Cabozantinib: A narrative drug review

Abstract

Cabozantinib is a tyrosine kinase inhibitor that has been approved as therapy for several solid tumors, including metastatic renal cell carcinoma, hepatocellular carcinoma, and differentiated thyroid cancer. To prepare this review, we comprehensively searched various websites, including the United States Food and Drug Administration, the European Medicine Agency Drug Manual, PubMed, Science Direct, and UpToDate using the search terms, “cabozantinib,” “renal cell carcinoma,” “hepatocellular carcinoma,” “differentiated thyroid cancer,” and “medullary thyroid cancer.” We shortlisted all the full-text articles published between 2011 and 2022. Out of a total of 788 manuscripts identified, we included 52. This review of cabozantinib details the pharmacodynamics, pharmacokinetics, clinical indications, adverse effects, safety, and the key research trials that investigated the use of cabozantinib. We have discussed the available clinical trial data and real-world outcomes, both with respect to the efficacy and safety of cabozantinib.

INTRODUCTION

Receptor tyrosine kinases are essential for the regulation of cellular processes, including metabolism, proliferation, survival, and migration. Genetic alterations can lead to abnormal receptor tyrosine kinase signaling, which results in tumor growth and metastasis in multiple cancer types by promoting angiogenesis, proliferation, and resistance to apoptosis. Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) play a critical role in cancer pathogenesis and are targeted by inhibitors or antibodies to the receptors of VEGF.

Cabozantinib is a small molecule kinase inhibitor that targets several receptor tyrosine kinases that are implicated in tumor development, angiogenesis, pathologic bone remodeling, drug resistance, and metastatic progression.^[1–3]

In this review, we discuss the chemistry, pharmacokinetics, drug interactions, clinical indications, safety profile, and key trials of cabozantinib in an attempt to give readers a clear understanding of the drug. Table 1 summarizes the key details of cabozantinib.

Table 1: Key features of cabozantinib

METHODS

For this review, we searched for clinical and observational studies of cabozantinib in patients with solid tumors. We searched for relevant articles using various sources, including the United States Food and Drug Administration (US FDA), European Medicines Agency Drug Manual, PubMed, Google Scholar, and UpToDate. We used the search terms, “renal cell carcinoma,” “RCC,” “hepatocellular carcinoma,” “HCC,” “metastatic medullary thyroid cancer,” “differentiated thyroid cancer,” “MTC,” and “cabozantinib” to identify relevant articles published between 2011 and 2022. In addition, we conducted an extensive online search using Google to identify any ongoing clinical trials of cabozantinib. We included 52 articles for this review [Figure 1].

Figure 1: Flow diagram depicting the methodology followed to identify the articles for the cabozantinib drug review (US FDA: United States Food and Drug Administration; EMA: European Medicines Agency)

HISTORY

Cabozantinib is a compound that is inherently active against several receptor tyrosine kinases. It was discovered and developed by Exelixis Inc., California, USA.^[4,5] Cabozantinib was first studied in murine cancer models of breast, lung, medullary thyroid, and prostate cancer.^[5] It was found to inhibit the MET protein, which is a receptor for the hepatocyte growth factor.^[6] On November 29, 2012, cabozantinib received FDA approval for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).^[7,8] On April 25, 2016, it was approved for the treatment of advanced renal cell carcinoma (RCC) in patients who had received prior anti-angiogenic therapy.^[8,9] On January 22, 2021, the FDA approved the combination of cabozantinib with nivolumab for the treatment of advanced RCC.^[10] Cabozantinib was also approved by the FDA on September 17, 2021, for the treatment of adult and pediatric patients (12 years and older) with locally advanced or metastatic differentiated thyroid cancer that had progressed on VEGF-targeted therapy and was refractory to or ineligible for radioactive iodine.^[9]

CHEMISTRY

The chemical structure of cabozantinib-s-malate (molecular formula: C₂₈H₂₄FN₃O₅·C₄H₆O₅, and molecular weight: 635.6 Daltons) consists of a pyridine ring with a fluorine atom and a 3-(morpholin-4-yl) propoxy group attached to it, as well as a 3-aminopyridine-2-carboxamide group and a 4-(6-(propan-2-yl) pyridin-3-yl) benzoic acid group [Figure 2]. The malic acid salt forms a crystalline solid with a white to almost white color.^[8]

