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

作者：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^*

来源：Oncotarget, 2015, 6(42): 44971-44984.

DOI：10.18632/oncotarget.6056

• epidermal growth factor receptor
• tyrosine kinase inhibitor
• esophageal squamous cell carcinoma
• biomarker

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.

• 出版日期2015-12-29