GlaxoSmithKline (GSK) announced results from a large, randomized, pivotal phase III study of its investigational small-molecule dual kinase inhibitor lapatinib ditosylate (Tykerb). In this study, the combination of lapatinib and capecitabine(Drug information on capecitabine) (Xeloda) vs capecitabine alone nearly doubled time to progression (36.9 weeks in the combination arm vs 19.7 weeks with capecitabine alone, P = .00032) in women with refractory advanced or metastatic HER2 (ErbB2)-positive breast cancer whose disease had progressed following treatment with trastuzumab(Drug information on trastuzumab) (Herceptin) and other cancer therapies. Median progression-free survival was 36.9 weeks for those receiving combination therapy compared with 17.9 weeks for those in the capecitabine monotherapy arm (P = .000045).

Results of this and several other lapatinib studies were presented at the 2006 American Society of Clinical Oncology (ASCO) annual meeting in Atlanta. GSK plans to file for regulatory approval of lapatinib in the United States and Europe in the second half of 2006.

"Because ErbB2-positive breast cancer may eventually progress during or following treatment with trastuzumab, there has been a need for an effective alternative treatment that can successfully block the function of ErbB2 in another way," said Dr. Charles Geyer, director of breast medical oncology at Allegheny General Hospital in Pittsburgh, and principal investigator for this trial. "These results indicate that lapatinib can provide a needed alternative when trastuzumab no longer appears to be helping to control the disease."

Study Details

The international, multicenter, open-label study (EGF100151) enrolled 392 patients who had advanced or metastatic breast cancer with documented ErbB2 overexpression and whose disease progressed following treatment with trastuzumab and other cancer therapies. The interim analysis included 321 patients (160 in the lapatinib-capecitabine arm and 161 in the capecitabine monotherapy arm).

Adverse events leading to discontinuation were similar in the lapatinib/capecitabine combination arm (14%) vs capecitabine alone (11%), as were overall adverse events. In the lapatinib/capecitabine arm, such reactions included diarrhea, hand-foot syndrome, and rash. An asymptomatic relative decrease of greater than or equal to 20% in left ventricular ejection fraction (LVEF), a measure of the strength of the heart observed through electrocardiogram, occurred in 2.5% of patients on the combination arm and less than 1% of patients on capecitabine; all patients recovered normal LVEF.

Lapatinib Activity in Other Settings

Additional analysis from the EGF100151 study suggests that lapatinib may play a role in decreasing the occurrence of brain metastases. Indeed, in the interim analysis, only four patients experienced CNS relapse in the lapatinib/capecitabine arm vs 11 in the capecitabine alone arm. Another study presented at ASCO provides further preliminary evidence suggesting that lapatinib may be effective in treating brain metastases associated with breast cancer. Reported by Dr. Nancy Lin of Dana-Farber Cancer Institute, the phase II trial evaluated lapatinib in 39 patients with HER2-positive breast cancer who had developed CNS metastases while on trastuzumab. Two patients achieved partial responses, and an additional five patients achieved stable disease for at least 16 weeks. The researchers concluded that there is sufficient evidence of preliminary clinical effect to suggest that lapatinib can penetrate the CNS.

Another trial, presented at ASCO by Dr. Neil L. Spector of GSK, evaluated lapatinib as a single agent in patients with relapsed or refractory inflammatory breast cancer. In this study, 57 patients were assigned to one of two groups—HER2 overexpressors and HER2 non-overexpressors. Both groups received daily lapatinib treatment. The analysis presented showed that 62% of patients who were HER2 overexpressors had a clinical response to the drug.