Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials.
OBJECTIVE
To analyze the cardiac safety of lapatinib, an oral, reversible, tyrosine kinase EGFR (ERBB1) and HER2 inhibitor, using prospective data collected in 44 clinical studies.


METHODS
Lapatinib (as monotherapy or in combination) was administered to 3689 patients in studies conducted between January 5, 2001, and September 30, 2006. Left ventricular ejection fraction (LVEF) was prospectively evaluated via multiple-gated acquisition scan or echocardiography at screening, every 8 weeks during therapy, and at withdrawal. We analyzed cardiac events defined as symptomatic (grade 3 or 4 left ventricular systolic dysfunction according to the National Cancer Institute Common Terminology Criteria for Adverse Events) or asymptomatic (LVEF decreases > or = 20% relative to baseline and below the institution's lower limit of normal; no symptoms).


RESULTS
A study-defined cardiac event was reported in 60 patients (1.6%) previously treated with anthracyclines (n=12), trastuzumab (n=14), or neither (n=34). These prior treatments were associated with a 2.2%, 1.7%, and 1.5% incidence of cardiac events, respectively. In most patients (53 patients, 83%), events were not preceded by symptoms. Mean times to onset and duration of LVEF decrease were 13.0 and 7.3 weeks, respectively. The decrease in LVEF was rarely severe; the mean nadir was 43%. In 40 patients for whom outcome was determined, 35 (88%) had a partial or full recovery regardless of continuation or discontinuation of lapatinib. No cardiac deaths occurred among patients treated with lapatinib.


CONCLUSIONS
Our review of data from 44 clinical studies revealed low levels of cardiotoxicity for lapatinib. Cardiac events were usually asymptomatic, caused reversible decreases in LVEF, and occurred at similar rates in patients who were and were not pretreated with anthracyclines or trastuzumab.
Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA. perez.edith@mayo.edu
Edith A
EA
Perez
Maria
M
Koehler
Julie
J
Byrne
Alaknanda J
AJ
Preston
Erica
E
Rappold
Michael S
MS
Ewer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D005260:Female; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects* / Q000627:therapeutic use; D013318:Stroke Volume / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib