TY - JOUR
T1 - A phase II biomarker-embedded study of lapatinib plus capecitabine as first-line therapy in patients with advanced or metastatic gastric cancer
AU - LaBonte, Melissa J.
AU - Yang, Dongyun
AU - Zhang, Wu
AU - Wilson, Peter M.
AU - Nagarwala, Yasir M.
AU - Koch, Kevin M.
AU - Briner, Colleen
AU - Kaneko, Tomomi
AU - Rha, Sun Young
AU - Gladkov, Oleg
AU - Urba, Susan G.
AU - Sakaeva, Dina
AU - Pishvaian, Michael J.
AU - Hsieh, Ruey Kuen
AU - Lee, Wei Ping
AU - Lenz, Heinz Josef
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/9
Y1 - 2016/9
N2 - An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinibinduced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinomaindependent of tumorHER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m2 twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve 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 adverse events 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 gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine.
AB - An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinibinduced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinomaindependent of tumorHER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m2 twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve 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 adverse events 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 gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine.
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U2 - 10.1158/1535-7163.MCT-15-0908
DO - 10.1158/1535-7163.MCT-15-0908
M3 - Article
C2 - 27325685
AN - SCOPUS:84990985684
SN - 1535-7163
VL - 15
SP - 2251
EP - 2258
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 9
ER -
