Cabometyx (Cabozantinib) Tablets First Multikinase Inhibitor Approved for the Treatment of Patients with Advanced Renal-Cell Carcinoma
Kidney cancer is the ninth most common cancer diagnosis in the United States.1 In 2016, approximately 63,000 cases of kidney cancer will be diagnosed in the United States, and more than 14,000 people will die from this disease.1 The incidence of kidney cancer increases with age, with the majority of patients diagnosed between the ages of 65 and 74 years. Men are twice more likely than women to have kidney cancer.1
Renal-cell carcinoma (RCC) is the most common subtype of kidney cancer.2 Early-stage RCC is typically asymptomatic. As the disease progresses, symptoms can include hematuria, lower back or abdominal pain, fatigue, weight loss, fever, and peripheral edema.2 Some patients with advanced RCC have an indolent disease course that lasts several years.3
RCC is often cured if it is diagnosed and surgically resected while localized to the kidney; the 5-year relative survival rate for patients with localized kidney cancer is 93%, which decreases to 12% for patients with distant disease.1,3
The management options for patients with advanced RCC include locoregional therapy to palliate symptoms of the primary tumor and/or of ectopic hormone production (ie, tumor embolization, radiation therapy, nephrectomy), as well as systemic drugs, including novel targeted agents.3
The costs associated with RCC have significantly increased with the introduction of these new drugs.4 Based on data from a private health insurance company in the United States, a 2015 assessment of treatment patterns and costs estimated that the median drug costs for advanced RCC increased nearly 500% from 2004 to 2010; the annual out-of-pocket cost for patients with metastatic RCC who received ≥2 targeted drugs during their first year of treatment exceeded $2500.4
Treatment of metastatic RCC has changed in the past decade in light of enhanced understanding of disease biology and new drug approvals. Multiple antiangiogenesis agents and immunotherapies are available, such that patients often receive several lines of therapy to attain disease control. For patients with metastatic RCC who are undergoing first-line therapy, current guidelines from the National Comprehensive Cancer Network (NCCN) recommend bevacizumab (Avastin) combined with interferon, sunitinib (Sutent), pazopanib (Votrient), temsirolimus (Torisel), axitinib (Inlyta), sorafenib (Nexavar) for selected patients, or high-dose interleukin-2 for selected patients, as well as participation in clinical trials.5
Category 1 drugs for patients with metastatic RCC that progressed after antiangiogenesis therapy include axitinib, nivolumab (Opdivo), and everolimus (Afinitor).5 Lenvatinib (Lenvima) combined with everolimus, sorafenib, sunitinib, pazopanib, temsirolimus, or bevacizumab can also be used for patients with relapsed metastatic RCC.5
Cabometyx Approved for Renal-Cell Carcinoma
On April 25, 2016, the US Food and Drug Administration (FDA) approved cabozantinib (Cabometyx; Exelixis) tablets, an orally administered multikinase inhibitor, for patients with advanced RCC that progressed after previous antiangiogenesis therapy.6,7
The FDA approval of cabozantinib tablets for patients with advanced RCC was granted after reviewing results from the METEOR clinical trial, a randomized, phase 3 study comparing the safety and efficacy of cabozantinib tablets with that of everolimus.6-8 In this study, patients with advanced RCC that had progressed after antiangiogenesis therapy who received cabozantinib tablets had a significantly lower risk for disease progression or death compared with patients who received everolimus. In addition, overall survival (OS) and objective response rate (ORR) findings favored cabozantinib tablets over everolimus.6-8
Of note, a capsule formulation of cabozantinib (Cometriq) was approved by the FDA in November 2012 for patients with metastatic medullary thyroid cancer.9 Cabozantinib capsules and cabozantinib tablets have distinct package inserts.