Figure 2: Chemical structure of cabozantinib

PHYSICAL PROPERTIES

Cabozantinib-s-malate is available in the form of film-coated tablets for oral use. The tablets come in three different strengths: 20 mg, 40 mg, and 60 mg. Each tablet contains an amount of cabozantinib-s-malate that is equivalent to 25, 51, or 76 mg, respectively. The tablets are colored white to off-white and are practically insoluble in water.^[8]

MECHANISM OF ACTION

Cabozantinib broadly inhibits various receptor tyrosine kinases, interrupting tumor growth and progression through multiple mechanisms. Cabozantinib’s multi-kinase inhibition can lead to several downstream effects. For example, the inhibition of MET can reduce cell proliferation, survival, and migration.^[6] Furthermore, cabozantinib’s inhibition of VEGFR2 can reduce angiogenesis, a process of forming new blood vessels to supply tumors with nutrients and oxygen.^[6] The inhibition of AXL can reduce drug resistance and metastasis. In addition, the inhibition of RET and KIT can affect the growth of medullary thyroid carcinoma.^[5] Cabozantinib inhibits other tyrosine kinases including GAS 6, receptor AXL, RET, ROS1, TYRO 3, MER, KIT, FLT3, and TIE 2.^[1,2,5,6]

DOSAGE

Dosing in approved situations

Cabozantinib capsules are approved for the treatment of metastatic MTC, and the tablet formulation is approved for metastatic RCC, hepatocellular carcinoma (HCC), and differentiated thyroid cancer.

• Metastatic MTC: 40 mg per day^[9,11,12]
• 1. The recommended dose reduction of cabozantinib for toxicities is provided in Table 2.
• Differentiated thyroid cancer: 60 mg per day^[13]
• Metastatic RCC
• 1. Single agent: 60 mg per day^[14,15]
  2. Combination with nivolumab: 40 mg per day^[16]
• HCC: 60 mg per day^[17]

Table 2: Cabozantinib dose reduction schedule for thyroid cancer grade 4 hematological toxicity or ≥grade 3 or intolerable grade 2 non-hematological toxicity

Dose modifications for adverse reactions

Upon resolution/improvement (i.e. return to baseline or resolution of the toxicity to Grade 1) of an adverse reaction, reduce the dose as follows:

• If previously receiving 60 mg daily dose, resume treatment at 40 mg daily.
• If previously receiving 40 mg daily dose, resume treatment at 20 mg daily.
• If previously receiving 20 mg daily dose, resume at 20 mg if tolerated, otherwise, discontinue.

Permanent discontinuation

Permanently discontinue in case of occurrence any of the following:

• Severe hemorrhage
• Development of gastrointestinal (GI) perforation or unmanageable fistula
• Serious thromboembolic event (e.g, myocardial infarction, cerebral infarction)
• Hypertensive crisis or severe hypertension despite optimal medical management
• Nephrotic syndrome
• Reversible posterior leukoencephalopathy syndrome

^{Dose modifications in case cabozantinib is being co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor[8,9]}

• Reduce the daily dose by 20 mg (e.g, from 60 to 40 mg daily, or from 40 to 20 mg daily).
• Resume the dose that was used prior to initiating the strong CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.

Dose modifications for co-administration with strong CYP3A4 inducers

• Increase the daily dose by 20 mg (e.g, from 60 to 80 mg daily, or from 40 to 60 mg daily), as tolerated.
• Resume the dose that was used prior to initiating the strong CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.
• Do not exceed a daily dose of 80 mg.

ADMINISTRATION AND THE EFFECT OF FOOD

Cabozantinib should be taken on an empty stomach, at least 2 hours (h) before or after eating, because taking it with food might increase its maximum concentration (C_max) and area under the curve (AUC). As compared to the fasting state, high-fat meals can raise the C_max and AUC by 41% and 57%, respectively.^[8,9,18] It is therefore recommended to avoid high-fat meals when taking cabozantinib. If the cabozantinib dose has been missed, it should not be taken within 12 h of the following planned dose.^[8,9] Cabozantinib should not be used with foods or nutritional supplements known to influence CYP3A4 substrates, such as grapefruit juice or St. John’s wort.^[8,9]

ABSORPTION

After oral administration, the peak cabozantinib plasma concentration is attained by 3 to 4 h. The plasma concentration shows a second peak at about 24 h due to enterohepatic circulation.^[8,9]

Repeat daily dosing of a cabozantinib capsule formulation for 19 days resulted in a four- to five-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by day 15.^[8,9]

DISTRIBUTION

Cabozantinib has a high degree of protein binding in human plasma, with more than 99.7% of the drug being bound to plasma proteins in vitro.^[8,9] There are, however, only minimal data available regarding the link between hypoalbuminemia and cabozantinib tolerability.

