CABOMETYX™ (cabozantinib) safety in the METEOR trial

Adverse reactions occurring in ≥10% of patients in the CABOMETYX™ arm1

CABOMETYX™(n=331) everolimus(n=322)
Adverse Reaction* All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients   
Gastrointestinal disorders
Diarrhea 74 11 28 2
Nausea 50 4 28 <1
Vomiting 32 2 14 <1
Stomatitis 22 2 24 2
Constipation 25 <1 19 <1
Abdominal pain§ 23 4 10 1
Dyspepsia 12 <1 5 0
General disorders and administration site conditions
Fatigue 56 9 47 7
Mucosal inflammation 19 <1 23 3
Asthenia 19 4 16 2
Metabolism and nutrition disorders
Decreased appetite 46 3 34 <1
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome 42 8 6 <1
Rash§ 23 <1 43 <1
Dry skin 11 0 10 0
Vascular disorders
Hypertension§ 39 16 8 3
Investigations
Weight decreased 31 2 12 0
Nervous system disorders
Dysgeusia 24 0 9 0
Headache 11 <1 12 <1
Dizziness 11 0 7 0
Endocrine disorders
Hypothyroidism 21 0 <1 <1
Respiratory, thoracic, and mediastinal disorders
Dysphonia 20 <1 4 0
Dyspnea 19 3 29 4
Cough 18 <1 33 <1
Blood and lymphatic disorders
Anemia 17 5 38 16
Musculoskeletal and connective tissue disorders
Pain in extremity 14 1 8 <1
Muscle spasms 13 0 5 0
Arthralgia 11 <1 14 1
Renal and urinary disorders
Proteinuria 12 2 9 <1

Laboratory Abnormalities Occurring in ≥25% of Patients in the CABOMETYX™ arm1

CABOMETYX™(n=331) everolimus(n=322)
Test All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients   
Chemistry
AST increased 74 3 40 <1
ALT increased 68 3 32 <1
Creatinine increased 58 <1 71 0
Triglycerides increased 53 4 73 13
Hypophosphatemia 48 8 36 5
Hyperglycemia 37 2 59 8
Hypoalbuminemia 36 2 28 <1
ALP increased 35 2 29 1
Hypomagnesemia 31 7 4 <1
Hyponatremia 30 8 26 6
GGT increased 27 5 43 9
Hematology
White blood cells decreased 35 <1 31 <1
Absolute neutrophil count decreased 31 2 17 <1
Hemoglobin decreased 31 4 71 17
Lymphocytes decreased 25 7 39 12
Platelets decreased 25 <1 27 <1

AST=Aspartate aminotransferase, ALT=Alanine aminotransferase, ALP=Alkaline phosphatase, GGT=Gamma glutamyl transferase.

*Percentages are treatment-emergent, all-causality events.
One subject randomized to everolimus received CABOMETYX™.
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0.
§These adverse reactions are grouped terms. For details, please see full Prescribing Information.

Most common adverse reactions1

  • The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation

Discontinuation rates1

  • Discontinuation rates due to adverse events were similar between CABOMETYX™ (10%) and everolimus (10%)

References: 1. CABOMETYX™ (cabozantinib) Prescribing Information. Exelixis, Inc., 2016. 2. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016. 3. Data on file. Exelixis, Inc. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.2.2016. © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed April 28, 2016. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Indication

CABOMETYX™ (cabozantinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy.

Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX™. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.

Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility―CABOMETYX may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information by clicking here.

+

Indication and Important Safety Information

Indication

CABOMETYX™ (cabozantinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy.

Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX™. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.