Exploring Predictors of Response to Dacomitinib in <i>EGFR</i>-Amplified Recurrent Glioblastoma.

Abstract

Despite the high frequency of <i>EGFR</i> genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for <i>EGFR</i> gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial. We retrospectively explored whether previously described <i>EGFR</i> extracellular domain (ECD)-sensitizing mutations in the context of <i>EGFR</i> gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration. We found that dacomitinib effectively penetrates contrast-enhancing GBM tumors. Among all 56 treated patients, 8 (14.3%) had a clinical benefit as defined by a duration of treatment of at least 6 months, of whom 5 (8.9%) remained progression free for at least 1 year. Presence of <i>EGFRvIII</i> or <i>EGFR</i> ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression. While dacomitinib was not effective in most patients with <i>EGFR</i>-amplified GBM, a subset experienced a durable, clinically meaningful benefit. Moreover, <i>EGFRvIII</i> and <i>EGFR</i> ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.