Abstract A50: Biomarker analysis of PTEN, targeted oncogenic mutations, and HPV in a phase II trial of the irreversible oral pan-human EGF receptor (HER) inhibitor dacomitinib (D) (PF-299804) as first-line treatment in recurrent and/or metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN).
Authors: Siu Lillian L. , Allo Ghassan , Pond Gregory R. , Zhang Tong , Ho James , Hotte Sebastien J. , Laurie Scott A. , Singh Simron , Winquist Eric , Chia Stephen K. L. , Chen Eric X. , Chan Kelvin K. , Mormont Christine , Quinn Susan , Wang Tao , Taylor Ian , Kamel-Reid Suzanne , Tsao Ming S. , Soulieres Denis 
Published: June 2012

Abstract
Background: The pan-HER inhibitor D has demonstrated single-agent activity in a phase II trial of 69 patients (pts) with first-line RM SCCHN, reporting an objective response rate (ORR) of 12.7%, median progression-free survival (PFS) of 12.1 weeks (wks) and median overall survival (OS) of 35.9 wks (Siu et al. ASCO 2011). The identification of biomarkers predictive of sensitivity or resistance is of top priority to assist with pt selection in the development of D in SCCHN.
Methods: Archival formalin-fixed paraffin-embedded (FFPE) tumor specimens were used for analysis. PTEN expression was measured by immunohistochemistry and predominant staining intensity of tumor cells was scored from 0 (absent) to 2+ (strong). Tumor DNA was subjected to mutation analysis using the OncoCarta panel 1.0 (238 mutations from 19 genes) on the Sequenom™ MassARRAY platform. Genotyping for HPV16 was performed using RT-PCR. Log-rank test was used to compare OS and PFS and Fisher's exact test was used to compare ORR between biomarker subgroups.
Results: Results for PTEN expression, mutation analysis and HPV status were available for 40, 47 and 40 pts respectively. For PTEN, 7 pts (17.5%) scored 0, 30 pts (75%) scored 1+ and 3 pts (7.5%) scored 2+. For mutation analysis, no mutations were identified in 42 pts (89%); 5 pts (11%) had the following mutations: PIK3CA E545K (n=2), NRAS G12C plus PIK3CA E542K (n=1), NRAS G12C plus PIK3CA E545K (n=1), NRAS G12C (n=1). For HPV status, 14 pts (35%) were HPV16+. Summary of the results are displayed in the Table. Although statistical significance was not demonstrated for any of the subgroup analyzes, pts who harbored oncogenic mutations trended to have poorer OS compared to those without (17.6 wks vs 35.9 wks, p=0.20), with no responders among 4 response-evaluable pts. Pts with HPV16+ tumors had lower ORR to D (0% vs 17%, p=0.28) but better OS than those with HPV16-tumors (49.6 wks vs 32.7 wks, p=0.10).
Conclusions: The data suggest a possible association between HPV16, PIK3CA and NRAS status and ORR or OS. Since these observations are based on a limited number of samples from a single arm study, a prospective trial designed for biomarker validation will be required to evaluate the strength of these associations and if these are prognostic vs predictive biomarkers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A50.