METABOLISM

Cabozantinib is primarily metabolized by the liver enzyme CYP3A4.^[8,9] The drug is broken down into four different metabolites: XL184 amide, XL184-N-oxide, 6-desmethyl amide sulfate, and XL184 monohydroxy sulfate. These metabolites also interact with various enzymes and transporters in the body. For example, they are substrates for CYP3A4 and weakly compete with it for binding sites. They are also non-competitive inhibitors of CYP2C8, inhibitors of CYP2C9 and CYP2C19, and inducers of CYP1A1. Additionally, the metabolites inhibit P-glycoprotein (P-gp) transport, which is responsible for transporting drugs out of cells and can affect drug distribution and elimination.

ELIMINATION

Cabozantinib has a long elimination half-life of approximately 4.5 days, indicating slow elimination from the body. The mean clearance (CL/F) at steady state was estimated to be 2.5 liters every hour. Cabozantinib and its metabolites are primarily excreted via the feces (54%), with a smaller proportion excreted in the urine (27%).

SPECIAL CONSIDERATIONS

Older persons

No specific dose modification is required in patients who are older than 65 years.

Pediatric population

Safety and efficacy of cabozantinib in children below the age of 18 years have not been established yet. Cabozantinib should be consumed once daily for children aged 12 years and above. In patients who weigh less than 40 kg, weight-based dosing is recommended. In those who weigh over 40 kg, flat dosing of 60 mg orally once a day is recommended. This dose regimen produces plasma exposure comparable to that seen in adults who take 60 mg once a day.^[8,9]

Renal dysfunction

In a study that assessed the effect of renal impairment on cabozantinib, the C_max and AUC of the total plasma cabozantinib were 19% and 30% greater, respectively, in persons with moderate renal impairment, compared to that in those with normal renal function. C_max and AUC were only 2% and 6-7% higher, respectively, in individuals with mild renal impairment than in those with normal renal function. The geometric least square (LS) means for unbound plasma cabozantinib were also assessed in the study, which revealed that in persons with mild renal impairment, the AUC was 0.2% higher, while that in those with moderate renal impairment was 17% higher. Unfortunately, no data are available for patients with severe renal impairment.^[8,9,19]

Suggested dosing of cabozantinib, based on the renal function:

• Mild to moderate (creatinine clearance ≥30 mL/min): No dose adjustment required.
• Severe (creatinine clearance <30 mL/min): No data.

Hepatic dysfunction

In a single-dose trial, the pharmacokinetics of cabozantinib was compared between people with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment and those with normal hepatic function.^[8,9,19] There was no clinically meaningful difference in the mean cabozantinib plasma exposure between patients with normal hepatic function and those with mild or moderate hepatic impairment. Cabozantinib pharmacokinetics, however, have not been studied in people with severe hepatic impairment. Hence, extreme caution should be exercised while prescribing cabozantinib for patients with significant hepatic impairment.

Suggested dosing of cabozantinib in patients with hepatic impairment:

• Mild (Child-Pugh A): No dose adjustment required.
• Moderate (Child-Pugh B): Reduce the starting dose to 40 mg/day.
• Severe (Child-Pugh C): Avoid use.

