title: Phase II clinical and exploratory biomarker study of dacomitinib in recurrent and/or metastatic esophageal squamous cell carcinoma.
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.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyo Song
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Yonsei Cancer Research Institute, JE-UK Laboratory of Molecular Cancer Therapeutics, Seoul, Korea.
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyunki
authors.initials: H
authors.lastname: Kim
authors.affiliation: Yonsei Cancer Research Institute, JE-UK Laboratory of Molecular Cancer Therapeutics, Seoul, Korea.
authors.forename: Kyoung-Ho
authors.initials: KH
authors.lastname: Pyo
authors.affiliation: Department of Hematology-Oncology, Samsung Medical Center, Seoul, Korea.
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.affiliation: Department of Hematology-Oncology, Samsung Medical Center, Seoul, Korea.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Department of Hematology-Oncology, Samsung Medical Center, Seoul, Korea.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Hematology-Oncology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.affiliation: Macrogen Inc., Seoul, Korea.
authors.forename: Nak-Jung
authors.initials: NJ
authors.lastname: Kwon
authors.affiliation: Division of Hemato-Oncology, Chungnam National University Hospital, Daejeon, Korea.
authors.forename: Hwan Jung
authors.initials: HJ
authors.lastname: Yun
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Gyeongnam Regional Cancer Center, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea.
authors.forename: Hoon-Gu
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
authors.forename: Ik-Joo
authors.initials: IJ
authors.lastname: Chung
authors.affiliation: Department of Hematology-Oncology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Hematology-Oncology, Yeungnam University Medical Center, Daegu, South Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Dae Joon
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Chang-Geol
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Department of Radiology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Hur
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Chung
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jun Chul
authors.initials: JC
authors.lastname: Park
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sung Kwan
authors.initials: SK
authors.lastname: Shin
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sang Kil
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yong Wha
authors.initials: YW
authors.lastname: Moon
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yong Chan
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Pathology, NSABP, Pittsburgh, PA, USA.|Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D018579:Patient Selection; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D052999:Quinazolinones / Q000009:adverse effects / Q000627:therapeutic use*; D056910:Republic of Korea; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; C525726:dacomitinib; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: biomarker; epidermal growth factor receptor; esophageal squamous cell carcinoma; tyrosine kinase inhibitor