An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib induced fluoropyrmiinde gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer (GC) or gastroesophageal junction (GeJ) adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1250mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1000mg/m2 BID, 14/21 days) plus lapatinib 1250mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives: response rate (RR), 5-month progression-free survival (PFS). Secondary objectives: overall survival (OS), PFS, time-to-response, duration-of-response, toxicity and identify associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives: modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. 68 patients were enrolled; (75% GC, 25% GeJ). 12 patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent AEs included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs 0%, p=0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced GC. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine.
- Received November 11, 2015.
- Revision received April 22, 2016.
- Accepted May 5, 2016.
- Copyright ©2016, American Association for Cancer Research.