Phase I study of lapatinib, a dual-tyrosine kinase inhibitor, and pemetrexed in the second-line treatment of advanced or metastatic non-small cell lung cancer

Abstract

e19027 Background: Lapatinib is an oral, reversible small-molecule inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). EGFR overexpression is very common in non-small-cell lung cancer (NSCLC), ranging from 30% to 83%, whereas HER2 overexpression occurs in about 20%. Pemetrexed is currently given as second-line therapy and achieves a 9% response rate. The rationale for EGFR/HER2 inhibition in combination with pemetrexed is to demonstrate clinical synergy as previously shown with gemcitabine, another fluoropyrimidine pathway inhibitor. Methods: Eligible patients included those with stage IIIB or IV NSCLC and European Cooperative Oncology Group performance status of 0–2 following 1 previous chemotherapy treatment. Patients were treated in 3 escalating dose levels (DLs) of pemetrexed (given intravenously every 21 days) and daily lapatinib (DL 0: 400 mg/1,250 mg; DL 1: 500 mg/1,250 mg; DL 2: 500 mg/1,500 mg, respectively). A standard phase 1, 3+3 trial design was used. The primary objective was to determine the optimal treatment regimen. Results: Eighteen patients were treated (DL 0: n=4, DL 1: n=8; DL 2: n=6). The most common adverse events (any grade) were diarrhea (61%), rash (44%), fatigue (28%), nausea (28%), anemia (28%), anorexia (22%), vomiting (22%), dyspnea (17%), and neutropenia (17%). Grade 3/4 adverse events were lymphocytopenia (n=5) and neutropenia (n=5). Other related grade 3 events were diarrhea (n=2), nausea (n=1), decreased ejection fraction (n=1), and increased alkaline phosphatase (n=1). The optimal treatment regimen was determined as lapatinib 1250 mg given with 500 mg pemetrexed after occurrence of 3 dose-limiting toxicities during the first cycle in DL 2 (grade 3 diarrhea, grade 4 lymphocytopenia, and grade 3 mucositis). No further dose-limiting toxicities were observed in DL 0 or DL 1. Preliminary evidence of clinical activity was encouraging, with 3 patients showing partial response. Conclusions: The combination of lapatinib with pemetrexed is well tolerated; encouraging activity has been demonstrated in pretreated NSCLC patients and warrants further studies. [Table: see text]