A phase II biomarker-embedded study of lapatinib plus capecitabine as first-line therapy in patients with advanced or metastatic gastric cancer

Melissa J. LaBonte, Dongyun Yang, Wu Zhang, Peter M. Wilson, Yasir M. Nagarwala, Kevin M. Koch, Colleen Briner, Tomomi Kaneko, Sun Young Rha, Oleg Gladkov, Susan G. Urba, Dina Sakaeva, Michael J. Pishvaian, Ruey Kuen Hsieh, Wei Ping Lee, Heinz Josef Lenz

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2251-2258
Number of pages8
JournalMolecular Cancer Therapeutics
Volume15
Issue number9
DOIs
Publication statusPublished - 2016 Sep

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Stomach Neoplasms
Biomarkers
Disease-Free Survival
Esophagogastric Junction
Therapeutics
Single Nucleotide Polymorphism
Pharmacokinetics
Gene Expression
Survival
Capecitabine
lapatinib
Appetite
Fluorouracil
Nausea
Genes
Fatigue
Diarrhea
Biopsy
Messenger RNA
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

LaBonte, Melissa J. ; Yang, Dongyun ; Zhang, Wu ; Wilson, Peter M. ; Nagarwala, Yasir M. ; Koch, Kevin M. ; Briner, Colleen ; Kaneko, Tomomi ; Rha, Sun Young ; Gladkov, Oleg ; Urba, Susan G. ; Sakaeva, Dina ; Pishvaian, Michael J. ; Hsieh, Ruey Kuen ; Lee, Wei Ping ; Lenz, Heinz Josef. / A phase II biomarker-embedded study of lapatinib plus capecitabine as first-line therapy in patients with advanced or metastatic gastric cancer. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 9. pp. 2251-2258.
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abstract = "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.",
author = "LaBonte, {Melissa J.} and Dongyun Yang and Wu Zhang and Wilson, {Peter M.} and Nagarwala, {Yasir M.} and Koch, {Kevin M.} and Colleen Briner and Tomomi Kaneko and Rha, {Sun Young} and Oleg Gladkov and Urba, {Susan G.} and Dina Sakaeva and Pishvaian, {Michael J.} and Hsieh, {Ruey Kuen} and Lee, {Wei Ping} and Lenz, {Heinz Josef}",
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LaBonte, MJ, Yang, D, Zhang, W, Wilson, PM, Nagarwala, YM, Koch, KM, Briner, C, Kaneko, T, Rha, SY, Gladkov, O, Urba, SG, Sakaeva, D, Pishvaian, MJ, Hsieh, RK, Lee, WP & Lenz, HJ 2016, 'A phase II biomarker-embedded study of lapatinib plus capecitabine as first-line therapy in patients with advanced or metastatic gastric cancer', Molecular Cancer Therapeutics, vol. 15, no. 9, pp. 2251-2258. https://doi.org/10.1158/1535-7163.MCT-15-0908

A phase II biomarker-embedded study of lapatinib plus capecitabine as first-line therapy in patients with advanced or metastatic gastric cancer. / LaBonte, Melissa J.; Yang, Dongyun; Zhang, Wu; Wilson, Peter M.; Nagarwala, Yasir M.; Koch, Kevin M.; Briner, Colleen; Kaneko, Tomomi; Rha, Sun Young; Gladkov, Oleg; Urba, Susan G.; Sakaeva, Dina; Pishvaian, Michael J.; Hsieh, Ruey Kuen; Lee, Wei Ping; Lenz, Heinz Josef.

In: Molecular Cancer Therapeutics, Vol. 15, No. 9, 09.2016, p. 2251-2258.

Research output: Contribution to journalArticle

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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

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.

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