General Information

Tykerb is an inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER-2 [ErbB2]) receptors. Mutations in either of these receptors have been shown to play a role in cancer.

Tykerb is specifically indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane and trastuzumab.

Mechanism of Action

Tykerb is an inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER-2 [ErbB2]) receptors. When the binding site is blocked signal molecules can no longer attach there and activate the tyrosine kinase, an enzyme which functions to stimulate cell division. The over-expression of EGFR and HER-2 have been associated with a number of cancers, including breast cancer.

Side Effects

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

• diarrhea
• palmar-plantar erythrodysesthesia
• nausea
• rash
• vomiting
• mucosal inflammation
• stomatitis
• pain in extremities
• dyspnea
• fatigue

Dosing/Administration

Tykerb is supplied as a 250 mg tablet designed for oral administration. The recommended initial dose of the drug is 1,250 mg (five tablets) given orally once daily on days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in two doses approximately 12 hours apart) on days 1-14 in a repeating 21-day cycle. Dividing the daily dose is not recommended. Tykerb should be discontinued in patients with decreased left ventricular ejection fraction (LVEF) that is grade 2 or greater by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the institution’s lower limit of normal. Treatment may be restarted at a reduced daily dose (1,000 mg) after a minimum of two weeks if the LVEF recovers to normal and the patient is asymptomatic. Patients with severe hepatic impairment should have their dose reduced. The concomitant use of strong CYP3A4 inhibitors and inducers should be avoided. If a grade 2 NIC CTC toxicity occurs, discontinuation or interruption with Tykerb may be considered. Treatment can be restarted at 1,250 mg/day when toxicity improves to grade 1 or less.

Clinical Trial Results

FDA approval of Tykerb in combination with capecitabine was based on the results of one clinical trial. This trial enrolled 399 subjects with HER-2 over-expressing locally advanced or metastatic breast cancer, progressing after prior treatment that included anthracyclines, taxanes and trastuzumab. Subjects were randomized to receive either Tykerb 1,250 mg once daily (continuously) plus capecitabine 2,000 mg/m2/day on days 1-14 every 21 days, or to receive capecitabine alone at a dose of 2,500 mg/m2/day on days 1-14 every 21 days. The primary endpoint was time to progression (TTP) defined as time from randomization to tumor progression or death related to breast cancer. The median TTP was 23.9 weeks for the combination treatment versus 18.3 weeks for capecitabine alone, for a response rate of 31.8 percent versus 17.4 percent, respectively.