Cabozantinib S -malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 4, 8, 9, 10, 16
Cabozantinib S -malate capsules (Cometriq®) are used for the treatment of progressive, metastatic medullary thyroid cancer.1, 3, 8 Cabozantinib (Cometriq®) has been designated an orphan drug by US Food and Drug Administration (FDA) for the treatment of this cancer.2
The current indication for cabozantinib (Cometriq®) is based principally on the results of a randomized, multicenter, double-blind, placebo-controlled, phase 3 study (EXAM) in patients with unresectable, locally advanced or metastatic medullary thyroid cancer who had evidence of actively progressive disease within 14 months prior to study entry according to Response Evaluation Criteria in Solid Tumors (RECIST).1, 3 In the EXAM study, 330 patients were randomized in a 2:1 ratio to receive either cabozantinib (140 mg) or placebo orally once daily, without food, until disease progression or intolerable toxicity occurred.1, 3 The primary efficacy end point of this study was progression-free survival according to RECIST; secondary endpoints included overall survival, objective response rate, and duration of response.1, 3 The median age of patients enrolled in the study was 55 years; 25% of the patients had received 2 or more prior systemic therapies and 21% had previously received a tyrosine kinase inhibitor.1, 3 Rearranged during transfection (RET) mutation status was positive, negative, or unknown in 48, 12, or 39% of the enrolled patients, respectively.1, 3
Patients receiving cabozantinib in the EXAM study demonstrated a longer median progression-free survival than those receiving placebo (11.2 versus 4 months, respectively).1, 3 The favorable treatment effect of cabozantinib on progression-free survival was consistent across patient subgroups, including RET mutation status and previous therapy with a tyrosine kinase inhibitor.3, 4 Patients receiving cabozantinib also had higher overall response rates (all were partial responses) compared with those receiving placebo (27 versus 0%), and their median duration of response was 14.7 months.1, 3, 4, 14 Overall survival was not substantially different between the cabozantinib and placebo groups in a planned interim analysis, an unplanned analysis requested by the FDA, and the final analysis.1, 3, 4, 17
The American Thyroid Association (ATA) published a guideline on management of medullary thyroid cancer in 2015.102 Single agent or combination cytotoxic chemotherapy regimens in patients with medullary thyroid cancer is characterized by low response rates and short durations of response; therefore, single agent or combination cytotoxic chemotherapy regimens are not recommended as first-line therapy in patients with persistent or recurrent medullary thyroid cancer.102 Systemic therapy with tyrosine kinase inhibitors targeting both rearranged during transfection (RET) proto-oncogene and vascular endothelial growth factor receptor (VEGFR) should be considered in patients with significant tumor burden and symptomatic or progressive metastatic disease.102 The ATA states that cabozantinib or vandetanib can be used as single-agent first-line therapy in patients with advanced progressive disease.102 Other experts also recommend cabozantinib and vandetanib (both strong recommendations based on high-quality evidence) as first-line systemic therapy in patients with progressive metastatic medullary thyroid cancer.101
Cabozantinib S -malate tablets (Cabometyx®) is used for the treatment of locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following VEGFR-targeted therapy in adult and pediatric patients ≥12 years of age who are refractory to or ineligible for radioactive iodine (iodine-131).16, 27 Safety and efficacy of cabozantinib tablets (Cabometyx®) for the treatment of previously treated, locally advanced or metastatic DTC in pediatric patients ≥12 years of age is supported by extrapolation of data from clinical studies evaluating cabozantinib tablets in adults and population pharmacokinetic data indicating that exposure to the drug in pediatric patients ≥12 years of age is similar to that in adults.16
Efficacy of cabozantinib tablets (Cabometyx®) has been evaluated in a randomized, double-blind, placebo-controlled trial (COSMIC-311) in patients with locally advanced or metastatic DTC.16, 27 Patients were enrolled in the study if they had DTC that progressed following VEGFR-targeted therapy and were refractory to or ineligible for radioactive iodine.16, 27 Patients were randomized to receive cabozantinib tablets 60 mg orally once daily or placebo with supportive care until disease progression or unacceptable toxicity occurred.16 Patients randomized to placebo were permitted to cross-over to cabozantinib tablets following confirmed disease progression.16 The primary efficacy end points were progression-free survival in the intent-to-treat population (187 patients) and objective response rate in the initial 100 randomized patients.16 In this study, the median age of patients was 65 years (range: 31-85 years); 53% were female, 70% were white, 19% were Asian, 2% were Black, 2% were American Indian or Alaska Native, 63% previously received lenvatinib, and 93% had metastatic disease.16 Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 46 or 54% of patients, respectively.16
At a median follow-up of 6.2 months in the intent-to-treat population, median progression-free survival had not been reached in patients receiving cabozantinib tablets and was 1.9 months in those receiving placebo (hazard ratio: 0.22 with a 95% confidence interval of 0.14-0.35).16 At the time of an updated progression-free survival analysis in 258 patients, median progression-free survival was 11 months in patients receiving cabozantinib tablets and was 1.9 months in those receiving placebo (hazard ratio: 0.22 with a 95% confidence interval of 0.15-0.31).16 At a median follow-up duration of 8.9 months in the initial 100 randomized patients, objective response was achieved in 15% of patients receiving cabozantinib tablets compared with none of those receiving placebo; these results did not meet the prespecified significance level.27
The ATA published a guideline on the management of adult patients with DTC in 2025.45 The guideline recommends an individualized approach to management.45 Patients with early-stage DTC with an excellent prognosis may require less aggressive tactics than patients with higher risk disease or those with an inadequate response to initial therapy.45 Initial therapy may involve surgical resection with postoperative radioiodine administration, serum thyroid stimulating hormone suppression, and other therapeutic strategies as appropriate in selected patients.45 In the guideline, cabozantinib is recommended as a second-line therapy for patients with radioiodine-refractory DTC without an actionable oncogenic driver alteration who have progressed or did not tolerate, prior multikinase inhibitor therapy.45
Cabozantinib S -malate tablets (Cabometyx®) are used as a single agent for the treatment of patients with advanced renal cell carcinoma (RCC); the drug also is used in combination with nivolumab as first-line treatment in patients with advanced RCC.16, 20