Cardiac dysfunction

Based on the limited data available, there are no specific dose recommendations for cabozantinib in patients with cardiac dysfunction. Patients with a history of cardiac disease should be carefully monitored while taking cabozantinib. Any signs or symptoms of cardiac dysfunction, such as chest pain, arrhythmias, or shortness of breath, should be promptly reported to a healthcare professional. Close monitoring of cardiac function with regular assessment of the left ventricular ejection fraction and electrocardiogram may be necessary in certain patients.^[8,9]

Pregnancy, lactation, and fertility

The carcinogenicity of cabozantinib has been studied in murine species. An increased incidence of benign pheochromocytoma or in combination with malignant pheochromocytoma has been observed. In embryofetal developmental studies done in rats and rabbits, cabozantinib was noted to cause increased post-implantation loss, and congenital disorders like cleft palate, lip, dermal aplasia, and small or missing lung lobe.^[8,9]

There have been no studies on cabozantinib in pregnant women, although animal evidence suggests that it may affect embryos and fetuses. Female patients on cabozantinib, as well as female partners of male patients, should avoid becoming pregnant throughout therapy and for at least 4 months after discontinuing cabozantinib. To guarantee efficacy, two types of contraception should be employed, including oral contraceptives in conjunction with another type of contraception.^[8,9]

Cabozantinib has been shown to be present in lactating rat milk, but it is unknown whether it is excreted in human milk. Women should avoid nursing while on cabozantinib therapy and for at least 4 months after the last dose of cabozantinib.^[8,9]

Although there is no indication that cabozantinib affects human fertility, preclinical safety data suggest that the medicine may influence both male and female fertility.^[8,9,20]

DRUG INTERACTIONS

Cabozantinib is metabolized by CYP3A4 and is also a substrate for the multi-drug resistance protein 2 (MRP2). CYP3A4 inhibitors can increase the plasma concentration of cabozantinib, while CYP3A4 inducers can decrease its level. Hence, concurrent administration of cabozantinib with strong CYP3A4 and MRP2 inhibitors can increase the plasma concentration, while strong inducers can reduce the levels of cabozantinib.^[8,9] Therefore, concurrent use of cabozantinib with such inhibitors should be avoided. Gastric pH modifying agents do not have any clinically significant consequences on the plasma concentration of cabozantinib. It should be noted, however, that individuals with genetic galactose intolerance, complete lactase deficiency, or glucose-galactose malabsorption should not consume cabozantinib as the tablet contains lactose.^[8,9]

CLINICAL INDICATIONS

The key clinical trials of cabozantinib are summarized in Table 3.

Table 3: Summary of trials that have evaluated the utility of cabozantinib

1) Renal cell carcinoma

1. Relapsed RCC (METEOR)
This was a multicenter, randomized, open-label phase III trial that included 658 patients with clear cell RCC who had previously received at least one VEGFR tyrosine kinase inhibitor. Patients were randomly assigned to either cabozantinib (330 patients) or everolimus (328 patients). In an unplanned interim analysis, the authors reported that the median overall survival (OS) was 21.4 months for cabozantinib, compared to 16.5 months for everolimus; hazard ratio [HR], 0.66 (95% confidence interval [CI]: 0.56-0.83), P < 0.001. The median progression-free survival (PFS) was also longer for cabozantinib at 7.4 months compared to 3.8 months for everolimus; HR, 0.58; 95% CI, 0.45-0.74; P < 0.001.^[14,30]

2. Treatment-naïve RCC, as a single agent (CABOSUN)
The CABOSUN trial was a multicenter, randomized, open-label phase II trial that included 157 patients with previously untreated, locally progressive, or metastatic RCC with a clear cell component. The patients were randomized to either cabozantinib (n = 79) or sunitinib (n = 78) in a 1:1 ratio. The study’s primary endpoint was PFS, with secondary endpoints including OS, objective response rate (ORR), and safety. Cabozantinib significantly increased the PFS over sunitinib, with a median PFS of 8.2 months in the cabozantinib arm versus 5.6 months in the sunitinib arm; HR, 0.48; 95% CI, 0.31-0.74; P < 0.001. The ORR was also higher in the cabozantinib group (20%) compared to that in the sunitinib group (9%); P < 0.001. However, there was no significant difference in OS between the two groups (HR, 0.80, P = 0.227). Both cabozantinib and sunitinib led to adverse events (grade 3 and higher in 68% of cabozantinib-treated patients versus 65% of sunitinib-treated patients); however, the spectrum and frequency of adverse events differed between the two groups. Cabozantinib commonly caused grade 3-4 hypertension, diarrhea, transaminase elevation, and fatigue, whereas sunitinib resulted in grade 3 and higher fatigue, thrombocytopenia, and diarrhea. Overall, CABOSUN proved that cabozantinib outperformed sunitinib in terms of PFS and ORR in patients with previously untreated, locally progressive, or metastatic RCC with a clear cell component.^[16]

