Citations

583 Background: Lapatinib is an orally bioavailable reversible, dual tyrosine kinase ErbB1 and ErbB2 inhibitor. Trastuzumab, an ErbB2 inhibitor, has been associated with cardiotoxicity. Methods: Left ventricular ejection fraction (LVEF) was monitored every 8 weeks using MUGA or echocardiogram. Cardiac risk factors including age, underlying cardiovascular disease, previous exposure to AC, trastuzumab, or mediastinal/left sided radiation (XRT) were also collected. LVEF data were evaluated for ≥ NCI CTC grade 3, or ≥ 20% decline relative to baseline (& below institutional LLN). Results: 1.3%, 37 of the 2812 subjects who have received lapatinib in all trials to date have experienced decreased LVEF. 22 of 37 patients received lapatinib monotherapy, the remaining 15 received lapatinib in combination with other chemotherapeutic agents. 68% (25/37) of patients were female, median age was 59 years. Decreased LVEF occurred within 9 weeks of treatment onset in 68% of cases. The event resolved/improved in 57% of cases: in 50% of these, lapatinib treatment was continued. Average event duration was 5 weeks. Four of 37 patients were symptomatic (0.1% incidence). Most symptomatic events responded promptly to standard CHF therapy. The majority of patients (92%, 34/37) had confounding factors that may have contributed to the event, including previous exposure to AC, trastuzumab or XRT, and/or medical history. 8 of 34 patients had a positive lapatinib dechallenge (LVEF recovered): 3 were symptomatic (signs of CHF) and 5 asymptomatic. 3 patients had no contributing factors: 1 experienced symptomatic decreased LVEF, the remaining 2 died due to disease progression whilst LVEF decrease was ongoing. 16 of 1307 patients participating in placebo controlled studies experienced decreased LVEF. Of these 8 are known to have received lapatinib, giving an incidence of 1.2% (8/654). Conclusions: Lapatinib-associated LVEF decrease is rarely symptomatic and generally reversible/non-progressive. Incidence was 1.3% in our population, less than the 3–6% incidence of asymptomatic LVEF decreases observed in the general population. Pharmacogenetic studies are ongoing to determine whether there is a link between ErbB2 polymorphisms and lapatinib cardiotoxicity. [Table: see text]

ABSTRACT Protective antigen (PA)-specific antibody and cell-mediated immune (CMI) responses to annual and alternate booster schedules of anthrax vaccine adsorbed (AVA; BioThrax) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: a 3-dose intramuscular (IM) priming series (0, 1, and 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30, and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, and 18 months) and two annual boosters (30 and 42 months) administered either subcutaneously (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time points. Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of gamma interferon (IFN-γ)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), lymphocyte stimulation indices (SI), and induction of IFN-γ, IL-2, IL-4, IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7, r 2 = 0.86, P < 0.0001, log 10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.)