Lapatinib is an oral receptor tyrosine kinase inhibitor, inhibiting both the ErbB-1 and ErbB-2 receptors. Lapatinib has been shown to have activity in ErbB-2–overexpressing breast cancer in several phase II and III clinical trials. Specifically, lapatinib is effective in patients with metastatic breast cancer, with inflammatory breast cancer, and possibly, with brain metastases. An ongoing clinical trial and another anticipated clinical trial will investigate lapatinib as adjuvant treatment in early-stage disease.
The pivotal phase III trial, comparing lapatinib plus capecitabine with capecitabine alone, was conducted in patients with refractory ErbB-2–positive metastatic breast cancer who had developed progressive disease following prior treatment with anthracyclines, taxanes, and trastuzumab. Patients were randomized to receive either oral lapatinib plus oral capecitabine or capecitabine alone. At the first protocol-specified interim analysis, the independent data monitoring committee unanimously recommended study termination based on a statistically significant advantage in the primary endpoint, time to progression (TTP). In the lapatinib plus capecitabine arm, the median TTP was 8.4 months, versus 4.4 months in the capecitabine-alone arm (p < .001). The overall response rate was 22% in the lapatinib plus capecitabine group and 14% in the capecitabine-alone group (p = .09) in the independent intent-to-treat analysis. The addition of lapatinib to capecitabine significantly improves TTP and is an effective regimen for women with advanced ErbB-2 – positive breast cancer. It is now FDA approved.
Tykerb/Xeloda is now FDA approved. TYKERB is indicated in combination with Xeloda® (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 Herceptin® (trastuzumab).
There has not been a study comparing Xeloda/Tykerb to Tykerb/Herceptin. For first line, it is in a trial: Capecitabine (Xeloda) and Lapatinib (Tykerb) as First-Line Therapy in HER2/Neu-Positive Breast Cancer, NCT00496
Another way to give Tykerb is with Femara. The addition of lapatinib to letrozole is well tolerated and leads to a significantly greater PFS time, ORR, and CBR than with letrozole alone in women with MBC who coexpress HR and HER-2. On January 29 2010, Tykerb had received FDA approval for use as a first-line breast cancer therapy in combination with the letrozole for the treatment of hormone-receptor positive metastatic breast cancer, in patients whose tumours overexpress the HER2/ErbB2 receptor and for whom hormonal therapy is indicated.
The combination of Tykerb/Taxotere is in an active trial: Lapatinib in Combination With Docetaxel in Patients With HER-2 Positive Advanced or Metastatic Breast Cancer (LapDoc). The objective of this phase I/ II study is therefore to assess the safety and efficacy of lapatinib in combination with docetaxel in patients with advanced cancer.
In the study by Di Leo et al, intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between lapatinib with paclitaxel versus paclitaxel alone, although differences in ORR and CBR were noted. In 86 HER-2–positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2–negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms. Patients with HER-2–negative or HER-2–untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2–positive patients. Amir et al provided tHe following interpretation fo this study:The appropriate conclusions to this study are that when administered with paclitaxel, lapatinib did not have a significant effect on time to progression, but was associated with a significantly increased risk of morbidity and a trend toward increased mortality.”
Use of Tykerb in patients who had not had antrhacyclines is supported by several phase II studies.
Angelo Di Leo, Henry L. Gomez, Zeba Aziz, Zanete Zvirbule, Jose Bines, Michael C. Arbushites, Stephanie F. Guerrera, Maria Koehler, Cristina Oliva, Steven H. Stein, Lisa S. Williams, Judy Dering, Richard S. Finn, Michael F.Phase III, Double-Blind, Randomized Study Comparing Lapatinib Plus Paclitaxel With Placebo Plus Paclitaxel As First-Line Treatment for Metastatic Breast Cancer Journal of Clinical Oncology, Vol 26, No 34 (December 1), 2008: pp. 5544-5552
Eitan Amir, Bostjan Seruga, Orit Freedman, and Ian Tannock Lapatinib Plus Paclitaxel As First-Line Therapy for Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Inappropriate Conclusions From a Company-Sponsored Study?
JCO Apr 10, 2009:1919
Gomez HL, Chavez MA, Doval DC et al. A phase II, randomized trial using the small molecule tyrosine kinase inhibitor lapatinib as a first-line treatment in patients with FISH positive advanced or metastatic breast cancer. J Clin Oncol 2005;23(suppl 16):203S.
Trudeau M, Johnston S, Kaufman et al. Lapatinib (Tycerb) monotherapy in patients with recurrent inflammatory breast cancer (IBC): Clinical activity and biologic predictors of response. Ann Oncol 2006;17(suppl 9):ix69
O’Shaughnessy J, Blackwell KL, Burstein H, et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May 30 – June 3, 2008; Chicago, Illinois. Abstract 1015
Schwartzberg, Lee S. , Franco, Sandra X. , Florance, Allison , O’Rourke, Lisa , Maltzman, Julie , Johnston, Stephen Lapatinib plus Letrozole as First-Line Therapy for HER-2+ Hormone Receptor-Positive Metastatic Breast Cancer
Oncologist 2010 15: 122-129;