“The efficacy profile demonstrated by Cabometyx in the METEOR trial, now complemented by the overall survival benefit, is highly compelling,” said Toni Choueiri, MD, Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “Cabometyx is distinct from other approved treatment options, as it targets multiple tyrosine kinases involved in the development of RCC, including MET, AXL and three VEGF receptors….The approval of Cabometyx is wonderful news for physicians who are looking for a new option for their previously treated patients with advanced kidney cancer.”10
Specialty Pharmacy Distribution
Cabozantinib is distributed to providers and hospitals through authorized specialty pharmacies and distributors, including Accredo Specialty Pharmacy, ASD Healthcare, Cardinal Health Specialty Distribution, CVS Caremark Specialty Pharmacy, Diplomat Specialty Pharmacy, McKesson Plasma and Biologics, McKesson Specialty Health, Oncology Supply, and Walgreens Specialty Pharmacy.11
Mechanism of Action
Cabozantinib blocks the activity of multiple tyrosine kinases, including MET; vascular endothelial growth factor (VEGF) receptor-1, -2, and -3; AXL; RET; ROS1; TYRO3; MER; KIT; TRKB; FLT-3; and TIE-2. These receptor tyrosine kinases affect normal cell function as well as pathologic processes, including oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.7
Dosing and Administration
The recommended dosage of cabozantinib tablets for advanced RCC is 60 mg once daily while receiving clinical benefit or until unacceptable toxicity.7
Cabozantinib tablets should not be taken with food. Patients should not eat for at least 2 hours before and at least 1 hour after taking cabozantinib tablets. The tablets should be swallowed whole, and should not be crushed.7
Cabozantinib tablets should not be substituted with cabozantinib capsules.7
The METEOR Pivotal Clinical Trial
The efficacy of cabozantinib tablets was established in the METEOR clinical trial, a randomized, open-label, multicenter study involving 658 patients with advanced RCC that progressed after ≥1 antiangiogenesis therapies. The study compared the efficacy and safety of cabozantinib tablets (N = 330) with that of everolimus (N = 328). Patients were stratified by the number of previous VEGF receptor tyrosine kinase inhibitors they had received, as well as their Memorial Sloan Kettering Cancer Center (MSKCC) risk group. Cabozantinib tablets and everolimus were dosed at 60 mg daily and 10 mg daily, respectively, until disease progression or unacceptable toxicity.7,8
The majority of the patients were male (75%) and Caucasian (83%), with a median age of 62 years.7,9 Overall, 69% had received 1 antiangiogenesis therapy.7 Based on the MSKCC risk groups, 46% were “favorable” (ie, no risk factors), 42% were “intermediate” (ie, 1 risk factor), and 13% were “poor” (ie, 2 or 3 risk factors).7 Approximately 50% of the patients had ≥3 organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%).7
The primary efficacy measure was progression-free survival (PFS), which was assessed by a blinded independent radiology review committee in the first 375 patients who were randomized to cabozantinib or to everolimus. The secondary end points were ORR and OS in the intent-to-treat population of 658 patients. Tumor assessments were conducted every 8 weeks for the first 12 months, followed by every 12 weeks thereafter.7
Significant improvements in PFS, OS, and ORR were reported with cabozantinib tablets compared with everolimus in the METEOR study.7,8 The median PFS was 7.4 months with cabozantinib and 3.8 months with everolimus (Table 1). The OS was 21.4 months with cabozantinib and 16.5 months with everolimus, and the ORR was 17% versus 3%, respectively (Table 2).
The safety of cabozantinib tablets was determined using data from 330 patients with advanced RCC. The median duration of treatment with cabozantinib tablets at the time of data analysis was 7.6 months (range, 0.3 months to 20.5 months).7
Adverse reactions that occurred in ≥25% of patients who received cabozantinib tablets included diarrhea (74%), fatigue (56%), nausea (50%), decreased appetite (46%), palmar-plantar erythrodysesthesia syndrome (PPES; 42%), hypertension (39%), vomiting (32%), weight loss (31%), and constipation (25%). Grade 3 or 4 adverse reactions and laboratory changes that occurred in ≥5% of patients who received cabozantinib were hypertension (16%), diarrhea (11%), fatigue (9%), PPES (8%), hyponatremia (8%), hypophosphatemia (8%), hypomagnesemia (7%), lymphocytopenia (7%), anemia (5%), and increased gamma-glutamyl transferase levels (5%).7
Adverse reactions leading to the discontinuation of therapy occurred in 10% of patients in each group (cabozantinib tablets or everolimus). The most frequent adverse reactions leading to the discontinuation of cabozantinib tablets were decreased appetite (2%) and fatigue (1%).7 The dose of cabozantinib tablets was reduced in 60% of patients secondary to diarrhea, PPES, fatigue, or hypertension.7
Cabozantinib has no contraindications.7
Warnings and Precautions
Severe hemorrhage has been reported with cabozantinib tablets. Fatal hemorrhages also occurred in the cabozantinib clinical program. This treatment should not be used in patients who have or are at risk for severe hemorrhage.7
Fistulas and gastrointestinal (GI) perforations were more common with cabozantinib tablets than with everolimus in the METEOR study. Fatal perforations have occurred in the cabozantinib clinical program. Cabozantinib tablets should be discontinued in patients with a GI perforation or a fistula that cannot be appropriately managed.7
Venous thromboembolism (7.3%), pulmonary embolism (3.9%), and arterial thromboembolism (0.9%) occurred with cabozantinib tablets. Fatal thrombotic events have occurred in the cabozantinib clinical program. Cabozantinib tablets should be discontinued in patients with arterial thromboembolic complications.7
Grade ≥3 hypertension was reported in 15% of patients who received cabozantinib tablets versus 3% of patients who received everolimus. Cabozantinib tablets should be withheld if hypertension cannot be controlled, or in patients with severe uncontrolled hypertension or hypertensive crisis.7
Grade 3 diarrhea occurred in 11% of patients who received cabozantinib and in 2% of patients who received everolimus. Cabozantinib tablets should be withheld in patients who have intolerable grade 2 diarrhea or grade 3 or 4 diarrhea that cannot be managed.7
Grade 3 PPES occurred in 8% of patients using cabozantinib and in <1% of those using everolimus. Cabozantinib tablets should be withheld in patients with intolerable grade 2 or 3 PPES. Upon improvement, treatment can be resumed at a reduced dose.7
Reversible posterior leukoencephalopathy syndrome (RPLS) occurred in the cabozantinib clinical program. Patients with seizures, headache, visual disturbances, confusion, or altered mental function should be evaluated for RPLS. Treatment should be discontinued if RPLS is observed.7
Use in Specific Populations
Because of the risk for fetal harm, females of reproductive potential should use effective contraception during treatment with cabozantinib tablets and for 4 months after the last dose. Cabozantinib tablets may compromise fertility in men and women.7
Women should not breastfeed during treatment with cabozantinib tablets and for 4 months after the last dose of cabozantinib tablets.7
Cabozantinib tablets have not been studied in children. No differences in safety and effectiveness were observed between older and younger patients in clinical trials.7
No dose adjustment is recommended for patients with mild-to-moderate renal impairment. Cabozantinib tablets have not been studied in patients with severe renal impairment.7
Dose reduction is recommended for patients with mild or moderate hepatic impairment. Cabozantinib tablets are not recommended for patients with severe hepatic impairment.7
Cabozantinib is the first oral multikinase inhibitor to demonstrate clinically meaningful extensions of PFS and OS, as well as enhanced rates of tumor response, in patients with advanced RCC that progressed after treatment with an antiangiogenesis tyrosine kinase inhibitor.10 The FDA’s approval of cabozantinib tablets offers oncologists and patients with advanced RCC that progressed after antiangiogenesis therapy another NCCN category 1 treatment option.5 Ongoing studies are evaluating the activity and safety of cabozantinib tablets in other solid tumors.12
- National Cancer Institute. SEER stat fact sheets: kidney and renal pelvis cancer. http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed July 27, 2016.
- American Cancer Society. Cancer facts & figures 2016. 2016. www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf. Accessed July 27, 2016.
- National Cancer Institute. Renal cell cancer treatment (PDQ)–health professional version. Updated April 18, 2016. www.cancer.gov/types/kidney/hp/kidney-treatment-pdq. Accessed July 27, 2016.
- Geynisman DM, Hu JC, Liu L, Tina Shih YC. Treatment patterns and costs for metastatic renal cell carcinoma patients with private insurance in the United States. Clin Genitourin Cancer. 2015;13:e93-e100.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): kidney cancer. Version 3.2016. May 26, 2016. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed July 27, 2016.
- US Food and Drug Administration. Cabozantinib (cabometyx). April 25, 2016. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm497483.htm. Accessed July 22, 2016.
- Cabometyx (cabozantinib) tablets [prescribing information]. South San Francisco, CA: Exelixis; April 2016.
- Choueiri TK, Escudier B, Powles T, et al; for the METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814-1823.
- US Food and Drug Administration. FDA approves Cometriq to treat rare type of thyroid cancer. Press release. November 29, 2012. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm330143.htm. Accessed July 22, 2016.
- Exelixis. Exelixis announces FDA approval of Cabometyx (cabozantinib) tablets for patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. Press release. April 25, 2016. http://ir.exelixis.com/phoenix.zhtml?c=120923&p=irol-newsArticle_print&ID=2161051. Accessed July 27, 2016.
- Exelixis. Accessing Cabometyx (cabozantinib) tablets. 2016. https://hcp.cabometyx.com/downloads/CABOMETYXSpecialtyPharmacyandDistributorFlashcard.pdf. Accessed September 12, 2016.
- ClinicalTrials.gov. Cabozantinib. Search results. https://clinicaltrials.gov/ct2/results?term=cabozantinib&Search=Search. Accessed July 22, 2016.