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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. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실)
Yonsei Authors
김대준(Kim, Dae Joon)
김주항(Kim, Joo Hang)
김현기(Kim, Hyunki) ORCID logo https://orcid.org/0000-0003-2292-5584
김혜련(Kim, Hye Ryun) ORCID logo https://orcid.org/0000-0002-1842-9070
김효송(Kim, Hyo Song) ORCID logo https://orcid.org/0000-0002-0625-9828
문용화(Moon, Yong Wha)
박준철(Park, Jun Chul) ORCID logo https://orcid.org/0000-0001-8018-0010
백순명(Paik, Soon Myung) ORCID logo https://orcid.org/0000-0001-9688-6480
신성관(Shin, Sung Kwan)
이상길(Lee, Sang Kil) ORCID logo https://orcid.org/0000-0002-0721-0364
이용찬(Lee, Yong Chan)
이창걸(Lee, Chang Geol) ORCID logo https://orcid.org/0000-0002-8702-881X
정현수(Chung, Hyun Soo)
조병철(Cho, Byoung Chul)
표경호(Pyo, Kyoung Ho) ORCID logo https://orcid.org/0000-0001-5428-0288
허진(Hur, Jin) ORCID logo https://orcid.org/0000-0002-8651-6571
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/157227
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