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Phase II clinical and exploratory biomarker study of dacomitinib in recurrent and/or metastatic esophageal squamous cell carcinoma

Authors
 Hyo Song Kim  ;  Sung-Moo Kim  ;  Hyunki Kim  ;  Kyoung-Ho Pyo  ;  Jong-Mu Sun  ;  Myung-Ju Ahn  ;  Keunchil Park  ;  Bhumsuk Keam  ;  Nak-Jung Kwon  ;  Hwan Jung Yun  ;  Hoon-Gu Kim  ;  Ik-Joo Chung  ;  Jong Seok Lee  ;  Kyung Hee Lee  ;  Dae Joon Kim  ;  Chang‑Geol Lee  ;  Jin Hur  ;  Hyunsoo Chung  ;  Jun Chul Park  ;  Sung Kwan Shin  ;  Sang Kil Lee  ;  Hye Ryun Kim  ;  Yong Wha Moon  ;  Yong Chan Lee  ;  Joo Hang Kim  ;  Soonmyung Paik  ;  Byoung Chul Cho 
Citation
 ONCOTARGET , Vol.6(42) : 44971-44984, 2015 
Journal Title
 ONCOTARGET 
Issue Date
2015
MeSH
Aged ; Aged, 80 and over ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use* ; Biomarkers, Tumor/antagonists & inhibitors ; Biomarkers, Tumor/genetics* ; Carcinoma, Squamous Cell/drug therapy* ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/mortality ; Carcinoma, Squamous Cell/pathology ; DNA Mutational Analysis ; Disease Progression ; Disease-Free Survival ; Esophageal Neoplasms/drug therapy* ; Esophageal Neoplasms/genetics ; Esophageal Neoplasms/mortality ; Esophageal Neoplasms/pathology ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Mutation ; Neoplasm Recurrence, Local* ; Patient Selection ; Precision Medicine ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/therapeutic use* ; Quinazolinones/adverse effects ; Quinazolinones/therapeutic use* ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/genetics ; Republic of Korea ; Time Factors ; Treatment Outcome
Keywords
biomarker ; epidermal growth factor receptor ; esophageal squamous cell carcinoma ; tyrosine kinase inhibitor
Abstract
The purpose of this study was to investigate the clinical activity, safety and predictive biomarkers of dacomitinib, an irreversible pan-HER inhibitor, in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M-ESCC). Patients, whose diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv 1.1. Predictive biomarker analyses included the characterization of somatic mutations and gene expression using the Ion Torrent AmpliSeq Cancer Hotspot Panel and Nanostring nCounter, and investigation of their relationship with clinical outcomes. Of the 48 evaluable patients, 6 (12.5%) achieved partial responses and 29 (60.4%) had stable disease. The median response duration was 7.1 months. The median progression free survival (PFS) and overall survival (OS) was 3.3 months (95% CI, 2.4-4.3 months) and 6.4 months (95% CI, 4.4-8.4 months). Adverse events were mostly grade 1-2. Gene set enrichment analysis revealed that ERBB signaling pathway is significantly enriched in patients with PFS ≥ 4 months (n = 12) than PFS < 4 months (n = 21) (p < 0.001). Upregulation of ERBB signaling pathway was significantly associated with longer PFS (5.0 vs. 2.9 months, P = 0.016) and OS (10.0 vs. 4.8 months, P = 0.022). The most frequent mutations were TP53 (61%) followed by CDKN2A (8%), MLH1 (8%), FLT3 (8%) and EGFR (8%). Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-ESCC. Screening of ERBB pathway-related gene expression profiles may help identify patients who are most likely benefit from dacomitinib.
Files in This Item:
T201506075.pdf Download
DOI
10.18632/oncotarget.6056
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dae Joon(김대준)
Kim, Joo Hang(김주항)
Kim, Hyunki(김현기) ORCID logo https://orcid.org/0000-0003-2292-5584
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Kim, Hyo Song(김효송) ORCID logo https://orcid.org/0000-0002-0625-9828
Moon, Yong Wha(문용화)
Park, Jun Chul(박준철) ORCID logo https://orcid.org/0000-0001-8018-0010
Paik, Soon Myung(백순명) ORCID logo https://orcid.org/0000-0001-9688-6480
Shin, Sung Kwan(신성관) ORCID logo https://orcid.org/0000-0001-5466-1400
Lee, Sang Kil(이상길) ORCID logo https://orcid.org/0000-0002-0721-0364
Lee, Yong Chan(이용찬) ORCID logo https://orcid.org/0000-0001-8800-6906
Lee, Chang Geol(이창걸) ORCID logo https://orcid.org/0000-0002-8702-881X
Chung, Hyun Soo(정현수)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Pyo, Kyoung Ho(표경호) ORCID logo https://orcid.org/0000-0001-5428-0288
Hur, Jin(허진) ORCID logo https://orcid.org/0000-0002-8651-6571
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/157227
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