A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer.
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. Mol Cancer Ther; 15(9); 2251-8. ©2016 AACR.
Azusa Pacific University, Azusa, California. Queen's University Belfast, Belfast, United Kingdom.
Melissa J
MJ
LaBonte
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
Dongyun
D
Yang
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
Wu
W
Zhang
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
Peter M
PM
Wilson
GlaxoSmithKline Clinical Development and Medical Affairs Oncology, Collegeville, Pennsylvania.
Yasir M
YM
Nagarwala
GlaxoSmithKline Clinical Pharmacology, Durham North Carolina.
Kevin M
KM
Koch
GlaxoSmithKline Oncology Clinical and Operational Sciences, Collegeville, Pennsylvania.
Colleen
C
Briner
GlaxoSmithKline Oncology Clinical and Operational Sciences, Collegeville, Pennsylvania.
Tomomi
T
Kaneko
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
Sun-Young
SY
Rha
Chelyabinsk Regional Clinical Oncology Dispensary, Chelyabinsk, Russia.
Oleg
O
Gladkov
University of Michigan Cancer Center, Ann Arbor, Michigan.
Susan G
SG
Urba
Bashkir Republican Clinical Oncology Dispensary, Ufa, Russia.
Dina
D
Sakaeva
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
Michael J
MJ
Pishvaian
Mackay Memorial Hospital, Taipei, Taiwan.
Ruey-Kuen
RK
Hsieh
Taipei Veterans General Hospital and Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
Wei-Ping
WP
Lee
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California. lenz@usc.edu.
Heinz-Josef
HJ
Lenz
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D000069287:Capecitabine / Q000008:administration & dosage; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D000077341:Lapatinib; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D016896:Treatment Outcome
D015415:Biomarkers; D000069287:Capecitabine; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases