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

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

doi: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

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

School of Medicine, Dentistry and Biomedical Sciences

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Abstract

An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 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/m(2) 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 language	English
Journal	Molecular Cancer Therapeutics
Volume	15
Issue number	9
DOIs	https://doi.org/10.1158/1535-7163.MCT-15-0908
Publication status	Published - 01 Sept 2016

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10.1158/1535-7163.MCT-15-0908Licence: Unspecified

A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer
© 2016 American Association for Cancer Research This work is made available online in accordance with the publisher’s policies.
Accepted author manuscript, 277 KBLicence: Unspecified

Melissa LaBonte Wilson
- M.LaBonteWilsonqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Senior Lecturer
- Patrick G Johnston Centre for Cancer Research
Person: Academic

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LaBonte Wilson, M., Yang, D., Wilson, P., Zhang, W., Nagarwala, Y., Koch, K., Briner, C., Kaneko, T., Rha, S.-Y., Gladkov, O., Urba, S., Sakaeva, D., Pishvaian, M., Hsieh, R.-K., Lee, W.-P., & Lenz, H.-J. (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, 15(9). https://doi.org/10.1158/1535-7163.MCT-15-0908

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

abstract = "An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 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/m(2) 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 Wilson}, Melissa and Dongyun Yang and Peter Wilson and Wu Zhang and Yasir Nagarwala and Kevin Koch and Colleen Briner and Tomomi Kaneko and Sun-Young Rha and Oleg Gladkov and Susan Urba and Dina Sakaeva and Michael Pishvaian and Ruey-Kuen Hsieh and Wei-Ping Lee and Heinz-Josef Lenz",

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LaBonte Wilson, M, Yang, D, Wilson, P, Zhang, W, Nagarwala, Y, Koch, K, Briner, C, Kaneko, T, Rha, S-Y, Gladkov, O, Urba, S, Sakaeva, D, Pishvaian, M, Hsieh, R-K, Lee, W-P & Lenz, H-J 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. https://doi.org/10.1158/1535-7163.MCT-15-0908

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 Wilson, Melissa

AU - Yang, Dongyun

AU - Wilson, Peter

AU - Zhang, Wu

AU - Nagarwala, Yasir

AU - Koch, Kevin

AU - Briner, Colleen

AU - Kaneko, Tomomi

AU - Rha, Sun-Young

AU - Gladkov, Oleg

AU - Urba, Susan

AU - Sakaeva, Dina

AU - Pishvaian, Michael

AU - Hsieh, Ruey-Kuen

AU - Lee, Wei-Ping

AU - Lenz, Heinz-Josef

PY - 2016/9/1

Y1 - 2016/9/1

N2 - An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 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/m(2) 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 lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 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/m(2) 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

U2 - 10.1158/1535-7163.MCT-15-0908

DO - 10.1158/1535-7163.MCT-15-0908

M3 - Article

SN - 1535-7163

VL - 15

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 9

ER -

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

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Melissa LaBonte Wilson

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