Pharmacological Class:
Kinase inhibitor.

Active Ingredient(s):
Cabozantinib 20mg, 80mg; caps.

Company
Exelixis, Inc.
Indication(s):
Treatment of progressive, metastatic medullary thyroid cancer (MTC).

Pharmacology:
Cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

Clinical Trials:
The safety and efficacy of Cometriq was assessed in a double-blind, controlled trial of 330 patients. The main efficacy outcome measures were progression-free survival (PFS), objective response (OR), and response duration. A statistically significant prolongation in PFS was demonstrated among Cometriq-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p <0.0001], with median PFS times of 11.2 months and 4 months in the Cometriq and placebo arms, respectively. Partial responses were observed only among patients in the Cometriq arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with Cometriq. There was no statistically significant difference in overall survival between the treatment arms at the planned interim analysis.

Legal Classification:
Rx

Adults:
Swallow whole. 140mg daily. Do not eat at least 2 hours before or 1 hour after dose. Continue until disease progression or unacceptable toxicity. Withhold for Grade 4 hematologic adverse reactions, ≥Grade 3 non-hematologic reactions or intolerable Grade 2 reactions. Upon improvement to Grade 1 or to baseline, reduce dose as follows: previously on 140mg daily, resume at 100mg daily; previously on 100mg daily, resume at 60mg daily; previously on 60mg daily, resume at 60mg if tolerated, otherwise discontinue. Concom­itant strong CYP3A4 inhibitor: reduce daily dose by 40mg; resume dose used prior to starting inhibitor 2–3 days after dis­con­tin­u­a­tion of inhibitor. Con­com­itant strong CYP3A4 i­nducers: increase daily dose by 40mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 180mg.

Children:
Not studied.

Warnings/Precautions:
Permanently discontinue if the following occurs: GI or non-GI perforation/fistula formation, severe hemorrhage, serious arterial thrombo­em­bolic events (eg, MI, cerebral infarction), nephrotic syndrome, malignant hypertension, ­hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome. Moderate-to-severe hepatic impairment: not recommended. Recent history of hemorrhage, hemoptysis: avoid. Stop treatment at least 28 days prior to scheduled surgery (including invasive dental procedures); withhold dose if dehiscence or wound healing complications require medical intervention. Monitor for bleeding, hypertension, proteinuria (measure urine protein regularly). Use effective contraception during and up to 4 months after completion of therapy. Pregnancy (Cat. D). Nursing mothers: not recommended.

Interaction(s)
Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarith­ro­mycin, atazanavir, nefazodone, saquinavir, telith­romycin, ritonavir, indinavir, nelfinavir, voriconazole, grapefruit or grapefruit juice) and strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort): see Adult dose.

Adverse Reaction(s)
Diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight/appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, constipation, increased AST, ALT, alkaline phospha­tase, lymphopenia, hypocalcemia, neutro­penia, thrombocytopenia, hypophospha­te­mia, hyper­bilirubinemia.

How Supplied:
140mg daily-dose carton—4 blister cards (each: 7x80mg and 21x20mg caps); 100mg daily-dose carton—4 blister cards (each: 7x80mg and 7x20mg caps); 60mg daily-dose carton—4 blister cards (each: 21x20mg caps)

LAST UPDATED:
1/18/2013