Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer

Abstract

Background: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), which are reported as overexpressed in 15%–45% of gastric cancers, making them potential targets.Patients and methods: The primary objective of this study was to assess response rate. Secondary objectives included overall survival (OS), toxicity, and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome. Lapatinib was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days.Results: The study enrolled 47 patients from February 2005 until May 2006. Four patients (9%) had a confirmed partial response (PR), 1 (2%) had an unconfirmed PR, and 10 (23%) had stable disease. Median (95% confidence interval) time to treatment failure was 1.9 (1.6–3.1) months and OS was 4.8 (3.2–7.4) months. Significant adverse events: one grade 4 cardiac ischemia/infarction, one grade 4 fatigue, and one grade 4 emesis. One treatment-related death was due to central nervous system ischemia. An exploratory analysis of markers revealed gene expression of HER2, interleukin (IL)-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS.Conclusions: Lapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients. Potential molecular correlatives were identified which warrant further validation.

Optimal chemotherapy for advanced gastric cancer: is there a global consensus?

“…Lapatinib, an oral tyrosine kinase inhibitor against both EGFR and HER2, has modest single activity in the firstline setting [57]. Results of the randomized phase III TRIO-013/Logic trial were recently presented [58].…”

A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer

“…Importantly, while TS overexpression The cut-off value of gene expression was based on our previous studies (31,38,47). d The cut-off value was based on the optimal cut-off point for PFS and P values were adjusted accordingly (48).…”

“…To date, lapatinib appears to have minimal activity as a single agent in first-line therapy of advanced/metastatic gastroesophageal junction and gastric cancer based upon preliminary data from phase II and III clinical studies (31)(32)(33). Although the study investigating lapatinib as first-line therapy in patients with advanced or metastatic gastric cancer met first-stage criteria and went on to complete enrollment (31), the study investigating lapatinib in relapsed adenocarcinoma of the esophagus stopped early because of rapid progression of disease.…”

Los receptores epidérmicos humanos en el cáncer gástrico: alteraciones moleculares y su papel como diana terapéutica

“…Es un inhibidor más potente para HER1 y HER2 que para HER4 (> 10×) 91 . Obtuvo los mejores resultados en pacientes con CG avanzado con paclitaxel 71 y en combinación con capecitabina y oxaliplatino 79 , en comparación con su administración unica 77 o combinada solo con capecitabina 79 (Tabla 2). El afatinib es un inhibidor irreversible de HER1 y HER2 que ha demostrado actividad antitumoral in vivo en pacientes con CG HER2+ 91,93 .…”