3. Treatment-naïve RCC, as part of a combination regimen (CheckMate 9ER)
CheckMate 9ER was a randomized phase III study comparing the combination of cabozantinib and nivolumab to sunitinib in patients with previously untreated advanced or metastatic RCC with intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria.^[31] A total of 651 patients were randomized to either cabozantinib 40 mg once daily orally in conjunction with nivolumab 240 mg (n = 323) intravenously every two weeks or sunitinib 50 mg (n = 328) daily taken orally for 4 weeks followed by 2 weeks off. The study demonstrated that, regardless of the patient’s risk group, the combination of cabozantinib and nivolumab was more efficacious than sunitinib in advanced RCC and led to better PFS, OS, ORR, and QOL. Median PFS for the patients treated with cabozantinib plus nivolumab combination was 16.6 versus 8.3 months; HR, 0.56; 95% CI, 0.46-0.68; P < 0.001 over 32.9 months of follow-up.^[23]

4. Real-world studies in the second line and beyond setting
Multiple real-world studies have been carried out in patients with advanced or metastatic RCC, with a range of histologies, including mixed or unreported histological subtypes.^[32–36] In 12 publications corresponding to 11 studies, the reported OS ranged from 9.1-25.4 months, and the PFS ranged from 5.6-12.5 months in 10 studies. The ORR or the clinical benefit rate (proportion of complete responses, partial responses, and stable disease) varied from 50-96% in 12 papers linked to 11 studies. In four studies, the time to treatment failure ranged from 5.7-7.4 months.

2. Thyroid cancer:

1. MTC (EXAM)
EXAM was a phase III double-blind trial in 330 individuals with metastatic MTC and radiographic progressive disease.^[11] Patients were randomized 2:1 to cabozantinib (140 mg orally daily) or to placebo. The primary endpoint was PFS. The median PFS with cabozantinib was 11.2 months versus 5.4 months for placebo (HR, 0.28; 95% CI, 0.19-040; P < 0.001). Cabozantinib led to prolongation of the PFS in all subgroups, including age, previous TKI therapy, and RET mutation status (hereditary or sporadic). Dose reduction was required in 79% of patients on cabozantinib and 65% required dose-holds. Adverse events led to treatment discontinuation in 8% of placebo-treated individuals and 16% of cabozantinib-treated patients.^[11]

2. Differentiated thyroid cancer (COSMIC-311)
COSMIC-311 was a phase III double-blind, randomized study in adult patients with locally advanced or metastatic differentiated thyroid carcinoma who had failed up to two prior VEGF-targeted treatments and were either refractory to or ineligible for radioactive iodine.^[13] A total of 258 individuals were randomly assigned 2:1 to receive cabozantinib 60 mg orally once a day or placebo. The main objective of the trial was to study the PFS, which was significantly improved in the cabozantinib group (11 months) compared to that in the placebo group (1.9 months); HR, 0.22; 96% CI, 0.15-0.32; P < 0.0001. Among the patients on cabozantinib, 56% required dose reductions and 72% required dose interruptions. Up to two dosage reductions were necessary for about 22% of the patients. The median time from starting the drug to the initial dose reduction was 57 days.

3. HCC:

1. Advanced relapsed refractory HCC (CELESTIAL)
CELESTIAL was a phase III randomized, double-blind, placebo-controlled study that enrolled 707 patients with advanced HCC, whose disease had progressed on sorafenib and who were not candidates for curative treatment.^[17] Participants were randomized 2:1 to receive cabozantinib (470 patients) or placebo (237 patients). The median OS in the cabozantinib group was 10.2 months, compared to 8 months in the placebo groups; HR, 0.76; 95% CI, 0.63-0.92; P = 0.005.^[37,38]

2. Real-world evidence in HCC
Real-world studies have found cabozantinib to be successful as a second or later-line treatment for HCC, with results consistent with those of the CELESTIAL trial. Two European studies reported that the median OS ranged from 7.8-12.9 months. Partial response (PR) was documented in 5% of patients in studies from Austria and Germany; another trial from Italy noted a median PFS of 5.1 months with a disease control rate (DCR) of 59%. These data suggest that cabozantinib may be efficacious in HCC, and while only a small percentage of patients may attain a partial response, the PFS and DCR are considerable.^[39,40]

4. Metastatic castration-resistant prostate cancer (mCRPC)

In the COMET-1 and COMET-2 studies, male patients with mCRPC were administered cabozantinib 60 mg (compared to prednisolone in COMET-1, and to mitoxantrone + prednisone [MP] in COMET-2). The majority (almost 90%) of patients had received at least three prior cancer treatments. The primary endpoint of COMET-1 was OS, which did not differ significantly between cabozantinib (682 individuals) and prednisolone (346 patients). Cabozantinib, on the other hand, resulted in excellent secondary outcomes (PFS). In the COMET-2 study, cabozantinib did not result in a significant improvement in the pain response compared to MP (15% vs 17%; P = 0.8).^[26,27] Despite this, those given cabozantinib (61 individuals) showed a trend toward a numerically longer OS than those treated with MP (n = 58; 9.0 months vs 7.9 months; HR, 0.70; 95% CI, 0.45-1.12; P = 0.121).^[41] There are no reported real-world studies of cabozantinib monotherapy in CRPC.

5. Various solid tumors (COSMIC-021)

COSMIC-021 was a multicenter open-label phase 1b study in 1732 adult patients with a variety of solid tumors including CRPC, RCC, urothelial, non-small-cell lung, endometrial, ovarian, triple negative breast, HCC, esophagogastric, colorectal, head-and-neck, and differentiated thyroid cancer. Thus far, promising results have been reported in the cohorts of CRPC with radiographic progression following treatment with either enzalutamide or abiraterone or both (n = 132),^[28] as well as RCC (clear cell and non-clear cell; n = 102).^[29] Treatment consisted of cabozantinib 40 mg per day with atezolizumab 1200 mg intravenously once every 3 weeks. At a median follow-up of 15.2 months, the objective response rate in the CRPC cohort was 23% (95% CI, 17-32). Grade ≥ 3 adverse events occurred in 55% patients. These toxicities included pulmonary embolism (8%), diarrhea (7%), fatigue (7%), hypertension (7%), and one fatal toxicity from dehydration.

ADVERSE EVENTS

Cabozantinib can induce a variety of side effects, and regular monitoring is essential during the first 8 weeks of treatment. Dose adjustments may be required to manage these reactions. Most adverse effects occur early in the treatment course. Common early adverse effects (within 8 weeks) include hypocalcemia, hypokalemia, thrombocytopenia, hypertension,^[42] palmar-plantar erythrodysesthesia syndrome, proteinuria, and GI events such as stomach discomfort, mucosal inflammation, constipation, diarrhea, and vomiting.

The adverse reactions in the patients who received cabozantinib in the various pivotal studies are provided in Table 4.

Table 4: Adverse reactions reported in pooled data of patients treated with cabozantinib in hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer (very common>10%, common: 1-10%, and uncommon<1%)

GI perforation

Cabozantinib has been reported to cause this rare but significant side effect. GI perforations were recorded in 0.9-2.6% of patients treated with single agent cabozantinib.^[43] In the METEOR trial that enrolled patients after prior VEGF-targeted treatment, 0.9% (3/331) of cabozantinib-treated patients with RCC experienced grade 2 or 3 GI perforations.^[14] In the CABOSUN trial (first-line RCC), 2.6% (2/79) patients in the cabozantinib arm had grade 4-5 perforations.^[15] The median time from starting cabozantinib to the development of a GI perforation was 5.9-10.0 weeks. In the CELESTIAL study,^[17] GI perforations occurred in 0.9% (4/467) cabozantinib-treated patients; all were grade 3 or 4. In CheckMate 9ER, the incidence of GI perforation was 1.3% (4/320), with one fatal event.^[16] These complications emphasize the need for continuous monitoring for adverse events in patients on cabozantinib, as well as prompt recognition and rapid therapy of symptoms such as stomach discomfort, nausea, and vomiting, which may be early signals of a perforation.^[44,45]

Hepatic encephalopathy

In the CELESTIAL trial for HCC,^[17,37] 5.6% (26/470) patients who received cabozantinib had a syndrome in which liver failure caused cerebral impairment. This was grade 3 or 4 in 2.8% of the patients, and one occurrence resulted in death. Hepatic encephalopathy developed after patients had been on cabozantinib for a median of 5.9 weeks. There were no incidences of hepatic encephalopathy reported in any of the trials investigating the role of cabozantinib in RCC (METEOR,^[14] CABOSUN,^[15] CheckMate 9ER,^[16] and COSMIC-311^[13]). As the risk is high during the first few weeks of therapy, patients should be closely monitored for symptoms of hepatic encephalopathy, and dose reductions may be required to control adverse effects.

