Oncotarget

Clinical Research Papers:

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

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 and Byoung Chul Cho _

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Oncotarget. 2015; 6:44971-44984. https://doi.org/10.18632/oncotarget.6056

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Abstract

Hyo Song Kim1,*, Sung-Moo Kim2,*, Hyunki Kim3, Kyoung-Ho Pyo2, Jong-Mu Sun4, Myung-Ju Ahn4, Keunchil Park4, Bhumsuk Keam5, Nak-Jung Kwon6, Hwan Jung Yun7, Hoon-Gu Kim8, Ik-Joo Chung9, Jong Seok Lee10, Kyung Hee Lee11, Dae Joon Kim12, Chang-Geol Lee13, Jin Hur14, Hyunsoo Chung15, Jun Chul Park15, Sung Kwan Shin15, Sang Kil Lee15, Hye Ryun Kim1, Yong Wha Moon1, Yong Chan Lee15, Joo Hang Kim1, Soonmyung Paik16,17 and Byoung Chul Cho1

1 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

2 Yonsei Cancer Research Institute, JE-UK Laboratory of Molecular Cancer Therapeutics, Seoul, Korea

3 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

4 Department of Hematology-Oncology, Samsung Medical Center, Seoul, Korea

5 Department of Hematology-Oncology, Seoul National University Hospital, Seoul, Korea

6 Macrogen Inc., Seoul, Korea

7 Division of Hemato-Oncology, Chungnam National University Hospital, Daejeon, Korea

8 Division of Hematology-Oncology, Department of Internal Medicine, Gyeongnam Regional Cancer Center, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea

9 Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, South Korea

10 Department of Hematology-Oncology, Seoul National University Bundang Hospital, Seongnam, Korea

11 Department of Hematology-Oncology, Yeungnam University Medical Center, Daegu, South Korea

12 Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea

13 Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea

14 Department of Radiology, Yonsei University College of Medicine, Seoul, Korea

15 Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

16 Division of Pathology NSABP, Pittsburgh, PA, USA

17 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea

* These authors have contributed equally to this work as co-first authors

Correspondence to:

Byoung Chul Cho, email:

Keywords: epidermal growth factor receptor, tyrosine kinase inhibitor, esophageal squamous cell carcinoma, biomarker

Received: June 25, 2015 Accepted: September 23, 2015 Published: October 09, 2015

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 45mg/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.


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