Efficacy of cabozantinib tablets (Cabometyx®) has been compared with everolimus in one open-label, randomized controlled trial (METEOR) in 658 patients with advanced RCC who had previously received at least 1 anti-angiogenic therapy.16, 18 Patients were randomized to receive cabozantinib tablets 60 mg orally once daily or everolimus 10 mg orally once daily until disease progression or unacceptable toxicity occurred.16 The primary efficacy end point was progression-free survival in the initial 375 randomized patients; other efficacy end points were objective response rate and overall survival.16 The median age of enrolled patients was 62 years; 75% were male, 69% received only one prior anti-angiogenic therapy, 46% were Memorial Sloan Kettering Cancer Center (MSKCC) favorable risk (0 risk factors), 42% were MSKCC intermediate risk (1 risk factor), and 13% were MSKCC poor risk (2 or 3 risk factors).16 Metastatic disease was present in 3 or more organs in 54% of patients and included the lung (63%), lymph nodes (62%), liver (29%), and bone (22%).16 Analysis of progression-free survival and overall survival occurred after a minimum duration of follow-up of 11 and 6 months, respectively.18 In this study, a substantial improvement in progression-free survival (7.4 versus 3.8 months; hazard ratio [HR] of 0.58 with a 95% confidence interval [CI] of 0.45-0.74), overall survival (21.4 versus 16.5 months; HR of 0.66 with a 95% CI of 0.53-0.83), and objective response rate (17% versus 3%) was observed in patients receiving cabozantinib compared with those receiving everolimus.16 Overall survival, progression-free survival, and objective response rates for cabozantinib- and everolimus-treated patients at the time of final analysis (at a median follow-up of 18.7 months) remained similar to the initial results.16, 21
Cabozantinib tablets (Cabometyx®) are used for the first-line treatment of patients with advanced RCC.16 Efficacy of cabozantinib tablets (Cabometyx®) has been compared with sunitinib in an open-label randomized trial (CABOSUN) in 157 patients with previously untreated advanced RCC.16, 19 Patients were randomized to receive cabozantinib tablets 60 mg orally once daily or sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off) until disease progression or unacceptable toxicity occurred.16 All patients were required to have intermediate- or poor-risk disease as defined by the International Metastatic RCC Database Consortium (IMDC).16 The primary efficacy end point was progression-free survival; secondary end points included overall survival and objective response rate.16 The median age of enrolled patients was 63 years; 78% were male, 81% were categorized as IMDC intermediate risk, and 19% had IMDC poor-risk disease.16 Bone metastases were present in 36% of patients.16 ECOG performance status scores were 0, 1, or 2 in 46, 41, or 13% of patients, respectively.16 At a median follow-up duration of 34.5 months, a substantial improvement in progression-free survival in patients receiving cabozantinib compared with those receiving sunitinib (8.6 versus 5.3 months; HR of 0.48 with a 95% CI of 0.31-0.74) was observed.16, 19 Median overall survival was 26.6 months with cabozantinib and 21.2 months with sunitinib (HR of 0.80 with a 95% CI of 0.53-1.21).19 Objective response rate (partial responses only) was 20% in patients receiving cabozantinib and 9% in those receiving sunitinib.16
Combination Therapy with Nivolumab
The CHECKMATE-9ER study was an open-label, randomized controlled trial comparing the combination of cabozantinib tablets (Cabometyx®) and nivolumab with sunitinib in 651 patients with previously untreated advanced RCC.16, 20 Patients were randomized to receive cabozantinib tablets 40 mg orally daily in combination with nivolumab 240 mg IV every 2 weeks, or sunitinib 50 mg orally daily for the first 4 weeks of each 6-week cycle (4 weeks on treatment followed by 2 weeks off).16 The primary efficacy end point was progression-free survival; secondary end points were overall survival and objective response rate.16
The median age of patients in the CHECKMATE-9ER study was 61 years; 74% were male, 82% were white, and 23% and 77% of patients had a baseline Karnofsky Performance Score (KPS) of 70-80% and 90-100%, respectively.16 Risk status by IMDC was favorable in 22% of patients, intermediate in 58%, and poor in 20%.16 At a median follow-up duration of 18.1 months, a substantial improvement in progression-free survival (16.6 versus 8.3 months; HR of 0.51 with a 95% CI, 0.41-0.64), overall survival (HR of 0.60; 95% CI, 0.40-0.89), and objective response rate (55.7% versus 27.1%; p<0.0001) was observed in patients receiving cabozantinib plus nivolumab compared with those receiving sunitinib.16, 20 Consistent results for progression-free survival were observed across prespecified subgroups of IMDC risk categories and PD-L1 tumor expression status.16
Clear-cell RCC represents the majority (approximately 80%) of malignant renal tumors in adults.47 In patients with advanced and/or metastatic clear-cell RCC, cytoreductive nephrectomy or other local therapeutic management (e.g. metastasectomy, thermal ablation, radiotherapeutic approaches) may be considered in select patients.47 Experts recommend programmed cell death protein 1 (PD-1)-targeted combinations (e.g., cabozantinib-nivolumab) as first-line systemic treatment for advanced clear-cell RCC, regardless of disease risk (i.e., favorable, intermediate, or poor), due to an improvement in overall survival with therapy.47 Cabozantinib monotherapy is an alternative option in intermediate- and poor-risk disease for patients who cannot receive first-line PD-1-targeted therapy.47
Cabozantinib S -malate tablets (Cabometyx®) are used for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib.16, 25 Cabozantinib (Cabometyx®) has been designated an orphan drug by FDA for the treatment of patients with HCC.2 Safety and efficacy of cabozantinib tablets (Cabometyx®) for this use is based principally on the results of a randomized controlled trial (CELESTIAL) in patients with HCC previously treated with sorafenib.16, 25
Efficacy of cabozantinib tablets (Cabometyx®) has been evaluated in a randomized, double-blind, placebo-controlled trial (CELESTIAL) in 704 patients with HCC previously treated with sorafenib.16, 25 In this study, patients were required to have Child-Pugh class A hepatic impairment.16, 25 Patients were randomized in a 2:1 ratio to receive cabozantinib tablets 60 mg orally once daily or placebo until disease progression or unacceptable toxicity occurred.16 The primary efficacy end point was overall survival; secondary end points were progression-free survival and objective response rate.16
The median age of patients in the CELESTIAL study was 64 years; 81% were male, 56% were white, and 34% were Asian.16 At baseline, 53% of patients had an ECOG performance status of 0 and 47% had performance status of 1.16 The etiology of HCC was attributed to hepatitis B virus, hepatitis C virus, or other etiology in 38, 21, or 40% of patients, respectively.16 Macroscopic vascular invasion or extra-hepatic tumor spread was present in 78% of patients and 41% had serum alpha-fetoprotein (AFP) concentrations ≥0.4 mg/L. 16 All patients had received prior sorafenib and 27% had received 2 prior systemic therapy regimens.16
In the CELESTIAL study, substantial improvements in overall survival (10.2 versus 8.0 months; hazard ratio of 0.76, 95% CI of 0.63-0.92), progression-free survival (5.2 versus 1.9 months; hazard ratio of 0.44, 95% CI of 0.36-0.52), and objective response rate (4% versus 0.4%) was observed in patients receiving cabozantinib compared with those receiving placebo.16
Management of early stage hepatocellular carcinoma generally includes liver transplantation, surgical resection, and ablation.52 Survival is usually less than 6 months in patients with untreated advanced stage hepatocellular carcinoma.52 Treatment of hepatocellular carcinoma is complicated by the presence of underlying liver disease, the extent and location of tumor, comorbidities, and performance status.51, 52 The American Society of Clinical Oncology (ASCO) states that the risk of potential toxicities and benefits of therapy should be considered when selecting therapy.51, 52
