At equivalent doses, the maximum plasma concentration (C_max) of the tablet formulation is 19% higher than the capsule formulation, but the area under the plasma concentration‐time curves (AUC) were similar with the two formulations [29]. In this review focusing on the RCC indication, we will discuss data obtained primarily with the tablet formulation.

Cabozantinib given as a tablet has a long plasma terminal half‐life of approximately 99 hours (in healthy volunteers and RCC patients) [30]. The AUC of cabozantinib given as a 60‐mg capsule is increased by 6% and 30% in patients with moderate or mild renal impairment, respectively, compared with people with normal renal function [31]; no data are available for the tablet formulation but the influence of renal impairment on cabozantinib pharmacokinetics is assumed to be formulation‐independent. Mild or moderate hepatic impairment increased the AUC of cabozantinib given as a 60‐mg capsule by 81% and 63%, respectively [31], and a similar effect of hepatic impairment on cabozantinib pharmacokinetics is assumed for the tablet formulation. In patients with hepatic impairment, both U.S. and EU labels recommend reducing the dose to 40 mg/day in case of mild‐to‐moderate impairment and not to use in case of severe impairment [30], [32]. In patients with mild‐to‐moderate renal impairment, the U.S. label recommends no dosage adjustment, whereas the EU label recommends caution [30], [32]. No experience is available in patients either with severe renal impairment or on dialysis, or in patients with severe hepatic impairment [30], [32].

In healthy individuals, when cabozantinib capsules were taken with a high‐fat meal, the time to reach maximum concentration was delayed by 2 hours, the C_max was increased by 41%, and the AUC was increased by 57% [33]. Concomitant drug use can also affect the pharmacokinetics of cabozantinib. Cabozantinib is primarily metabolized by cytochrome P450 (CYP) 3A4. Coadministration of the CYP3A4 inducer rifampicin results in a 77% decrease in the AUC of cabozantinib in healthy volunteers. Likewise, cotreatment with the CYP3A4 inhibitor ketoconazole results in a 38% increase in the cabozantinib AUC [34]. Caution is therefore required when administering cabozantinib with strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, and protease inhibitors [30], [35]. Chronic administration of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, and enzalutamide with cabozantinib should be avoided [30], [35]. In preclinical models, cabozantinib also inhibits CYP2C8 (Ki_app 4.6 µM), but the C_max and AUC of the CYP2C8 substrate rosiglitazone were not significantly changed when coadministered with cabozantinib [34]. Cabozantinib solubility is pH dependent, but coadministration of the proton pump inhibitor (PPI) esomeprazole had no effect on the cabozantinib AUC [33]. Therefore, PPIs or gastric pH‐altering agents are not contraindicated with cabozantinib and no dose adjustment is indicated [30]. Cabozantinib at a dose of 40 mg/day has also been tested in a phase I trial in patients with glioblastoma, and no pharmacokinetic interactions with temozolomide were observed in this setting [36].

Efficacy Data.

Cabozantinib has been clinically assessed in several cancers including RCC [22], [23], [37], MTC [21], [38], prostate cancer [24], [39], non‐small cell lung cancer [40], [41], breast cancer [42], multiple myeloma [43], pancreatic cancer [44], and hepatocellular carcinoma [45]. Results from three phase III trials, in RCC, MTC, and prostate cancer, have been published [21], [22], [23], [24].

In the 658 advanced RCC patients recruited in the METEOR trial who had progressed after VEGFR‐targeted therapy, cabozantinib 60 mg/day was compared with everolimus 10 mg/day [22], [23]. Median progression‐free survival (PFS; the primary endpoint) was significantly longer (7.4 months) with cabozantinib than with everolimus (3.9 months; hazard ratio [HR] 0.51; 95% confidence intervals [CI] 0.41–0.62) [23]. Objective response rate (ORR) was 17% with cabozantinib and 3% with everolimus (p < .0001) [23]. Overall survival (OS) was significantly prolonged with cabozantinib (21.4 months) compared with everolimus (16.5 months; HR 0.66; 95% CI 0.53–0.83) [23]. A post‐hoc analysis of the 153 patients who had received previous sunitinib treatment estimated a median PFS of 9.1 months (95% CI 5.6–11.2) with cabozantinib and 3.7 months (95% CI 1.9–4.2) with everolimus [22].

Cabozantinib has also been evaluated as first‐line treatment in advanced or metastatic RCC in the CABOSUN randomized phase II study, which included patients with Eastern Cooperative Oncology Group performance status 0–2 and intermediate or poor risk according to International Metastatic Renal Cell Carcinoma Database Consortium criteria. Median PFS was significantly improved with cabozantinib (8.2 months) compared with sunitinib (5.6 months; HR 0.66; 95% CI 0.46–0.95) in this setting [46]. ORR was 46% with cabozantinib and 18% with sunitinib [46]. Median OS was 30.3 months with cabozantinib and 21.8 months with sunitinib (HR 0.80; 95% CI 0.50–1.26) [46]. Although intriguing, these results derive from a relatively small phase II trial.

Safety Data from Cabozantinib Trials in RCC Patients.

The incidence of the most frequent AEs reported in the METEOR (data cut‐off date December 31, 2015) and CABOSUN (data cut‐off date April 11, 2016) trials in cabozantinib‐treated patients are summarized in Table 1 and Figure 1 (more detail can be found in the primary publications) [23], [46]. The incidence of AEs irrespective of causality in both groups of METEOR was 100% [23]. In the METEOR trial, grade 3 or 4 AEs occurred in 71% of cabozantinib patients and 60% of everolimus patients [23], and 62% and 25% patients had dose reductions in the cabozantinib and everolimus groups, respectively [23]. A total of 12% of cabozantinib patients and 11% of everolimus patients discontinued treatment because of an AE unrelated to disease progression [23]. In CABOSUN, there was a similar rate of all‐grade AEs with cabozantinib (99%) and sunitinib (99%) [46]. In CABOSUN, the incidence of grade 3 or 4 AEs was 67% with cabozantinib and 68% with sunitinib [46]. A total of 58% and 49% of cabozantinib and sunitinib patients required dose reductions, respectively [46]. AEs led to treatment discontinuation in 20% and 21% of patients in the cabozantinib and sunitinib groups, respectively [46].

Table 1. Overview of the safety findings from the METEOR phase III trial (data cut‐off date December 31, 2015) [23] and the CABOSUN phase II trial (data cut‐off date April 11, 2016) [46] of cabozantinib (most frequent events in the cabozantinib arm of these studies).

Adverse events reported here are those with a frequency ≥20% in the cabozantinib arm for the METEOR trial and with a frequency ≥30% in either study group for the CABOSUN trial. Adverse events with a frequency ≥20% in the everolimus arm of METEOR or ≥30% in the sunitinib arm of CABOSUN but with a frequency <20% in the cabozantinib arm of METEOR or <30% in the cabozantinib arm of CABOSUN have been excluded here.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cabo., cabozantinib; Comp., comparator; mRCC, metastatic renal cell carcinoma; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.

Figure 1.

Frequency of all‐grade adverse events in the METEOR trial (data cut‐off date December 31, 2015) [23] (A) and in the CABOSUN trial (data cut‐off date April 11, 2016) [46] (B). Shown are the most frequent events in the cabozantinib arm of these studies. Adverse events reported here are those with a frequency ≥20% in the cabozantinib arm for the METEOR trial and with a frequency ≥30% in either study group for the CABOSUN trial. Adverse events with a frequency ≥20% in the everolimus arm of METEOR or ≥30% in the sunitinib arm of CABOSUN but with a frequency <20% in the cabozantinib arm of METEOR or <30% in the cabozantinib arm of CABOSUN have been excluded here. In METEOR, a total of 12% of cabozantinib patients and 11% of everolimus patients discontinued treatment because of an adverse event unrelated to disease progression. In CABOSUN, adverse events led to treatment discontinuation in 20% and 21% of patients in the cabozantinib and sunitinib groups, respectively.

This article focuses on the most frequently occurring AEs that are likely to be encountered routinely. We will provide an explanation of this safety profile and recommendations for the optimal management of AEs associated with cabozantinib therapy.

Management of Adverse Events Associated with Cabozantinib Therapy

Most of the AEs reported with cabozantinib can be ascribed to VEGFR inhibition and are consistent with the AEs observed with other VEGFR tyrosine kinase inhibitors (TKIs). An awareness of the mode of action can help the physician anticipate potential drug interactions, and an appreciation of the most common AEs can focus evaluation of past and current medical conditions that could be affected by cabozantinib‐related toxicity. Table 2 summarizes the most frequent AEs in the cabozantinib arm and recommendations for their management.

Table 2. Management of adverse events with cabozantinib in renal cell carcinoma patients.

Abbreviations: LoE, Level of Evidence; NA, not applicable.

Diarrhea.

Diarrhea occurred in 75% and 72% of patients receiving cabozantinib in the METEOR and CABOSUN trials, respectively (Fig. 1A and 1B) [23], [46]. In the METEOR and CABOSUN trials, 13% and 10% of patients had diarrhea of grade 3 or worse, respectively (Table 1) [23], [46]. Diarrhea was severe enough to result in cabozantinib dose reductions in 16% of patients (when the starting dose was 60 mg/day) [22]. This AE affects a sizeable proportion of patients, and needs to be recognized early and managed appropriately.

Diarrhea was severe enough to result in cabozantinib dose reductions in 16% of patients (when the starting dose was 60 mg/day). This AE affects a sizeable proportion of patients, and needs to be recognized early and managed appropriately.

Diarrhea may be a more frequent AE with multikinase inhibitors than when the VEGF pathway alone is inhibited. However, VEGF and VEGFR are highly expressed in the intestines [47], [48]; therefore, VEGF pathway inhibition may have a predominant role in the development of this AE during cabozantinib treatment. KIT inhibition may also provide a mechanism for diarrhea [49]. In metastatic triple negative breast cancer patients, cabozantinib was reported to have immunomodulatory effects, with a notable increase in CD8+ T lymphocytes and CD14+ monocytes, which could also contribute to diarrhea [42].

General approaches to the management of diarrhea include measures such as avoidance of foods that may cause bowel movements [50]. Consumption of grated oxidized apples [51], 90% cocoa chocolate, carob powder [52], clay [53] and dried blueberries (personal communication) may help reduce bowel movements, and probiotics have been shown to reduce the incidence of diarrhea induced by chemotherapy [54]. Several drugs, such as loperamide, may also be used to slow intestinal transit and thus reduce the risk of diarrhea [55]. None of the management options for diarrhea have been tested for effectiveness in patients receiving cabozantinib, and the approach may depend upon the physician and patient's preference. However, the general guidance for the management of diarrhea during cancer chemotherapy may be employed in this circumstance [56]. Likewise, guidelines for the treatment of diarrhea induced by specific anticancer agents (e.g., lapatinib) could also be used [57]. As diarrhea might to some extent be caused by an exocrine pancreatic insufficiency, medical replacement of pancrelipase should be considered, particularly in patients who report fatty stools and bowel movements during the meal or shortly afterwards [58], [59].

Fatigue.

Fatigue was reported at a frequency of 59%, with grade 3 fatigue affecting 11% of patients receiving cabozantinib in the METEOR trial [23] (Table 1; Fig. 1A). Fatigue also occurred with a high frequency in the cabozantinib arm of CABOSUN, with 86% reporting fatigue at any grade and 6% reporting fatigue at grade 3 [46] (Fig. 1B). The 60 mg/day dose of cabozantinib was reduced due to fatigue in 10% of patients in the METEOR trial [22].

Fatigue is associated with many patient‐specific factors, tumor types and classes of anticancer treatment, and is a frequently observed AE with all VEGFR inhibitors [58], [60]. A recent systematic review suggested that five recently approved multikinase inhibitors (including cabozantinib) all increased the risk of all‐grade and high‐grade fatigue in cancer patients (relative risk of 1.43 [95% CI 1.23–1.66] and 1.97 [95% CI 1.44–2.70], respectively) [60]. The association between FLT3 inhibition and severe fatigue in acute myeloid leukemia [61], [62] provides indirect evidence for a potential mechanism for the fatigue observed with cabozantinib treatment. Fatigue with cabozantinib can also be ascribed to genomic, psychological or lifestyle factors, which are inherent to the individual patient. Interleukin 6 polymorphisms were associated with fatigue, and a genetic association between tumor necrosis factor‐α and sleep disturbances was also reported [63], [64]. In cancer patients, distinguishing between depression and fatigue is challenging, as fatigue can be caused by depression, which may require treatment with antidepressants [65]. Physical inactivity and increased body mass index have been reported to be predictors of fatigue [66]. Cancer itself is also considered as a trigger for fatigue due to tumor‐generated chronic inflammation [67], which can result in sickness behavior [68]. The potential increase in the incidence of hypothyroidism and hypophosphatemia with cabozantinib may contribute to fatigue in many patients. In addition, weight loss and loss of appetite are frequent AEs with cabozantinib and these, along with dehydration following diarrhea, may contribute to the high incidence of fatigue.

As with diarrhea, management of fatigue should involve nonpharmacological interventions. Aerobic exercise significantly reduces fatigue associated with cancer [69], and may therefore be useful in cabozantinib recipients who are fit enough to exercise. However, due to the advanced nature of the cancer when second‐line cabozantinib is prescribed, this approach may not be feasible for many patients. In male patients with severe fatigue, assessment of testosterone levels should be performed. TKIs were shown to induce hypotestosteronemia, which is clinically associated with fatigue and asthenia [70]. If testosterone deficiency is confirmed, replacement therapy should be considered. Hypothyroidism should be corrected if necessary. Infliximab and etanercept were reported to reduce fatigue in other conditions, such as breast cancer and psoriasis [71], [72], but there are no data on the use of these agents in RCC patients receiving cabozantinib. The most recent Cochrane review of treatment for cancer‐related fatigue (including VEGF inhibitor‐induced fatigue) was published before the availability of data on cabozantinib [73]. Based upon data from five studies in patients with a variety of cancers, the authors of this review suggested that psychostimulant drugs, such as methylphenidate, may be effective in improving cancer‐related fatigue [73]. However, using pharmacological treatment for fatigue management may be expensive, and is challenged by unknown drug interactions.

Hypertension.

Hypertension was reported at a frequency of 37% in the cabozantinib arm of the METEOR trial, and 15% of patients had grade 3 or higher hypertension (Table 1; Fig. 1A) [23]. A total of 81% of patients in the CABOSUN trial reported hypertension, with grade 3/4 hypertension having an incidence of 28% (Table 1; Fig. 1B) [46]. A meta‐analysis of phase II and III trials of cabozantinib (in various indications) reported an increased risk of all‐grade hypertension and high‐grade hypertension [74], but even high‐grade hypertension may not increase treatment withdrawals among patients receiving cabozantinib [24].

Hypertension is observed with all VEGF pathway inhibitors, and is likely linked to a decrease in nitric oxide (NO) leading to vasoconstriction [75], [76]. The VEGF pathway activates endothelial NO synthase (eNOS) [77], [78], and the inhibition of the VEGF pathway was reported to reduce the endothelial expression of eNOS in the kidney [76]. Other VEGFR‐inhibition‐related mechanisms may contribute to hypertension, such as the inhibition of the vasodilator prostacyclin [79]. TKIs can induce hypothyroidism, which can lead to increased diastolic blood pressure [58].

Regular monitoring of blood pressure is essential for patients receiving cabozantinib, potentially with the aid of home monitoring, but guidance is needed on the optimum frequency of such monitoring [58]. Thresholds for initiating antihypertension treatment and the choice of treatment, according to underlying cardiovascular comorbidities, should generally follow guidelines on the management of hypertension. However, nondihydropyridine calcium‐channel blockers that inhibit CYP3A4 should be avoided. When the underlying cardiovascular comorbidity does not drive the choice of antihypertensive agent, angiotensin‐receptor blockers may be the antihypertensive agent of choice because these have been shown to inhibit angiotensin II‐mediated growth and migration of cancer cells and angiogenesis [80]. The angiotensin‐receptor blocker losartan stimulated pro‐apoptotic signaling pathways regardless of the p53 mutation status in pancreatic cancer [81], and similar results were obtained in various tumor types [82]. In addition, beta‐blockers were shown to induce apoptosis in endothelial cells [83]; therefore, these agents may also be of value for reducing hypertension induced by VEGF pathway inhibitors.

Hand‐Foot Syndrome.

HFS (palmar‐plantar erythrodysesthesia) is a potentially painful dermatological condition that was reported at a frequency of 43% in the cabozantinib arm of the METEOR trial; 8% of patients had grade 3 or higher HFS (Table 1; Fig. 1A) [23]. The 60 mg/day dose of cabozantinib was reduced due to HFS in 11% of patients [22]. In the CABOSUN trial, 42% of patients experienced HFS, with 8% of patients reporting grade ≥3 HFS (Fig. 1B). A meta‐analysis of 831 patients who had received cabozantinib suggested an approximate overall incidence of HFS of 35% and an incidence of grade 3 HFS of 10% [25]. When HFS occurs during cabozantinib treatment, dose reduction or interruption may be required, especially if the AE is grade 3 or higher [25], [84]. Although HFS does not appear to directly affect survival, the dose modification or interruption it leads to could potentially limit the antitumor effect [85].

