A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy

Abstract

1015 Background: Lapatinib (L) is an oral, small-molecule inhibitor of EGFR and HER2 with a mechanism of action distinct from that of trastuzumab (T). Preclinical data suggest synergy between L and T. We studied L alone and in combination with T in pts with HER2+ MBC who progressed on T. Methods: Eligible women had received prior anthracycline and taxane therapy, had MBC with measurable lesions or bone-only disease, and had progressed on prior T-containing therapy. Pts were stratified by hormone receptor status and visceral/nonvisceral disease, then randomized to receive either L (1,500 mg QD) or L (1,000 mg QD) plus T (2 mg/kg weekly after 4 mg/kg loading dose). If pts progressed on the L arm, they could cross over to the L+T arm. The primary endpoint was PFS (investigator assessment), and secondary endpoints were clinical benefit rate (CBR) at 24 wks, RR, and OS. Results: 296 pts were randomized. All pts had received prior T; the median number of prior chemotherapy regimens was 6. Combination therapy significantly improved PFS and CBR; RR and OS were similar in both arms (Table). Both treatment regimens were generally well tolerated. Grade 1/2 diarrhea was higher in the L+T arm (53% vs 41%); acneiform rash was more common in the L-alone arm, likely due to higher L dose. Asymptomatic decline in LVEF (> 20% and below LLN) occurred in 5% of pts in L+T arm and 2% of pts in L-alone arm. 1 death occurred due to cardiac toxicity in the L+T arm. Conclusions: This is the largest study of 2 targeted agents in HER2+ MBC and the first to demonstrate the synergy of L+T in a phase III setting. Improved clinical outcome was achieved with the combination of L+T in pts progressing on T-based therapy and without a substantial change in the side effect profile. The role of combined anti-HER2 therapy, in combination with chemotherapy, in less heavily pretreated patients with early stage disease is ongoing in the ALTTO (Adjuvant L and/or T Treatment Optimization) study. Endpoint L L + T Hazard/OR 95% CI P value PFS (median, wks) * 8.4 12.0 0.77 0.6, 1.0 0.029 CBR (%) * 13.2 25.2 2.1 1.1, 4.2 0.020 RR (%) * 6.9 10.3 1.5 0.6, 3.9 0.46 OS (median, wks) 39 51.6 0.75 0.5, 1.1 0.106 * Intent to treat. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline Exelixis, GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline