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 ShinSang Kil Lee, Hye Ryun Kim, Yong Wha Moon, Yong Chan Lee, Joo Hang Kim, Soonmyung Paik, Byoung Chul Cho

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)44971-44984
Number of pages14
JournalOncotarget
Volume6
Issue number42
DOIs
Publication statusPublished - 2015 Jan 1

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Biomarkers
Disease-Free Survival
Platinum
Mutation
Survival
Transcriptome
Up-Regulation
Esophageal Squamous Cell Carcinoma
PF 00299804
Ions
Safety
Gene Expression
Drug Therapy
Genes
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Kim, Hyo Song ; Kim, Sung Moo ; Kim, Hyunki ; Pyo, Kyoung Ho ; Sun, Jong Mu ; Ahn, Myung Ju ; Park, Keunchil ; Keam, Bhumsuk ; Kwon, Nak Jung ; Yun, Hwan Jung ; Kim, Hoon Gu ; Chung, Ik Joo ; Lee, Jong Seok ; Lee, Kyung Hee ; Kim, Dae Joon ; Lee, Chang Geol ; Hur, Jin ; Chung, Hyunsoo ; Park, Jun Chul ; Shin, Sung Kwan ; Lee, Sang Kil ; Kim, Hye Ryun ; Moon, Yong Wha ; Lee, Yong Chan ; Kim, Joo Hang ; Paik, Soonmyung ; Cho, Byoung Chul. / Phase II clinical and exploratory biomarker study of dacomitinib in recurrent and/or metastatic esophageal squamous cell carcinoma. In: Oncotarget. 2015 ; Vol. 6, No. 42. pp. 44971-44984.
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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.",
author = "Kim, {Hyo Song} and Kim, {Sung Moo} and Hyunki Kim and Pyo, {Kyoung Ho} and Sun, {Jong Mu} and Ahn, {Myung Ju} and Keunchil Park and Bhumsuk Keam and Kwon, {Nak Jung} and Yun, {Hwan Jung} and Kim, {Hoon Gu} and Chung, {Ik Joo} and Lee, {Jong Seok} and Lee, {Kyung Hee} and Kim, {Dae Joon} and Lee, {Chang Geol} and Jin Hur and Hyunsoo Chung and Park, {Jun Chul} and Shin, {Sung Kwan} and Lee, {Sang Kil} and Kim, {Hye Ryun} and Moon, {Yong Wha} and Lee, {Yong Chan} and Kim, {Joo Hang} and Soonmyung Paik and Cho, {Byoung Chul}",
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Kim, HS, Kim, SM, Kim, H, Pyo, KH, Sun, JM, Ahn, MJ, Park, K, Keam, B, Kwon, NJ, Yun, HJ, Kim, HG, Chung, IJ, Lee, JS, Lee, KH, Kim, DJ, Lee, CG, Hur, J, Chung, H, Park, JC, Shin, SK, Lee, SK, Kim, HR, Moon, YW, Lee, YC, Kim, JH, Paik, S & Cho, BC 2015, 'Phase II clinical and exploratory biomarker study of dacomitinib in recurrent and/or metastatic esophageal squamous cell carcinoma', Oncotarget, vol. 6, no. 42, pp. 44971-44984. https://doi.org/10.18632/oncotarget.6056

Phase II clinical and exploratory biomarker study of dacomitinib in recurrent and/or metastatic esophageal squamous cell carcinoma. / Kim, Hyo Song; Kim, Sung Moo; Kim, Hyunki; Pyo, Kyoung Ho; Sun, Jong Mu; Ahn, Myung Ju; Park, Keunchil; Keam, Bhumsuk; Kwon, Nak Jung; Yun, Hwan Jung; Kim, Hoon Gu; Chung, Ik Joo; Lee, Jong Seok; Lee, Kyung Hee; Kim, Dae Joon; Lee, Chang Geol; Hur, Jin; Chung, Hyunsoo; Park, Jun Chul; Shin, Sung Kwan; Lee, Sang Kil; Kim, Hye Ryun; Moon, Yong Wha; Lee, Yong Chan; Kim, Joo Hang; Paik, Soonmyung; Cho, Byoung Chul.

In: Oncotarget, Vol. 6, No. 42, 01.01.2015, p. 44971-44984.

Research output: Contribution to journalArticle

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T1 - Phase II clinical and exploratory biomarker study of dacomitinib in recurrent and/or metastatic esophageal squamous cell carcinoma

AU - Kim, Hyo Song

AU - Kim, Sung Moo

AU - Kim, Hyunki

AU - Pyo, Kyoung Ho

AU - Sun, Jong Mu

AU - Ahn, Myung Ju

AU - Park, Keunchil

AU - Keam, Bhumsuk

AU - Kwon, Nak Jung

AU - Yun, Hwan Jung

AU - Kim, Hoon Gu

AU - Chung, Ik Joo

AU - Lee, Jong Seok

AU - Lee, Kyung Hee

AU - Kim, Dae Joon

AU - Lee, Chang Geol

AU - Hur, Jin

AU - Chung, Hyunsoo

AU - Park, Jun Chul

AU - Shin, Sung Kwan

AU - Lee, Sang Kil

AU - Kim, Hye Ryun

AU - Moon, Yong Wha

AU - Lee, Yong Chan

AU - Kim, Joo Hang

AU - Paik, Soonmyung

AU - Cho, Byoung Chul

PY - 2015/1/1

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N2 - 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.

AB - 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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