The mechanisms of HFS development are not known, but other TKIs such as sunitinib and sorafenib induce this AE [46], [86], [87]. Hypothetical mechanisms explaining the occurrence of HFS with cabozantinib include interference of pericyte‐mediated endothelial survival mechanisms leading to damage to the capillary endothelium in the hands and feet [88]. KIT inhibition is also thought to mediate HFS because it is strongly expressed in the ductal epithelium of eccrine glands [89] where the drug can be excreted [58].

General management of HFS in patients treated with VEGF pathway inhibitors has been reviewed [84]. Specific recommendations for the management of HFS caused by sorafenib and sunitinib have also been published [85]. Prophylactic measures include pedicure to remove hyperkeratosis, use of emollients, topical exfoliation, and protection of pressure‐sensitive areas. For low‐severity cases of HFS, the use of urea cream and clobetasol cream, and analgesics if pain control is needed, may be sufficient to manage the AE [25]. Urea cream is recommended as a prophylactic measure with usage from the first day of cabozantinb treatment [84]. Patient education is also important so that patients can proactively detect and help manage HFS, thus preventing or reducing its severity [90].

Nausea.

Nausea occurred at a frequency of 53% in the cabozantinib arm of the METEOR trial, and 5% of patients had grade 3 nausea (Table 1; Fig. 1A) [23]. This AE was present in 32% of patients treated with cabozantinib in the CABOSUN trial and 3% of patients had grade 3 nausea (Table 1; Fig. 1B) [46].

Although there is no evidence‐based recommendation for the management of nausea induced by cabozantinib, metoclopramide and ondansetron used for the management of nausea with cytotoxic chemotherapy could be used in this setting. The potential effects of ondansetron on QT prolongation [91] and the potential drug interaction between cabozantinib and ondansetron should be considered [92]. Marijuana drops for nausea could also be considered [93]. Treating nausea may help patients with decreased appetite (see below).

Weight Loss and Decreased Appetite.

Weight loss and decreased appetite are also observed in patients treated with cabozantinib. In the METEOR trial, 35% of patients had weight loss and 47% of patients had loss of appetite (Fig. 1A) [23]. Up to 3% of patients had grade 3 loss of weight or appetite (Table 1) [23]. In CABOSUN, 32% of patients experienced weight loss and 4% of patients had grade 3 weight loss (Table 1; Fig. 1B) [46].

Weight loss is a frequently observed phenomenon in patients with different tumor types. A speculative mechanism accounting for weight loss in oncology patients includes an interplay between cytokines, tumor products inducing lipolysis and protein degradation, and neuropeptides [94], [95]. Conflicting results on the effect of cytokines on weight were reported, with studies showing no association between cytokines and weight loss in patients [96], and studies in animals showing reduced food intake after cytokine administration [97].

There is limited information on the weight maintenance strategies among patients receiving cabozantinib. Agents that help patients dealing with anorexia, or who need to gain weight and increase appetite, such as medroxyprogesterone acetate, could be assessed in this setting [98]. Appetite loss may be associated with nausea. Management approaches discussed above for nausea could improve appetite in some circumstances.

Stomatitis.

Stomatitis occurred in 22% of patients in the cabozantinib arm of the METEOR trial, but only 2% of patients have this AE at grade 3 (Table 1; Fig. 1A) [23]. Dysgeusia, reported at a frequency of 24% in METEOR, is often associated with stomatitis in patients receiving cabozantinib [23]. Oral mucositis and dysgeusia were reported at a frequency of 36% and 41% in CABOSUN, respectively (Fig. 1B) [46]. A few patients (5.1%) experienced grade 3 or 4 oral mucositis [46]. These AEs infrequently necessitate dose reduction or temporary cessation of cabozantinib [24] but are likely to have an impact on patient quality of life.

Stomatitis induced by targeted agents differs from chemotherapy‐induced stomatitis. The presentation of stomatitis is also different with different TKIs [58]. The mechanism of drug‐induced stomatitis is not known but may relate to a reduction in the capillaries in the tongue induced by VEGFR inhibition or other effects such as oral and gut flora changes.

