Abstract

<div>AbstractPurpose:<p>The EORTC-90111–24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck (HNSCC). We investigated afatinib-induced tumor and microenvironment modifications by comparing pre- and posttreatment tumor biopsies.</p>Patients and Methods:<p>Thirty treatment-naïve patients with primary HNSCC were randomized. Twenty-five patients received afatinib for 14 days before surgery (40 mg 1×/day) and 5 patients were attributed to the control arm. Biopsies were taken at work-up and during surgery. Good quality RNA samples were used for omics analyses. The control arm was enlarged by samples coming from our previous similar window study.</p>Results:<p>IHC analyses of afatinib-treated tumor biopsies showed a decrease in pEGFR (<i>P</i> ≤ 0.05) and pERK (<i>P</i> ≤ 0.05); and an increase in CD3<sup>+</sup> (<i>P</i> ≤ 0.01) and CD8<sup>+</sup> (<i>P</i> ≤ 0.01) T-cell infiltration, and in CD3<sup>+</sup> (<i>P</i> ≤ 0.05) T-cell density. RNA sequencing analyses of afatinib-treated tumor samples showed upregulation of inflammatory genes and increased expression scores of signatures predictive of response to programmed cell death protein 1 blockade (<i>P</i> ≤ 0.05). In posttreatment biopsies of afatinib-treated patients, two clusters were observed. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition (EMT) and activation of cancer-associated fibroblasts (CAF) compared with cluster 2 and controls.</p>Conclusions:<p>Short-term treatment with afatinib in primary HNSCC induces CD3<sup>+</sup> and CD8<sup>+</sup> tumor infiltration and, in some patients, EMT and CAF activation. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.</p></div>

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