Abstract CT229: A phase II and biomarker study of an irreversible pan-human EGF receptor (HER) tyrosine kinase inhibitor, dacomitinib, in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN)
Authors: Kim Han Sang , Kwon Hyung Joo , Ahn Myung-Ju , Kang Byung Woog , Sun Jong-Mu , Yoon Dok-Hyun , Park Keon U. , Lee Se-Hoon , Koh Yoon Woo , Kim Se Hun , Choi Eun Chang , Kim Hye Ryun , Kim Hyo Song , Kim Joo Hang , Cho Byoung Chul 
Published: May 2015

Abstract
Background: Dacomitinib is an oral irreversible tyrosine kinase inhibitor of EGFR, HER2 and HER4 signaling. The goals of this study were to investigate the clinical activity, safety and predictive biomarkers of dacomitinib in R/M-SCCHN.
Methods: Patients with R/M-SCCHN were eligible if they had progressed on platinum-based chemotherapy or considered platinum-intolerant, and were treated with dacomitinib 45mg/day. The primary endpoint was objective response rate (ORR) by RECIST v1.1; Secondary endpoints included progression-free survival rate (PFS), overall survival (OS) and safety. We charaterized somatic mutations using the Ion AmpliSeq™ platform (2,800 mutations from 50 genes), gene copy number (86 genes) and gene expression (230 genes) using NanoString nCounter® and CDKN2A (p16INK4A) expression by immunohistochemistry, and investigated their relationship with clinical outcomes.
Results: A total of 48 patients were enrolled and evaluable for efficacy and toxicity. Patient and disease characteristics included median age (61 years; range, 30-82); male (85%); ECOG performance status 0/1/2 (4%/75%/21%); locoregional/distant metastatic/both (31/23/46%); oral cavity/larynx/oropharynx primary (38%/19%/23%); prior chemotherapy regimens 0/1/≥2 (8%/52%/40%). Ten patients (21%) had partial responses and 31 patients (65%) had stable diseases. With a median 8.4 months of follow up, the median PFS and OS were 3.9 months (95% CI, 2.9-5.0) and 8.2 months (95% CI, 5.8-10.3). Adverse events (AEs) were mostly grade 1-2 and manageable. The most common AEs were skin toxicities (paronychia, 65%; acneiform dermatitis, 44%) and diarrhea (52%). Results from the biomarker analyses were available in 28 patients for AmpliSeq™, 31 patients for gene copy number, and 12 patients for gene expression. Mutations in PIK3CA and PTEN was significantly associated with shorter PFS (2.5 vs 5.4 months, P=0.013). There were trends toward higher ORR (23% vs 0) for patients with wild PIK3CA and PTEN, with unusually long durations of response (5.1, 5.4, 5.8, 13.1, and 18.9 months, respectively). Increased gene expression of proinflammatory chemokines and inflammatory response modulators (IL6, IL8, PTGS2, PLA2G2A) was significantly associated with shorter PFS (1.9 vs 6.8 months, P=0.001). Patients with low gene expression of proinflammatory chemokines also tend to have higher ORR (40% vs 0), with unusually long durations of response (18.9 and 5.4 months, respectively).
Conclusions: Dacomitinib demonstrated promising efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K pathway mutation and proinflammatory chemokines may help identify which R/M-SCCHN patients are likely to gain a benefit from dacomitinib.
Citation Format: Han Sang Kim, Hyung Joo Kwon, Myung-Ju Ahn, Byung Woog Kang, Jong-Mu Sun, Dok-Hyun Yoon, Keon Uk Park, Se-Hoon Lee, Yoon Woo Koh, Se Hun Kim, Eun Chang Choi, Hye Ryun Kim, Hyo Song Kim, Joo Hang Kim, Byoung Chul Cho. A phase II and biomarker study of an irreversible pan-human EGF receptor (HER) tyrosine kinase inhibitor, dacomitinib, in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT229. doi:10.1158/1538-7445.AM2014-CT229