Good oral hygiene and diet control (e.g., avoidance of spicy food) may help control stomatitis [99]. There are no data to support any particular management strategy of stomatitis in patients receiving cabozantinib; therefore, previously suggested prophylactic agents [100] or treatments [99] may be worth assessing in this situation. Olive oil mouthwash and sucralfate mouthwash can be used prophylactically. Doxycycline mouthwash (two tablets dissolved in 250 mL water) and triamcinolonacetonide ointment are other potential treatment options [101].

Other Clinically Important Adverse Events.

Gastrointestinal (GI) perforations are rare AEs in RCC patients receiving a VEGF pathway‐targeted inhibitor [102]. This AE was not reported in the publications of METEOR or CABOSUN either because it had a frequency <10% and <30%, respectively, or it was not observed during the trials [22], [46]. GI perforations seem to occur in patients presenting with bowel comorbidities such as abdominal carcinomatosis, ulcer, bowel tumor necrosis, or prior abdominal or pelvic radiotherapy [103]. Close monitoring with frequent radiographic evaluations when patients present with an increased risk is the main prophylactic recommendation [104]. Treatment discontinuation is recommended when GI perforation occurs [58].

Any‐grade hypothyroidism occurred in 23% of patients in the cabozantinib arm of the METEOR trial [23]. The frequency of hypothyroidism was not reported in the CABOSUN trial [46]. Hypothyroidism with VEGFR inhibitors can be mediated by on‐ and off‐target inhibition, the latter being more speculative [58]. Guidelines recommend replacement with thyroxine in patients with thyroid‐stimulating hormone >10 mIU/L [105]. Interestingly, hypothyroidism was reported to have an antitumoral effect, possibly due to proliferative and proangiogenic properties of T4 [106], [107]. However, T3 depletion may cause cardiac AEs [107]. Hormone replacement therapy for hypothyroidism is therefore necessary. An innovative, personalized approach would consist of administering a combination of T3 and T4 with an optimal T4/T3 ratio [108].

Any‐grade anemia was experienced by 19% of patients in the cabozantinib arm of the METEOR trial and 33% of patients in CABOSUN [23], [46]. Grade 3 or higher anemia was observed in 6% and 1% of patients in METEOR and CABOSUN, respectively [23], [46]. Generally, myelotoxicity with TKIs has been ascribed to the inhibition of the KIT receptor [109]. To detect and manage myelotoxicity, a blood cell count every 2 weeks may be appropriate, although this would depend on the degree of blood cell production suppression. If grade 3 myelotoxicity reoccurs, dose reduction is recommended after recovery [110].

Conclusion

Direct evidence to support management approaches specific for cabozantinib‐associated AEs is limited, and the discussion in this review aims to help with this process and provide guidance based on clinical experience. Cabozantinib has proven benefits in RCC and MTC, with the potential to improve patient outcomes in other cancers. However, as with many other multitarget TKIs, the AEs need to be carefully managed to ensure treatment adherence and avoid a negative impact on patients’ quality of life. The safety profile of cabozantinib can lead to treatment interruptions and/or dose reductions, which emphasizes the need to understand and manage these AEs. Nevertheless, dose reductions do not appear to impact on the overall positive outcome of this therapy in RCC.

The safety profile of cabozantinib can lead to treatment interruptions and/or dose reductions, which emphasizes the need to understand and manage these AEs. Nevertheless, dose reductions do not appear to impact on the overall positive outcome of this therapy in RCC.

VEGFR inhibition explains the mechanism for some of the AEs associated with cabozantinib, and which are common to all VEGFR inhibitors. However, inhibition of other targets of cabozantinib including KIT may contribute toward some of the more frequent AEs such as diarrhea. Awareness of the safety profile coupled with careful monitoring and proactive supportive measures may reduce the need for dose reduction or treatment interruptions.

Author Contributions

Conception/design: Manuela Schmidinger, Romano Danesi

Manuscript writing: Manuela Schmidinger, Romano Danesi

Final approval of manuscript: Manuela Schmidinger, Romano Danesi

Disclosures

Manuela Schmidinger: Pfizer, Novartis, Roche, Ipsen, Exelixis, Bristol‐Myers Squibb, Astellas, Eisai (C/A, H); Romano Danesi: Roche, Bristol‐Myers Squibb, Merck Sharp & Dohme, Celgene, Janssen‐Cilag, Sanofi‐Genzyme (C/A, H).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board