Zaks, Tal

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 Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49