The 2024 ASCO guideline update on systemic therapy for advanced hepatocellular carcinoma states that lenvatinib, sorafenib, or durvalumab may be offered as first-line therapy for patients with advanced hepatocellular carcinoma, Child-Pugh class A, and an ECOG performance status of 0 or 1 when therapy with atezolizumab plus bevacizumab or durvalamab plus tremelimumab is contraindicated.51 ASCO also states that tyrosine kinase inhibitors (i.e., cabozantinib, lenvatinib, sorafenib) may be used as second-line therapy† following therapy with various first-line treatment options.51
The decision to pursue second-line therapy and choice of treatment should be based on patient and clinician preferences and other factors (i.e., comorbidities, liver function, performance status, and potential for benefit and risk of harm).51
Cabozantinib S -malate tablets (Cabometyx®) are used for the treatment of adults and pediatric patients ≥12 years of age with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic and extra-pancreatic neuroendocrine tumors.16 Cabozantinib (Cabometyx®) has been designated an orphan drug by FDA for the treatment of patients with pancreatic neuroendocrine tumors.2
Efficacy of cabozantinib tablets (Cabometyx®) has been evaluated in a randomized, double-blind, placebo-controlled trial (CABINET) in adult patients with previously treated, locally advanced or metastatic, well- or moderately differentiated tumors of extrapancreatic or pancreatic origin.16, 53 Two independent cohorts of patients were enrolled (those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors).53 Patients were required to have previously received treatment with ≥1 FDA-approved therapy (e.g., everolimus, sunitinib, or lutetium Lu 177 dotate), other than somatostatin analogs.16, 53 In CABINET, patients in both cohorts were initially randomized in a 2:1 ratio to receive cabozantinib tablets 60 mg orally once daily or placebo until disease progression or unacceptable toxicity occurred; treatment interruption and dose reductions were specified for adverse event management.16, 53 Patients administered placebo were permitted to crossover to cabozantinib therapy after confirmation of disease progression.16, 53 The primary efficacy end point was time from randomization to radiographic progressive disease.53
At baseline, a total of 203 patients were included in the extrapancreatic neuroendocrine tumor cohort and 95 in the pancreatic neuroendocrine tumor cohort.53 The demographic and baseline characteristics in both cohorts were balanced between cabozantinib and placebo, except more patients assigned to receive cabozantinib in the extrapancreatic neuroendocrine tumor cohort had tumors of unknown primary site than patients in that cohort assigned placebo.53
Results revealed a significant improvement in median progression-free survival with cabozantinib as compared to placebo in both the extrapancreatic neuroendocrine tumor cohort (8.4 versus 3.9 months) and the pancreatic neuroendocrine tumor cohort (13.8 versus 4.4 months).53 The incidence of confirmed objective response was 5% and 19% in the cabozantinib groups within the extrapancreatic and pancreatic cohorts, respectively; no patients in the placebo groups of either cohort had a confirmed objective response.53
Dispensing and Administration Precautions
Cabozantinib S -malate is administered orally as capsules (Cometriq®) or tablets (Cabometyx®).1, 16
Cometriq® capsules : Cabozantinib S -malate is administered orally once daily.1 The drug should not be administered with food; patients should not eat for at least 2 hours before and at least 1 hour after taking cabozantinib capsules.1 Cabozantinib capsules should be swallowed whole with a full glass (at least 240 mL) of water; the capsules should not be opened or crushed.1
Cabometyx® tablets : Cabozantinib S -malate is administered orally once daily.16 The drug should not be administered with food; patients should take cabozantinib tablets at least 1 hour before or at least 2 hours after eating.16 Cabozantinib tablets should be swallowed whole; the tablets should not be crushed, chewed, or split.16
If a dose of cabozantinib is missed, the missed dose should not be taken within 12 hours of the next dose.1, 16
Store cabozantinib capsules (Cometriq®) or tablets (Cabometyx®) at 20-25°C; excursions are permitted from 15-30°C.1, 16
Dosage of cabozantinib, which is commercially available as cabozantinib S -malate, is expressed in terms of cabozantinib.1, 16
Cometriq® capsules and Cabometyx® tablets are not interchangeable.1, 16
The recommended adult dosage of cabozantinib (Cometriq®) as a single agent for the treatment of progressive, metastatic medullary thyroid cancer is 140 mg (one 80-mg and three 20-mg capsules) once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
The recommended dosage of cabozantinib (Cabometyx®) as a single agent for the treatment of locally advanced or metastatic differentiated thyroid cancer in adults with body weight ≥40 kg is 60 mg once daily.16 Continue therapy until disease progression or unacceptable toxicity occurs.16
The recommended dosage of cabozantinib (Cabometyx®) as a single agent for the treatment of locally advanced or metastatic differentiated thyroid cancer in pediatric patients ≥12 years of age with body weight ≥40 kg is 60 mg once daily.16 The recommended pediatric dosage in patients ≥12 years of age with body weight <40 kg is 40 mg once daily.16 Continue therapy until disease progression or unacceptable toxicity occurs.16
The recommended adult dosage of cabozantinib (Cabometyx®) as a single agent for advanced renal cell carcinoma is 60 mg once daily.16 Continue therapy until disease progression or unacceptable toxicity occurs.16
Combination Therapy with Nivolumab
The recommended adult dosage of cabozantinib (Cabometyx®) for the first-line treatment of advanced renal cell carcinoma is 40 mg once daily in combination with nivolumab monotherapy (240 mg every 2 weeks by IV infusion over 30 minutes or 480 mg every 4 weeks by IV infusion over 30 minutes) or in combination with nivolumab/hyaluronidase (600 mg/10,000 units every 2 weeks by subcutaneous administration over approximately 3-5 minutes or 1200 mg/20,000 units every 4 weeks by subcutaneous administration over approximately 3-5 minutes).16 Continue therapy until disease progression or unacceptable toxicity for cabozantinib or until disease progression or unacceptable toxicity for up to 2 years for nivolumab or nivolumab/hyaluronidase.16
The recommended adult dosage of cabozantinib (Cabometyx®) as a single agent for the treatment of previously treated hepatocellular carcinoma is 60 mg once daily.16 Continue therapy until disease progression or unacceptable toxicity occurs.16
The recommended dosage of cabozantinib (Cabometyx®) as a single agent for the treatment of previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic and extra-pancreatic neuroendocrine tumors in adults with body weight ≥40 kg is 60 mg once daily.16 Continue therapy until disease progression or unacceptable toxicity occurs.16
The recommended dosage of cabozantinib (Cabometyx®) as a single agent for the treatment of previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic and extra-pancreatic neuroendocrine tumors in pediatric patients ≥12 years of age with body weight ≥40 kg is 60 mg once daily.16 The recommended pediatric dosage in patients ≥12 years of age with body weight <40 kg is 40 mg once daily.16 Continue therapy until disease progression or unacceptable toxicity occurs.16
Dosage Modification for Toxicity
Cabozantinib tablets should be withheld if intolerable grade 2 adverse reactions, grade 3 or 4 adverse reactions, or osteonecrosis of the jaw (ONJ) occurs.16
Upon resolution or improvement of the adverse effect (i.e., return to baseline or resolution to grade 1), the dosage should be reduced; however, in some cases, the drug should be permanently discontinued.16 If dosage reduction is required, see Table 1.16
Recommended Dosage | First Dosage Reduction to | Second Dosage Reduction to |
|---|---|---|
60 mg daily in adults and pediatric patients ≥12 years of age with bodyweight ≥40 kg | 40 mg daily | 20 mg dailya |
40 mg daily in pediatric patients ≥12 years of age with bodyweight <40 kg | 20 mg daily | 20 mg every other daya |
40 mg daily in combination with nivolumab | 20 mg daily | 20 mg every other daya |
aIf previously receiving lowest dosage, resume therapy at same dosage.16 If lowest dosage not tolerated, discontinue cabozantinib tablets.16
If an adverse reaction occurs during therapy with cabozantinib tablets, modify dosage accordingly (see Table 2).16
Adverse Reaction and Severity | Modification |
|---|---|
Hemorrhage | |
Grade 3 or 4 | Permanently discontinue therapy |
GI Perforation | |
Any grade | Permanently discontinue therapy |
Fistula Formation | |
Grade 4 | Permanently discontinue therapy |
Thromboembolic Events | |
Any grade acute myocardial infarction (MI) | Permanently discontinue therapy |
Grade 2 or higher cerebral infarction | Permanently discontinue therapy |
Grade 3 or 4 arterial thromboembolic events | Permanently discontinue therapy |
Grade 4 venous thromboembolic events | Permanently discontinue therapy |
Hypertension | |
Grade 3 hypertension or hypertensive crisis | Withhold therapy; when blood pressure is adequately controlled to grade 2 or less, resume at reduced dosage (see Table 1); permanently discontinue therapy for uncontrolled hypertension |
Grade 4 hypertension or hypertensive crisis | Permanently discontinue therapy |
Diarrhea | |
Grade 2-4 | Withhold therapy; when diarrhea improves to grade 1 or less, resume at reduced dosage (see Table 1) |
Palmar-plantar Erythrodysesthesia | |
Grade 2 (intolerable) or grade 3 | Withhold therapy; when palmar-plantar erythrodysesthesia improves to grade 1 or less, resume at reduced dosage (see Table 1) |
Proteinuria | |
Grade 2 or 3 | Withhold therapy; when proteinuria improves to grade 1 or less, resume at reduced dosage (see Table 1) |
Nephrotic syndrome | Permanently discontinue therapy |
Osteonecrosis of the Jaw (ONJ) | |
Any grade | Withhold therapy; when ONJ completely resolves, resume at reduced dosage (see Table 1) |
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) | |
Any grade | Permanently discontinue therapy |
Other Adverse Effects | |
Grade 2 (intolerable) or grade 3-4 | Withhold therapy; when adverse effect resolves or improves to grade 1 or less, resume at reduced dosage (see Table 1) |
If hepatotoxicity occurs when cabozantinib tablets (Cabometyx®) are used in combination with nivolumab, the dosage of cabozantinib tablets should be reduced as described in Table 3.16 When used in combination with nivolumab, the recommended dosage modifications, usual cautions, precautions, and contraindications associated with nivolumab must be considered in addition to those associated with cabozantinib tablets.16
Liver Function Test Abnormalities | Dosage Modification |
|---|---|
ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN | Withhold both cabozantinib tablets and nivolumab and consider corticosteroid therapy; when hepatotoxicity resolves or improves to grade 1 or less, may resume one or both of the drugs |
ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN | Permanently discontinue cabozantinib and nivolumab |
Cabozantinib capsules should be withheld if grade 4 hematologic adverse effects, grade 3 or greater nonhematologic adverse effects, intolerable grade 2 adverse effects (as defined by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]), or osteonecrosis of the jaw (ONJ) occurs.1 Upon resolution or improvement of the adverse effect (i.e., return to baseline or resolution to grade 1), the dosage of cabozantinib should be reduced as follows: in patients previously receiving 140 mg daily, cabozantinib therapy should be resumed at a dosage of 100 mg daily; in patients previously receiving 100 mg daily, cabozantinib therapy should be resumed at a dosage of 60 mg daily; and in patients previously receiving 60 mg daily, cabozantinib therapy should be resumed at a dosage of 60 mg daily, if tolerated.1 Otherwise, cabozantinib therapy should be discontinued.1
Cabozantinib capsules should be permanently discontinued in patients who develop GI perforation or grade 4 fistula formation, severe hemorrhage, acute myocardial infarction or arterial or venous thromboembolic events requiring medical intervention, nephrotic syndrome, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, reversible posterior leukoencephalopathy syndrome, or cardiac failure (depending on severity).1
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of cabozantinib tablets with drugs that are strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 should be avoided .16 If concomitant use of a strong CYP3A4 inhibitor cannot be avoided, reduce the daily dosage of cabozantinib tablets by 20 mg (e.g., from 60 mg to 40 mg daily, or from 40 mg to 20 mg daily, or from 20 mg daily to 20 mg every other day in pediatric patients ≥12 years of age with bodyweight <40 kg).16 If concomitant use of the strong CYP3A4 inhibitor is discontinued, the dosage of cabozantinib tablets should be returned to the dosage used prior to initiation of the strong CYP3A4 inhibitor 2-3 days following discontinuance of the strong CYP3A4 inhibitor.16
Concomitant use of cabozantinib tablets with drugs that are strong or moderate inducers of CYP3A4 should be avoided .16 Foods or dietary supplements (e.g., St. John's wort [ Hypericum perforatum ]) that are known to induce CYP450 activity should be avoided during therapy.16 If concomitant use of a strong or moderate CYP3A4 inducer cannot be avoided, increase the daily dosage of cabozantinib tablets by 20 mg (e.g., from 60 mg to 80 mg daily, or from 40 mg to 60 mg daily) as tolerated.16 If concomitant use of the strong or moderate CYP3A4 inducer is discontinued, the dosage of cabozantinib tablets should be returned to the dosage used prior to initiation of the strong or moderate CYP3A4 inducer 2-3 days following discontinuance of the strong or moderate CYP3A4 inducer.16 The daily dosage of cabozantinib tablets should not exceed 80 mg.16
Concomitant use of cabozantinib capsules with drugs that are strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 should be avoided .1 If concomitant use of a strong CYP3A4 inhibitor cannot be avoided, reduce the daily dosage of cabozantinib capsules by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily).1 If concomitant use of the strong CYP3A4 inhibitor is discontinued, the dosage of cabozantinib capsules should be returned to the dosage used prior to initiation of the strong CYP3A4 inhibitor 2-3 days following discontinuance of the strong CYP3A4 inhibitor.1
Chronic concomitant use of strong CYP3A4 inducers should be avoided in patients receiving cabozantinib tablets if alternative therapy is available.1 Foods or dietary supplements (e.g., St. John's wort [ Hypericum perforatum ]) that are known to induce CYP3A4 should be avoided during therapy with the drug.1 If concomitant use of a strong CYP3A4 inducer cannot be avoided, increase the daily dosage of cabozantinib capsules by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated.1 If concomitant use of the strong CYP3A4 inducer is discontinued, the dosage of cabozantinib capsules should be returned to the dosage used prior to initiation of the strong CYP3A4 inducer 2-3 days following discontinuance of the strong CYP3A4 inducer.1 The daily dosage of cabozantinib capsules should not exceed 180 mg.1
