ASCO Lapatinib (Tykerb), an oral small-molecule reversible dual inhibitor of HER1 (EGFR) and HER2 tyrosine kinases, is emerging as a promising option for HER2-positive breast cancer patients, investigators of phase II and III trials reported at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO). Clinical evidence suggests that lapatinib, unlike trastuzumab (Herceptin), can cross the blood-brain barrier to treat brain metastases, which develop in about one-third of HER2-positive breast cancer patients.
Lapatinib and trastuzumab activity may be complementary, researchers said, and there is potential for synergy, as lapatinib blocks the intracellular portion of HER1 and HER2 homodimers and heterodimers, while trastuzumab blocks the extracellular portion of HER2.
In a scientific special session, Charles E. Geyer, Jr., MD, of Allegheny General Hospital, Pittsburgh, presented results of a phase III international multicenter trial showing substantial improvement in time to progression (TTP) with the oral combination of lapatinib plus capecitabine (Xeloda) and fewer brain metastases vs capecitabine alone in HER2-positive women with locally advanced or metastatic trastuzumab-refractory disease.
Dr. Geyer said there is preclinical evidence that dual blockade of signaling may be more effective than single-agent inhibition provided by agents such as trastuzumab. An important rationale for combining lapatinib and capecitabine, he explained, is that "inhibition of HER1 has been seen in preclinical studies to possibly potentiate one of the major metabolites of capecitabine, 5'-DFUR. This has been shown with gefitinib [Iressa] and with a dual inhibitor that is closely related to lapatinib."
The study included 321 capecitabine-naive women with advanced HER2-positive breast cancer refractory to an anthracycline or taxane in the adjuvant or metastatic setting and to trastuzumab in the metastatic setting. All eligible patients had measurable disease by RECIST and normal left ventricular ejection fraction (LVEF). Disease status was assessed every two cycles at 6-week intervals for the first 6 months and then every 12 weeks until progression. Patients were randomized to combination therapy (lapatinib 1,250 mg/m2 daily continuously plus capecitabine 1,000 mg/m2/bid on days 1 to 14 every 3 weeks) or capecitabine alone at 1,250 mg/m2/bid daily on days 1 to 14 every 3 weeks.
'Clinically Meaningful' Results
After an independent radiographic review committee determined that 114 of 321 patients had met progression criteria of the protocol, a planned interim analysis was performed by an independent statistician and then reviewed by an Independent Data Monitoring Committee (IDMC). On March 20, 2006, the IDMC recommended accrual be discontinued, citing demonstration of "a clinically meaningful statistically significant advantage in the primary endpoint TTP in the combination vs the capecitabine-alone group," according to Dr. Geyer. TTP was 36.9 weeks with combination therapy vs 19.7 weeks with capecitabine alone (HR 0.51, 95% CI 0.35 to 0.74, P = .00016).
There was a similar advantage in progression-free survival (PFS); median PFS was 36.9 weeks in the combination group vs 17.9 weeks with capecitabine alone (HR 0.48, P = .000045). The overall response rate was higher with lapatinib/capecitabine, at 22.5% vs 14.3% for capecitabine alone, but did not reach statistical significance. In addition, Dr. Geyer reported, fewer women treated with lapatinib/capecitabine developed central nervous system (CNS) relapses, compared with women who received capecitabine alone (4 vs 11 patients, respectively).