The combination of Tykerb® (lapatinib) and Herceptin® (trastuzumab) improves progression-free survival with a trend toward improved survival compared with Tykerb monotherapy among HER2-positive breast cancer patients who have progressed on prior Herceptin-containing regimens. These results were recently presented at the 2008 annual meeting of the American Society of Clinical Oncology (ASCO).

Tykerb monotherapy is an effective treatment for metastatic HER2-positive breast cancer that has progressed following Herceptin. As well, the use of Herceptin following progression on Herceptin-based therapies in HER2-positive breast cancer is a common practice, despite a lack of supportive evidence for this practice. Given that studies with cell lines of HER2-positive breast cancer demonstrate synergistic activity with Herceptin and Tykerb, and that both targeted agents have different mechanisms through which anticancer activity is derived (Herceptin blocks HER2 through the PI3 kinase signaling pathway and Tykerb blocks HER2 and EGFR), researchers sought to determine whether the combination of Tykerb and Herceptin in HER2-positive breast cancer that had progressed on prior Herceptin therapy could improve outcomes compared with Tykerb alone.

The current clinical trial (EGF104900 trial) was an open-label, Phase III clinical trial that randomized 296 patients to Tykerb plus Herceptin or Tykerb alone in the treatment of HER2-positive, recurrent breast cancer. Patients had received an average of four or five prior chemotherapy regimens and an average of three prior Herceptin-containing regimens for metastatic disease, with a median time from the last Herceptin regimen being approximately 25 days. Nearly half of all patients were hormone-positive. Patients were randomized to Tykerb (1,500 mg/day) or Tykerb (1,000 mg/day) plus Herceptin (4 mg/kg loading dose followed by 2 mg/kg per week). The following table summarizes the main findings of this clinical trial:

• When adjusting for performance score and extent of disease, overall survival improvement approached significance in the Tykerb/Herceptin arm over Tykerb alone (HR = 0.71;95% CI: 0.50-1.01; P = .0596).
• Adverse events were similar between the two groups except for diarrhea which occurred in 60% of patients treated with combination therapy versus 48% for those treated with Tykerb alone (P=0.03).

Comments: These researchers concluded that the addition of Herceptin to Tykerb significantly improves PFS and clinical benefit compared with Tykerb alone in heavily pre-treated patients with HER2-positive, metastatic breast cancer who have progressed on prior Herceptin-therapies.

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Reference: 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