Cabometyx (cabozantinib) - 4 indications

Scroll down for information on each indication:

• For treatment experienced patients with advanced renal cell carcinoma; approved 04/01/2016
• For patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; approved 01/01/2019.
• For use in combination with Opdivo (nivolumab) for the first-line treatment of advanced renal cell carcinoma; approved 01/01/2021
• For patients >12 years of age with locally advanced or metastatic differentiated thyroid cancer that has progressed following prior VEGFR-targeted therapy; approved September of 2021

General Information

Cabometyx (cabozantinib) is a kinase inhibitor.

Cabometyx is specifically indicated for the following:

• the treatment of patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy. 
• patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
• in combination with Opdivo (nivolumab) for the first-line treatment of advanced renal cell carcinoma.
• for patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible

Cabometyx is supplied as tablets for oral administration Scroll down for dosing recommendations for each indication.

Mechanism of Action

Cabometyx (cabozantinib) is a kinase inhibitor.  Cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment. 

Opdivo (nivolumab) is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

Side Effects

Adverse effects associated with the use of Cabometyx may include, but are not limited to, the following:

• diarrhea
• fatigue
• nausea
• decreased appetite
• palmar-plantar erythrodysesthesia syndrome
• hypertension
• vomiting
• weight decreased
• constipation

Adverse effects associated with the use of Cabometyx plus Opdivo may include, but are not limited to, the following:

• diarrhea
• fatigue
• hepatotoxicity
• PPE
• stomatitis
• rash
• hypertension
• hypothyroidism
• musculoskeletal pain
• decreased appetite
• nausea
• dysgeusia
• abdominal pain
• cough
• upper respiratory tract infection

Indication 1 - treatment experienced patients with advanced renal cell carcinoma

approved 04/01/2016

Dosing/Administration

The recommended dosage of Cabometyx as a single agent is 60 mg once daily without food until the patient no longer experiences clinical benefit or experiences unacceptable toxicity. Do not administer Cabometyx with food. Administer at least 1 hour before or at least 2 hours after eating. Swallow Cabometyx tablets whole. Do not crush the tablets. Do not take a missed dose within 12 hours of the next dose.

Clinical Trial Results

The FDA approval was based on a randomized study in which patients with advanced renal cell carcinoma who had received prior anti-angiogenic therapy received either cabozantinib 60 mg orally once daily (N=330) or everolimus 10 mg orally once daily (N=328). The primary endpoint was progression-free survival among the first 375 randomized subjects. Median progression-free survival in this group was 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively (p<0.0001). Median overall survival in the intent-to-treat population was 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (p=0.0003). Confirmed response rate was 17% in the cabozantinib arm and 3% in the everolimus arm.

Indication 2 - patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

approved 01/01/2019

Dosing/Administration

The recommended dosage is 60 mg once daily without food until disease progression or unacceptable toxicity.  Do not administer Cabometyx with food. Administer at least 1 hour before or at least 2 hours after eating. Swallow Cabometyx tablets whole. Do not crush the tablets. Do not take a missed dose within 12 hours of the next dose.

Clinical Trial Results

The FDA approval of Cabometyx for HCC was based on the phase 3 CELESTIAL trial, a global randomized, double-blind, placebo-controlled trial in 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). Cabometyx demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo. In the pivotal CELESTIAL trial, median OS was 10.2 months with cabozantinib versus 8.0 months with placebo. Median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo. Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo. Disease control (partial response or stable disease) was achieved by 64 percent of patients in the cabozantinib group compared with 33 percent of patients in the placebo group.

Indication 3 - for use in combination with Opdivo (nivolumab) for the first-line treatment of advanced renal cell carcinoma

approved 01/01/2021

Dosing/Administration

The recommended dose is Cabometyx 40 mg orally, once daily, administered in combination with nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years. Administer at least 1 hour before or at least 2 hours after eating. Do not substitute Cabometyx tablets with cabozantinib capsules.

Clinical Trial Results

The FDA approval of Cabometyx plus Opdivo was based on CheckMate -9ER, an open-label, randomized (1:1), multi-national phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma with a clear cell component. A total of 651 patients (22% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to Cabometyx at a dose of 40 mg QD and Opdivo (n = 323) versus sunitinib (n = 328). The primary endpoint is PFS. Secondary endpoints include OS and ORR. The combination regimen significantly improved overall survival (OS) compared with sunitinib. Median OS has not yet been reached in either treatment arm. Median progression-free survival (PFS) was doubled at 16.6 months for Cabometyx in combination with Opdivo compared with 8.3 months for sunitinib. Objective response rate (ORR) was also doubled: 56% with Cabometyx in combination with Opdivo and 27% with sunitinib.

Indication 4 - patients >12 years of age with locally advanced or metastatic DTC that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible

Approved September 2021

Dosing/Administration

The recommended dosage of Cabometyx as a single agent for adult and pediatric patients 12 years of age and older with BSA greater than or equal to 1.2 m2 is 60 mg once daily until disease progression or unacceptable toxicity administered as recommended.

 The recommended dosage of Cabometyx as a single agent in pediatric patients 12 years of age and older with BSA less than 1.2 m2 is 40 mg once daily until disease progression or unacceptable toxicity administered as recommended.

Clinical Trial Results

The approval is based on results from COSMIC-311, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial. The trial enrolled 258 patients with radioactive iodine-refractory DTC who progressed after up to two prior VEGFR-targeted therapies. Patients were randomized in a 2:1 ratio to receive either Cabometyx 60 mg or placebo once daily. At a planned interim analysis, Cabometyx significantly reduced the risk of disease progression or death versus placebo in the intent-to-treat population. At a follow-up analysis with a median follow-up of 10.1 months, the median progression-free survival (PFS) as assessed by blinded independent radiology committee was 11.0 months for patients treated with Cabometyx (n=170) compared with 1.9 months for patients treated with placebo (n=88).