General Information

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.

Tykerb is supplied as a 250 mg tablet designed for oral administration. The recommended initial dose of the drug is 1,250 mg (5 tablets) given orally once daily on days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 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 stron 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 Results

FDA Approval
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% versus 17.4%, respectively.

Ongoing Study Commitments

GlaxoSmithKline has agreed to perform an in vivo drug interaction study of the ability of steady-state lapatinib dosing to alter the pharmacokinetics of a single dose of midazolam. A positive finding in this study may initiate a need for further studies.
Protocol Submission: October1, 2005
Study Start: Ongoing
Final Report Submission: June 2008

GlaxoSmithKline has agreed to perform an in vivo drug interaction study of the ability of steady-state lapatinib dosing to alter the pharmacokinetics of a single dose of paclitaxel or rosiglitazone. A positive finding in this study may initiate a need for further studies.
Protocol Submission: October 7, 2002
Study Start: Ongoing
Final Report Submission: June 2007

GlaxoSmithKline has agreed to perform an in vivo drug interaction study of the ability of steady-state lapatinib dosing to alter the pharmacokinetics of a single dose of digoxin. A positive finding in this study may initiate a need for further studies.
Protocol Submission: September 2007
Study Start: November 2007
Final Report Submission: December 2009

GlaxoSmithKline has agreed to submitting the results of the survival analysis of Study EGF100151 at 75% of the events.
Protocol Submission: November 2003
Study Start: Ongoing
Final Report Submission: June 2008

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.

Literature References

Montemurro F, Valabrega G, Aglietta M Lapatinib: a dual inhibitor of EGFR and HER2 tyrosine kinase activity. Expert opinion on biological therapy 2007 Feb;7(2):257-68.

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D Lapatinib plus capecitabine for HER2-positive advanced breast cancer. The New England journal of medicine 2006 Dec 28;355(26):2733-43.

Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, Untch M, Rusnak DW, Spehar G, Mullin RJ, Keith BR, Gilmer TM, Berger M, Podratz KC, Slamon DJ Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Advances in cancer research 2006 Feb 1;66(3):1630-9.

Chu I, Blackwell K, Chen S, Slingerland J The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Advances in cancer research 2005 Jan 1;65(1):18-25.

Burris HA 3rd Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. The oncologist 2004;9 Suppl 3:10-5.