Cabometyx® : In patients with moderate hepatic impairment (Child-Pugh class B), the initial dosage of cabozantinib tablets should be reduced from 60 mg daily to 40 mg daily or, in pediatric patients ≥12 years of age with bodyweight <40 kg, the initial dosage should be reduced from 40 mg daily to 20 mg daily.16
Cometriq® : In patients with mild to moderate hepatic impairment, the recommended initial dosage of cabozantinib capsules is 80 mg.1
Dosage adjustment is not necessary in patients with mild or moderate renal impairment.1, 16 The manufacturer states that there is no experience with cabozantinib capsules or tablets in patients with severe renal impairment and does not make specific dosage recommendations for such patients.1, 16
The manufacturer makes no specific dosage recommendations for geriatric patients.1, 16
GI perforations and fistulas, including serious and fatal cases, were reported in 1-3 and 1%, respectively, of cabozantinib-treated patients.1, 16 Non-GI fistulas, including tracheal/esophageal fistulas, were reported in 4% of patients receiving cabozantinib capsules (Cometriq®).1
Patients receiving cabozantinib should be monitored for symptoms of perforations and fistulas.1, 16 Cabozantinib should be permanently discontinued in patients who develop a GI perforation or grade 4 fistula.1, 16
Serious, sometimes fatal, hemorrhage, including hemoptysis and GI hemorrhage, has been reported with cabozantinib.1, 16 The incidence of grade 3 or greater adverse hemorrhagic events was higher in patients receiving cabozantinib capsules (Cometriq®) compared with those receiving placebo (3 versus 1%, respectively).1 In clinical trials, grade 3 to 5 hemorrhagic events occurred in 5% of patients receiving cabozantinib tablets (Cabometyx®) for the treatment of renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), or differentiated thyroid cancer (DTC).16
Patients receiving cabozantinib should be monitored for signs and symptoms of bleeding.1, 16 The drug should not be used in patients with severe hemorrhage or a recent history of hemorrhage, hemoptysis, hematemesis, or melena.1, 16 Cabozantinib should be withheld prior to surgery and discontinued if grade 3 or 4 hemorrhage occurs.1, 16
Cabozantinib therapy is associated with an increased incidence of thromboembolic events.1, 16 Venous thromboembolism was reported in 6 or 3% of patients receiving cabozantinib capsules (Cometriq®) or placebo, respectively, and arterial thromboembolism was reported in 2 or 0% of patients receiving cabozantinib capsules (Cometriq®) or placebo, respectively.1 Venous or arterial thromboembolism, including fatal cases, was reported in 7 or 2%, respectively, of patients receiving cabozantinib tablets (Cabometyx®).16
Cabozantinib should be permanently discontinued in patients who develop an acute myocardial infarction or arterial or venous thromboembolic event that requires medical intervention.1, 16
Inhibitors of vascular endothelial growth factor receptor (VEGFR) may impair wound healing,1, 9, 10 and wound-healing complications have been reported in patients receiving cabozantinib.1, 16
The manufacturer recommends that cabozantinib be discontinued at least 3 weeks prior to elective surgery, including invasive dental procedures.1, 16 Therapy with the drug may be resumed at least 2 weeks following major surgery based on clinical judgment of adequate wound healing.1, 16 The safety of resuming cabozantinib after resolution of wound healing complications has not been established.1, 16
Cabozantinib is associated with an increased incidence of treatment-induced hypertension.1 Nearly all patients receiving cabozantinib capsules (Cometriq®) experienced elevated blood pressure; stage 1 or 2 hypertension occurred in 61% of patients receiving cabozantinib compared with 30% of those receiving placebo in the phase 3 clinical study.1 Hypertension was reported in 37% of patients receiving cabozantinib tablets (Cabometyx®); grade 3 or 4 hypertension occurred in 16% and <1% of patients, respectively.16
Do not initiate cabozantinib in patients with uncontrolled hypertension.1, 16 Blood pressure should be monitored prior to initiation of cabozantinib and periodically during therapy.1 Cabozantinib should be temporarily withheld for hypertension that is not adequately controlled with medical management; when controlled, cabozantinib therapy should be resumed at a reduced dosage.1 Cabozantinib should be permanently discontinued for hypertensive crisis, or persistent uncontrolled hypertension despite optimal medical management (i.e., antihypertensive therapy).1
Severe and fatal cardiac failure has been reported; cardiac failure occurred in 0.9% of patients treated with cabozantinib capsules (Cometriq®) and 0.5% of patients treated with cabozantinib tablets (Cabometyx®) monotherapy.1, 16 The median time to cardiac failure onset was 76 days (range: 60-92 days) and 73 days (range: 44-159 days) for capsules or tablets, respectively.1, 16
Clinicians should monitor for signs and symptoms of cardiovascular events and consider baseline and periodic assessment of left ventricular ejection fraction.1, 16 Dependent upon severity, the dose of cabozantinib may be withheld and subsequently reinitiated at a reduced dose upon recovery or permanently discontinued.1, 16
Osteonecrosis of the jaw (ONJ) has been reported in <1% of cabozantinib-treated patients.1, 16 The condition may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or delayed healing of the mouth or jaw following dental surgery.1, 16
An oral examination should be performed prior to initiation of cabozantinib and periodically during therapy.1, 16 Patients should be advised to maintain good oral hygiene during treatment.1, 16 For patients requiring invasive dental procedures, cabozantinib therapy should be withheld for at least 3 weeks prior to scheduled surgery, if possible.1, 16 In patients who develop ONJ, cabozantinib should be withheld until complete resolution of ONJ.1, 16
The manufacturer of cabozantinib tablets (Cabometyx®) states that therapy may be resumed at a reduced dosage following resolution of ONJ.16
Diarrhea has been reported in 62-63% of patients receiving cabozantinib therapy; grade 3-4 diarrhea has been reported in 10-16% of patients.1, 16
Withhold cabozantinib until diarrhea improves to grade 1, and then resume the drug at a reduced dosage.1, 16 When resuming cabozantinib capsules (Cometriq®), the dosage should be reduced only for intolerable grade 2 diarrhea, grade 3 diarrhea unresponsive to standard antidiarrheal therapy, or grade 4 diarrhea.1
Palmar-plantar Erythrodysesthesia Syndrome
Palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) occurred in 45-50% of cabozantinib-treated patients, and was severe (grade 3 or greater) in 13% of patients.1, 16 In addition, a hand-foot skin reaction with subungual splinter hemorrhages and hypertension has been reported in at least one patient receiving the drug.11
If palmar-plantar erythrodysesthesia syndrome occurs, temporary interruption of cabozantinib and dosage reduction may be necessary.1, 16
Proteinuria was observed in 2-8% of patients receiving cabozantinib, including one patient with nephrotic syndrome, compared with none of those receiving placebo.1, 16 Urine protein should be monitored regularly during cabozantinib therapy.1, 16 Cabozantinib should be permanently discontinued in patients who develop nephrotic syndrome.1, 16 If proteinuria occurs, temporary interruption of cabozantinib and dosage reduction may be necessary.1, 16
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in one (less than 1%) patient receiving cabozantinib.1, 16 RPLS is a syndrome of subcortical vasogenic edema that may manifest with seizures, headache, visual disturbances, confusion, or altered mental function.1 Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.1
The possible diagnosis of RPLS should be considered in any patient receiving cabozantinib who presents with neurologic manifestations suggestive of RPLS.1, 16 Cabozantinib should be permanently discontinued in patients who develop RPLS.1, 16
Grade 3 or 4 hepatotoxicity and elevated ALT/AST concentrations occurred in patients receiving cabozantinib tablets (Cabometyx®) in combination with nivolumab at a higher frequency compared with cabozantinib alone.16 Grade 3 and 4 elevations in serum ALT or AST concentrations were observed in 11% of patients receiving cabozantinib tablets in combination with nivolumab.16 Grade 2 elevations in ALT/AST concentrations (ALT or AST >3 times ULN) were reported in 83 patients, 23 of whom received systemic corticosteroids; elevated ALT/AST concentrations resolved to grade 0 or 1 in 89% of patients who experienced grade 2 elevations.16 Among 44 patients with grade 2 or greater elevations in ALT or AST concentrations who were rechallenged with either cabozantinib tablets or nivolumab as a single agent or with both drugs, recurrence of grade 2 or greater elevations in ALT or AST concentrations was observed in 2 patients receiving cabozantinib, 2 patients receiving nivolumab, and 7 patients receiving both cabozantinib and nivolumab.16
Withhold cabozantinib tablets (Cabometyx®) and resume at a reduced dosage based on severity.16 Monitor liver enzymes prior to and periodically during therapy; more frequent monitoring should be considered when cabozantinib is used in combination with nivolumab.16 For elevated liver enzymes, temporarily interrupt therapy with cabozantinib tablets (Cabometyx®) and nivolumab and consider administration of systemic corticosteroids.16
Primary or secondary adrenal insufficiency has been reported in patients receiving cabozantinib tablets (Cabometyx®) in combination with nivolumab.16 Adrenal insufficiency occurred in 4.7% (grade 3 in 2.2% and grade 2 in 1.9%) of patients with RCC who received cabozantinib tablets (Cabometyx®) in combination with nivolumab.16 Approximately 80% of 15 patients who developed adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids; adrenal insufficiency resolved in 4 of 15 patients.16 Combination therapy with cabozantinib and nivolumab was withheld because of development of adrenal insufficiency in 9 patients and 6 of these patients were rechallenged with therapy following improvement of symptoms; all 6 patients received hormone replacement therapy and adrenal insufficiency recurred in 2 patients.16
For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement therapy, as clinically indicated.16 Withhold cabozantinib (Cabometyx®) and/or nivolumab therapy and resume cabozantinib (Cabometyx®) at a reduced dosage depending on severity.16
Thyroid dysfunction, primarily hypothyroidism, occurred in 19% of patients receiving cabozantinib tablets (Cabometyx®), including grade 3 in 0.4% of patients.16 Assess patients for signs of thyroid dysfunction prior to initiation of cabozantinib (Cabometyx®); monitor for signs and symptoms of thyroid dysfunction during treatment and manage as clinically indicated.16
Hypocalcemia has been reported in 13% of patients receiving cabozantinib tablets (Cabometyx®), including grade 3 in 2% and grade 4 in 1% of patients.16 In the COSMIC-311 trial of patients with differentiated thyroid cancer, hypocalcemia occurred in 36% of patients receiving cabozantinib tablets (Cabometyx®), including grade 3 in 6% and grade 4 in 3% of patients.16 Hypocalcemia occurred in 52% of patients treated with cabozantinib capsules (Cometriq®), including Grade 3 or 4 in 12% of patients.1
Monitor serum calcium levels and replace calcium as necessary.1, 16 Withhold cabozantinib and resume at reduced dosage following recovery of hypocalcemia or permanently discontinue therapy depending on severity.1, 16
Fetal/Neonatal Morbidity and Mortality
Cabozantinib may cause fetal harm if administered to pregnant women; the drug has been shown to be embryotoxic, fetotoxic, and teratogenic in animals (e.g., fetal loss, skeletal variations, visceral variations, malformations).1, 16
Females of reproductive potential should be advised to use an effective method of contraception while receiving cabozantinib and for 4 months after discontinuance of therapy.1, 16 If cabozantinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1, 16
A pregnancy test should be performed prior to initiation of the drug in females of reproductive potential and such females should be advised to use effective contraceptive methods while receiving the drug and for 4 months after the last dose.1, 16 Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.1, 16
It is not known whether cabozantinib or its metabolites are distributed into human milk.1, 16 The effects of the drug on breast-fed infants or on the production of milk are unknown.1, 16 Because of the potential for serious adverse reactions to cabozantinib in breast-fed infants, advise women not to breast-feed during treatment with cabozantinib and for 4 months after the last dose.16
Females and Males of Reproductive Potential
Females of reproductive potential should be advised to use an effective method of contraception while receiving cabozantinib and for 4 months after the last dose.1, 16
There are no data on the effect of cabozantinib on human fertility.1, 16 However, cabozantinib impaired male and female fertility in animal studies.1, 16
Safety and effectiveness of cabozantinib tablets (Cabometyx®) for the treatment of differentiated thyroid cancer (DTC) and neuroendocrine tumors have been established in pediatric patients ≥12 years of a safety and effectiveness in patients <12 years of age have not been established.16
Safety and efficacy of cabozantinib tablets (Cabometyx®) for the treatment of DTC and neuroendocrine tumors in pediatric patients ≥12 years of age is supported by extrapolation of data from clinical studies evaluating cabozantinib tablets in adults and population pharmacokinetic data indicating that exposure to the drug in pediatric patients ≥12 years of age is similar to that in adults.16
Physeal widening has been observed in children with open growth plates when treated with cabozantinib tablets (Cabometyx®).16 Physeal and longitudinal growth monitoring is recommended in children with open growth plates.16
Safety, efficacy, and pharmacokinetics of cabozantinib capsules (Cometriq®) have not been established in pediatric patients.1 Systemic exposure of cabozantinib (Cabometyx®) in pediatric patients ≥12 years of age at the recommended dosages is expected to be comparable to the exposure in adults at a dosage of 60 mg once daily.16
Clinical studies of cabozantinib capsules (Cometriq®) did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 The pharmacokinetics of cabozantinib capsules (Cometriq®) do not appear to be affected by age in adults (20-86 years of age).1
Clinical studies of cabozantinib (Cabometyx®) included patients ≥65 years of age at frequencies of 38-55% for patients ≥65 years of age and of 5-15% for patients ≥75 years of age.16 No overall differences in safety or effectiveness were observed between these patients and younger patients.16
Results of a population pharmacokinetic analysis showed no clinically important differences in cabozantinib exposure between patients with normal liver function and those with mild hepatic impairment.16 In a pharmacokinetic study, cabozantinib exposure increased by 63% in patients with moderate hepatic impairment.16 The pharmacokinetics of cabozantinib have not been studied in patients with severe (Child-Pugh class C) hepatic impairment.1, 16
Cometriq® : In patients with mild to moderate hepatic impairment, the recommended initial dosage of cabozantinib capsules (Cometriq®) is 80 mg daily.1 Use of cabozantinib (Cometriq®) is not recommended in patients with severe hepatic impairment.1
Cabometyx® : In patients with moderate hepatic impairment (Child-Pugh class B), the initial dosage of cabozantinib tablets (Cabometyx®) should be reduced from 60 mg daily to 40 mg daily or, in pediatric patients ≥12 years of age with bodyweight <40 kg, the initial dosage should be reduced from 40 mg daily to 20 mg daily.16 Use of cabozantinib (Cabometyx®) should be avoided in patients with severe hepatic impairment.16
The pharmacokinetics of cabozantinib capsules (Cometriq®) have not been studied in patients with severe renal impairment (estimated glomerular filtration rate <29 mL/minute per 1.73 m2 as estimated by Modification of Diet in Renal Disease equation) or renal impairment requiring dialysis.1, 16
Dosage adjustment of cabozantinib is not recommended in patients with mild or moderate renal impairment.1, 16
Adverse effects reported in ≥25% of patients receiving cabozantinib capsules (Cometriq®) include diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), weight loss, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation.1
Laboratory abnormalities reported in ≥25% of patients receiving cabozantinib capsules (Cometriq®) include increased AST concentrations, increased ALT concentrations, lymphopenia, increased alkaline phosphatase concentrations, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.1
Adverse effects reported in ≥20% of patients receiving cabozantinib tablets (Cabometyx®) as a single-agent: Diarrhea, fatigue, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.16
Adverse effects reported in ≥20% of patients receiving cabozantinib tablets (Cabometyx®) in combination with nivolumab: Diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.16
Cabozantinib is metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A4.1, 4 Inhibition of CYP3A4 reduced the formation of the drug's N -oxide metabolite by more than 80%.1 Inhibition of CYP2C9 had minimal effects on cabozantinib metabolite formation (i.e., less than a 20% reduction).1 Inhibition of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 2E1 had no effect on cabozantinib metabolite formation.1
In vitro, cabozantinib is an inhibitor of CYP2C8.1, 16 Cabozantinib is not an inhibitor of CYP isoenzymes 1A2 or 2D6.1, 14, 16
Cabozantinib is an inducer of CYP1A1 messenger RNA (mRNA) in human hepatocyte incubations, but does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 mRNA or isoenzyme-associated enzyme activities.1
Cabozantinib is an inhibitor, but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system.1 Cabozantinib is a substrate of MRP2 in vitro.1, 16
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4 and Other CYP-450 Isoenzymes
Concomitant use of cabozantinib with strong inhibitors of CYP3A4 may increase systemic exposure of cabozantinib.1, 16 When the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 27 days) was administered concomitantly with cabozantinib capsules (as a single 140-mg dose) in healthy individuals, plasma cabozantinib exposure increased by 38%.1, 14, 16
Concomitant use of cabozantinib with strong CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, voriconazole) should be avoided if alternative therapy is available.1, 16 If concomitant use of a strong CYP3A4 inhibitor cannot be avoided, reduce the daily dosage of cabozantinib capsules (Cometriq®) by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily) and the daily dosage of cabozantinib tablets (Cabometyx®) by 20 mg (e.g., from 60 mg to 40 mg daily, or from 40 mg to 20 mg daily, or from 20 mg daily to 20 mg every other day in pediatric patients ≥12 years of age with bodyweight <40 kg).16 If concomitant use of the strong CYP3A4 inhibitor is discontinued, the cabozantinib dosage should be returned (2-3 days following discontinuance of the strong CYP3A4 inhibitor) to the dosage used prior to initiation of the strong CYP3A4 inhibitor.1, 16
The manufacturer states that foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit CYP isoenzymes, including CYP3A4, should not be ingested during cabozantinib therapy.1, 13
Inducers of CYP3A4 and Other CYP-450 Isoenzymes
Chronic concomitant use of strong or moderate inducers of CYP3A4 with cabozantinib may reduce systemic exposure of cabozantinib.1, 16 When the strong CYP3A4 inducer rifampin (600 mg daily for 31 days) was administered concomitantly with cabozantinib capsules (as a single 140-mg dose) in healthy individuals, plasma cabozantinib exposure decreased by 77%.1, 14
Chronic concomitant use of strong or moderate CYP3A4 inducers (e.g., carbamazepine, dexamethasone, rifabutin, rifampin, rifapentine, phenobarbital, phenytoin, St. John's wort [ Hypericum perforatum ]) with cabozantinib should be avoided if alternative therapy is available.1, 14, 16 If concomitant use with a strong or moderate CYP3A4 inducer cannot be avoided, increase the daily dosage of cabozantinib capsules (Cometriq®) by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated and the daily dosage of cabozantinib tablets (Cabometyx®) by 20 mg (e.g., from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated.1, 16 If concomitant use of the strong or moderate CYP3A4 inducer is discontinued, the cabozantinib dosage should be returned (2-3 days following the discontinuance of the strong or moderate CYP3A4 inducer) to the dosage used prior to initiation of the strong or moderate CYP3A4 inducer.1, 16 The daily dosage of cabozantinib capsules (Cometriq®) should not exceed 180 mg.1 The daily dosage of cabozantinib tablets (Cabometyx®) should not exceed 80 mg.16
The manufacturer states that foods or dietary supplements (e.g., St. John's wort [ Hypericum perforatum ]) that are known to induce CYP activity, including CYP3A4, should be avoided during cabozantinib therapy.1
Drugs Affected by Hepatic Microsomal Enzymes
Cabozantinib is an inhibitor of CYP2C8 in vitro; however, a clinical study suggests that clinically relevant effects on exposure to CYP2C8 substrate drugs is unlikely.1, 16
Drugs Affecting Multidrug Resistance Protein
Cabozantinib is a substrate of multidrug resistance protein (MRP) 2 in vitro.1, 16 Therefore, MRP2 inhibitors (e.g., abacavir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, tenofovir) may have the potential to increase plasma concentrations of cabozantinib; monitor for increased cabozantinib toxicity.1, 16
Drugs Affected by the P-glycoprotein Transport System
Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities in a bidirectional assay system.1, 16 Therefore, cabozantinib may have the potential to increase plasma concentrations of concomitantly administered substrates of P-gp.1, 16
Grapefruit products are CYP3A4 inhibitors and should be avoided during cabozantinib therapy because of the potential for increased cabozantinib concentrations.1, 13, 16
Cabozantinib at steady-state plasma concentrations (100 mg or more daily of the capsule formulation for a minimum of 21 days) did not affect single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (peak concentration and area under the concentration-time curve [AUC]) in patients with solid tumors.1, 12, 16 A clinically important pharmacokinetic interaction with these drugs therefore appears unlikely.12, 14
