Cardiac safety of the lapatinib/letrozole combination as first-line therapy in patients (pts) with metastatic breast cancer (MBC)

1095 Background: Cardiotoxicity of traztuzumab therapy increases in pts pretreated with anthracyclines (A), radiotherapy to left breast, hypertension, or low baseline ejection fraction (EF). We report the cardiac safety profile of lapatinib, an oral, dual EGFR/HER-2 tyrosine kinase inhibitor, in a chemotherapy naïve or A-exposed pts with MBC. Methods: Women (n = 1286) with endocrine sensitive, previously untreated MBC received lapatinib and letrozole (L+L) or letrozole and placebo (L+P): 33% received previous A; 48% previous tamoxifen; <1% previous trastuzumab (T); <2% previous aromatase inhibitor. EF was evaluated by MUGA or echocardiogram at baseline, every 8 wk and at study withdrawal. Rate of cardiac events (NCI CTCAE grading), median time to onset, and duration of EF depression were assessed. Results: Cardiac events (CE; MEDRA terms: ejection fraction decreased, left ventricular dysfunction, ventricular dysfunction and cardiac failure) were infrequent in both arms. Grade 3/4 and 1/2 CE were reported in 0.9% and 4.0% of pts, respectively, in the L+L arm, and in 0.3% and 2.1%, respectively, in the L+P arm. The only symptomatic CE was a grade 4 event in the L+L arm. There was no apparent relationship between previous A exposure and CE frequency and severity. Median L exposure was 40 wk on L+L, 38 wk on L+P. Median time to onset and duration of EF decrease were 21.8 and 8.1 wk, respectively, on L+L, and 34.6 and 5.4 wk, respectively on L+ P. On the L+L arm, the dose was adjusted/interupted for 8 CE cases, discontinued for 6, and unchanged for 22. On the L+P arm, interuption of L was reported for 2 CE cases, discontinuation for 5, and in 7 CE events there was no change in therapy. Eight CE on L+L and 1 CE on L+P had not resolved as of the last report. Conclusions: This is the first long-term evaluation of lapatinib cardiac signals in a controlled trial in a trastuzumab-naïve MBC pt population. The frequency of cardiac events and degree of absolute EF decrease was low and occurred at similar rates in pts with or without anthracycline exposure. These encouraging cardiac safety data in first line metastatic BC study are promising for the ongoing study of lapatinib in patients with early HER-2+ BC treated on ALTTO trial. [Table: see text]