Abstract
Abstract Background MEHD is a novel dual-action humanized IgG1 antibody that blocks ligand binding to EGFR and HER3, inhibiting all major ligand-dependent HER complex signaling. Preclinical and Phase 1a clinical data suggested ligand-driven HER3 signaling as a promising target for therapy in a subset of patients with SCCHN. Results from the MEHGAN study showed comparable objective response rates and PFS for MEHD and Cet (Fayette et al, ESMO 2014). Here we report the results of comprehensive and comparative biomarker analyses from that study. Methods Archival and fresh (as available) tumor tissues were evaluated to characterize the biology of anti-HER therapy in SCCHN, and to identify potential predictive biomarkers for improved outcomes with MEHD compared to Cet, with particular attention to the HER3 ligand NRG1. NRG1 and ERBB3 RNA expression was measured by both ISH (data analysis are ongoing) and qRT-PCR. Additionally, extensive gene expression analyses and HPV detection were performed by qRT-PCR. Results Of 121 randomized patients in MEHGAN, 107 had archival tissues with sufficient tumor content and quality for biomarker analyses. Key findings include: 1) Most patients with CT RECIST responses on either treatment arm had higher (≥ median) tumor expression levels of NRG1 as measured by qRT-PCR 2) EGFR ligands such as amphiregulin were co-expressed with NRG1, consistent with preclinical analysis in an independent panel of SCCHN tumor samples (Genentech data on file). 3) 24 HPV (+) patients (20%) were identified, consistent with published prevalence reports. 4) Higher EGFR and HER3 ligand expression was observed in HPV (-) samples relative to HPV (+) samples and, moreover, no responses were seen in HPV (+) patients. These results are consistent with prior correlative ligand observations and may point to differential roles for HER signaling biology in HPV (-) versus HPV (+) SCCHN. Conclusions NRG1 expression did not predict enhanced responsiveness to MEHD versus Cet or, conversely, resistance to Cet. NRG1 and EGFR ligands appear to have similar expression patterns in SCCHN. Higher levels of NRG1 and EGFR ligands were associated with greater activity for both MEHD and Cet, and were consistently observed in HPV (-) SCCHN versus HPV (+) SCCHN. These data suggest distinct HER signaling biology in these 2 patient groups and warrant further evaluation to potentially inform treatment approaches in SCCHN. * We would like acknowledge and thank all of the MEHGAN study investigators and patients. Citation Format: Elicia Penuel, Amy V. Kapp, An Do, Rachel Tam, Teiko Sumiyoshi, Chaitra Marathe, Susan Sa, Franklin Peale, Mark Lackner, Scott Holden, Tanguy Seiwert, Andrea Pirzkall. Biomarker evaluation in a randomized phase 2 study of MEHD7945A (MEHD) versus cetuximab (Cet) in ≥2 line recurrent/metastatic (R/M) squamous cell carcinomas of the head and neck (SCCHN) [MEHGAN]. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1553. doi:10.1158/1538-7445.AM2015-1553
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