Cabozantinib S -malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 4, 8, 9, 10 Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.1, 6, 7, 9, 10 Various tyrosine kinases and pathways are abnormally activated in medullary thyroid carcinoma cells (e.g., rearranged during transfection [RET] proto-oncogene mutations are associated with the development of hereditary medullary thyroid cancer).6, 7, 9 In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the activity of multiple receptor tyrosine kinases, including RET; met proto-oncogene encoding hepatocyte growth factor (c-MET); vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3; stem cell factor receptor (c-Kit); tropomyosin receptor kinase B (trkB); fms-like tyrosine kinase 3 (Flt-3); AXL; and TIE-2.1, 9, 10 These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes (e.g., oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment).1
The absolute oral bioavailability of cabozantinib has not been established.4 Following oral administration of cabozantinib capsules or tablets, median time to peak plasma concentrations of cabozantinib ranged from 2-5 or 3-4 hours, respectively.1, 16 Repeated daily administration of cabozantinib capsules (Cometriq®) for 19 days resulted in fourfold to fivefold mean cabozantinib accumulation (based on area under the concentration-time curve [AUC]) compared with single-dose administration; steady-state concentrations of the drug were achieved in 15 days.1, 16 Following a single 140-mg dose of cabozantinib capsules or tablets, peak plasma concentration of cabozantinib tablets was 19% higher compared with cabozantinib capsules; however, a less than 10% difference in AUC was observed between the tablet and capsule formulations.16 A high-fat meal increased the peak plasma concentration and AUC of cabozantinib by 41 and 57%, respectively, relative to fasted conditions following administration of a single 140-mg oral dose of cabozantinib capsules (Cometriq®) in healthy individuals.1, 16 Cabozantinib is highly bound (99.7% or more) to plasma proteins.1, 16 Cabozantinib is metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A4, and is a substrate of CYP3A4 in vitro.1, 4, 16 Inhibition of CYP3A4 reduced the formation of the cabozantinib N -oxide metabolite by greater than 80%; inhibition of CYP2C9 had minimal effects on cabozantinib metabolite formation (i.e., less than a 20% reduction).1, 16 Inhibition of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 2E1 had no effect on cabozantinib metabolite formation.1, 16 Following administration of a single dose of radiolabeled cabozantinib in healthy individuals, approximately 81% of the total administered radioactivity was recovered with 54% in feces and 27% in urine within 48 days.1, 16 The elimination half-life of cabozantinib capsules or tablets is approximately 55 or 99 hours, respectively.1, 4, 16
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Cabozantinib S -malate can only be obtained through a specialty pharmacy.28, 29 Specific information regarding distribution of the drug is available by telephone at 844-900-3272 or at [Web] or [Web].28, 29
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 20 mg (of cabozantinib) | Cometriq® | Exelixis |
80 mg (of cabozantinib) | Cometriq® | Exelixis | ||
Tablets | 20 mg (of cabozantinib) | Cabometyx® | Exelixis | |
40 mg (of cabozantinib) | Cabometyx® | Exelixis | ||
60 mg (of cabozantinib) | Cabometyx® | Exelixis | ||
Kit | 84 Capsules, Cabozantinib S -malate 20 mg (of cabozantinib) (Cometriq®) | Cometriq® 60 mg Daily Dose Blister Cards (available in a package containing 4 blister cards) | Exelixis | |
28 Capsules, Cabozantinib S -malate 20 mg (of cabozantinib) (Cometriq®) 28 Capsules, Cabozantinib S -malate 80 mg (of cabozantinib) (Cometriq®) | Cometriq® 100 mg Daily Dose Blister Cards (available in a package containing 4 blister cards) | Exelixis | ||
84 Capsules, Cabozantinib S -malate 20 mg (of cabozantinib) (Cometriq®) 28 Capsules, Cabozantinib S -malate 80 mg (of cabozantinib) (Cometriq®) | Cometriq® 140 mg Daily Dose Blister Cards (available in a package containing 4 blister cards) | Exelixis |
1. Exelixis, Inc. Cometriq® (cabozantinib) capsules prescribing information. South San Francisco, CA; 2025 Oct. [Web]
2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. [Web]
3. Schoffski P, Elisei R, and the EXAM Study Group. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol . 2012; 30 (May 20 Suppl): Abstract No. 5508.
4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 203756Orig1s000: Summary review. From FDA website. [Web]
6. Gómez K, Varghese J, Jiménez C. Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. J Thyroid Res . 2011; 2011:815826. [PubMed 21687607]
7. Giunti S, Antonelli A, Amorosi A et al. Cellular signaling pathway alterations and potential targeted therapies for medullary thyroid carcinoma. Int J Endocrinol . 2013; 2013:803171. [PubMed 23509459]
8. Kurzrock R, Sherman SI, Ball DW et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol . 2011; 29:2660-6. [PubMed 21606412]
9. Hart CD, De Boer RH. Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer. Onco Targets Ther . 2013; 6:1-7. [PubMed 23319867]
10. Nagilla M, Brown RL, Cohen EE. Cabozantinib for the treatment of advanced medullary thyroid cancer. Adv Ther . 2012; 29:925-34. [PubMed 23104465]
11. Cho YT, Chan CC. Cabozantinib-induced hand-foot skin reaction with subungual splinter hemorrhages and hypertension: a possible association with inhibition of the vascular endothelial growth factor signaling pathway. Eur J Dermatol . 2013; :. [PubMed 23518371]
12. Bowles DW, Kessler DW, Jimeno A. Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib). Drugs of Today . 2011; 47:857-68. [PubMed 22146228]
13. Hanley MJ, Cancalon P, Widmer WW et al. The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol . 2011; 7:267-86. [PubMed 21254874]
14. Exelixis, Inc., South San Francisco, CA: Personal communication.
16. Exelixis, Inc. Cabometyx® (cabozantinib) tablets prescribing information. Alameda, CA; 2025 Oct. [Web]
17. Schlumberger M, Elisei R, Müller S et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol . 2017; 28:2813-2819. [PubMed 29045520]
18. Choueiri TK, Escudier B, Powles T et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med . 2015; 373:1814-23. [PubMed 26406150]
19. Choueiri TK, Hessel C, Halabi S et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. Eur J Cancer . 2018; 94:115-125. [PubMed 29550566]
20. Choueiri TK, Powles T, Burotto M et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med . 2021; 384:829-841. [PubMed 33657295]
21. Choueiri TK, Escudier B, Powles T et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol . 2016; 17:917-927. [PubMed 27279544]
25. Abou-Alfa GK, Meyer T, Cheng AL et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med . 2018; 379:54-63. [PubMed 29972759]
27. Brose MS, Robinson B, Sherman SI et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol . 2021; 22:1126-1138. [PubMed 34237250]
28. Exelixis Inc. Accessing Cometriq® capsules. [Web]
29. Exelixis Inc. Accessing Cabometyx® tablets. [Web]
45. Ringel MD, Sosa JA, Baloch Z et al. 2025 American Thyroid Association management guidelines for adult patients with differentiated thyroid cancer. Thyroid . 2025; 35:841-985.
47. Powles T, Albiges L, Bex A et al. Renal cell carcinoma: ESMO clinical practice guideline for diagnosis, treatment, and follow-up. Ann Oncol . 2024;35(8):692-706.
51. Gordan JD, Kennedy EB, Abou-Alfa GK et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update. J Clin Oncol . 2024; :1-21. [PubMed 38502889]
52. National Cancer Institute. Adult primary liver cancer treatment - health professional version. Revised April 17, 2025. [Web]
53. Chan JA, Geyer S, Zemla T, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med . 2025;392:653-65.
101. Filetti S, Durante C, Hartl D et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol . 2019; 30:1856-1883. [PubMed 31549998]
102. Wells SA Jr, Asa SL, Dralle H et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid . 2015; 25:567-610. [PubMed 25810047]
103. Institute for Safe Medication Practices (ISMP). ISMP list of confused drug names (2024).