Diarrhea

Cabozantinib has been reported to cause diarrhea relatively commonly in several clinical trials. In the METEOR study in patients with RCC who had previously received VEGF-targeted therapy,^[1] 74% (245/330) patients who received cabozantinib developed diarrhea, with 11% experiencing grades 3-4 diarrhea. The median time to onset was around 4.9 weeks. In CABOSUN,^[15] 73% (57/79) patients with treatment-naïve RCC who received cabozantinib developed diarrhea, which was severe (grades 3-4) in 10%. In the HCC trial (CELESTIAL^[17,37]), 54% (251/470) of the cabozantinib-treated patients developed diarrhea, which was severe (grade 3/4) in 9.9%. The median time to onset was 4.1 weeks. In the differentiated thyroid cancer trial (COSMIC-311^[13]), 62% (105/170) of the cabozantinib-treated patients developed diarrhea, with 7.6% experiencing severe diarrhea (grade 3/4 events). In CheckMate 9ER (advanced RCC first-line therapy),^[16] 64.7% (207/323) patients who were treated with the combination of cabozantinib and nivolumab reported diarrhea, with 8.1% (27/323) having severe diarrhea.

Fistula

In METEOR,^[14] 1.2% (4/331) of the patients developed fistulae, two of which were anal fistulae, with a median time to development of 30.3 weeks. In the CABOSUN^[15] trial, in which cabozantinib therapy was administered to 79 patients with treatment-naïve RCC, there was no report of fistula development. Fistulae were recorded in 1.5% of patients (7/467) in CELESTIAL,^[17,37] with a median time to onset of the fistula of 14 weeks. In COSMIC-311,^[13] 1.8% (3/170) of the cabozantinib-treated patients reported fistulae. In patients with advanced RCC on first-line nivolumab (CheckMate 9ER),^[16] 0.9% (3/323) developed fistulae, all grade 1 in severity.

Hemorrhage

In clinical studies, there have been reports of fatal bleeding episodes in patients who were on cabozantinib. The frequency of major bleeding incidents (grade ≥3) varied among trials. After prior VEGFR-targeted therapy, 2.1% (7/331) of cabozantinib-treated patients in METEOR^[14,30] experienced severe bleeding events, with a median time to onset of 20.9 weeks. In the treatment-naïve RCC study (CABOSUN^[15]), 5.1% (4/78) cabozantinib-treated patients experienced severe bleeding. In the HCC study, CELESTIAL,^[17,37] 7.3% (34/467) cabozantinib-treated patients experienced grade ≥3 bleeding, with a median time to onset of 9.1 weeks. Grade ≥3 bleeding events were recorded in 1.9% of patients in the first-line RCC trial using the combination of cabozantinib and nivolumab in CheckMate 9ER.^[16] In the differentiated thyroid cancer study (COSMIC-311^[13]), 2.4% (4/470) of the cabozantinib-treated patients experienced severe bleeding events, with a median time to onset of 14 weeks.

Posterior reversible encephalopathy syndrome (PRES)

Cabozantinib is known to rarely cause PRES. One case (1/470) of PRES was seen in a patient with differentiated thyroid cancer in the COSMIC-311 study.^[13] There were no cases of PRES reported in METEOR,^[14] CABOSUN,^[15] CheckMate9ER,^[16] or CELESTIAL.^[17,37]

Transaminase elevation

Combining cabozantinib with nivolumab in previously untreated individuals with advanced RCC increased the risk of elevated liver enzymes (CheckMate 9ER,^[16] METEOR^[14]). In CheckMate 9ER,^[16] 10.1% of patients who received the combination regimen had grade 3 or 4 elevated alanine transaminase (ALT) levels, while 8.2% had grade 3 or 4 increased aspartate transaminase (AST) levels. In comparison, in the METEOR trial,^[14] 3.6% (12/330) patients had elevated ALT levels and 3.3% (10/330) had elevated AST levels. The median time to the development of raised ALT or AST levels was 10.1 weeks, and the elevations decreased to grades 0-1 in 91% of cases, with a median resolution time of 2.3 weeks in patients with grade 2 increased ALT or AST. Among patients with increased liver enzymes, recurrence of grade 2 elevated ALT or AST was identified in four patients who received cabozantinib (n = 10), three patients who received nivolumab (n = 3), and eight patients who received both cabozantinib and nivolumab (n = 25).^[8,9]

Hypothyroidism

In the METEOR^[14] study, the incidence of hypothyroidism was 21% (68/331) among patients who had previously received VEGFR-targeted treatment. The incidence was 23% (18/78) in patients with RCC who received cabozantinib as first-line therapy in the CABOSUN trial.^[15] The incidence of hypothyroidism was 8.1% (38/467) in the CELESTIAL study,^[17,37] which examined the use of cabozantinib in HCC, with just 0.4% (2/467) being grade 3. In the differentiated thyroid cancer study (COSMIC-311^[13]), the incidence was 2.4% (3/125), with all cases being grades 1-2 and none required treatment adjustment.^[10] In CheckMate 9ER,^[16] which examined the combination of cabozantinib and nivolumab as first-line treatment for advanced RCC, the incidence of hypothyroidism was 35.6% (114/320).

Impaired wound healing

Wound complications have been observed with cabozantinib, and the drug should be stopped at least 28 days prior to elective surgery, including dental procedures, if possible. The decision to resume cabozantinib after surgery should be based on clinical judgment and the demonstration of adequate wound healing.^[8,44]

COST-EFFECTIVENESS

Several studies have examined the cost-effectiveness of cabozantinib.^[46,47] The health benefits of cabozantinib were estimated to be 2.26 life years (LYs) and 1.78 quality-adjusted life years (QALYs). Cabozantinib outperformed axitinib and everolimus in terms of cost-effectiveness, with cost-effectiveness ratios of 98,967 GBP/QALY and 137,450 GBP/QALY, respectively.^[46] Cabozantinib was less expensive and more effective than nivolumab, with an additional cost of 6,742 GBP and a QALY difference of 0.18. Cabozantinib had a total mean cost per patient of $56,621 in a German model, whereas optimal supportive care cost $2064 per patient. The incremental cost-effectiveness ratios were $375,470/QALY39 and $306,778/life year.^[47] Cabozantinib and optimal supportive care were determined to cost $177,496 and $4630, respectively, using US pricing, with incremental cost-effectiveness ratios of $972,049/life year and $1,189,706/QALY.^[46–48]

INDIAN DATA

Multiple generics of cabozatinib are now available in India at a cost less than `10,000 per month. There are no clinical trial data or real-world data available from India regarding cabozantinib.

QULAITY OF LIFE

The METEOR trial’s QOL^[14,49] study revealed that patients who received cabozantinib reported more diarrhea and nausea symptoms than those who were on everolimus. Cabozantinib, on the other hand, has been shown to result in a longer time to deterioration of QOL than everolimus, with a period of 5.5 months against 3.7 months (HR, 0.65; P < 0.001). Interestingly, cabozantinib improved QOL in patients with bone metastases.^[50,51] In the CELESTIAL trial^[48] in advanced HCC, cabozantinib showed a clinically and statistically significant increase in QALYs compared to the placebo group. Cabozantinib’s mean QALY changes ranged from +0.092 to +0.185. In the CheckMate 9ER study, the combination of cabozantinib and nivolumab led to a significant prolongation in the time to deterioration of QOL compared to sunitinib.^[52]

CONCLUSION

Cabozantinib is effective in the treatment of metastatic RCC, thyroid cancer, and HCC. It has also been shown to have promising efficacy in other solid cancers. It is critical to remember that cabozantinib may result in adverse effects such as diarrhea, bleeding, and, in rare cases, gastrointestinal perforation. Despite its high price, cabozantinib has been demonstrated to be more cost-effective than alternative treatment choices.

Financial support and sponsorship

Nil.

Conflicts of interest

Kumar Prabhash and Vanita Noronha are members of the editorial board of Cancer Research, Statistics and Treatment. As such, they may have had access to information and/or participated in decisions that could be perceived as influencing the publication of this manuscript. However, they had recused themselves from the peer review, editorial, and decision-making process for this manuscript, to ensure that the content was objective and unbiased.