Discussion
toxicity, non-metastatic HNSCC, tumor, HNSCC
TUMOR, RESIDUAL TUMOR
Short course of afatinib in untreated, operable, non-metastatic HNSCC patients induced a high rate of partial metabolic responses and partial responses according to RECIST1.1 without delaying surgery. Baseline phosphorylation levels of RB1, ERK1/2, and HER4 correlated with metabolic responses to afatinib. At the cellular level, we showed a significant enrichment of tumor-infiltrating B cells under afatinib in responders, while at the molecular level, the NF-kappa B signaling was found to be enriched among upregulated genes in non-responders. In post-hoc analyses, we reported the negative prognostic values of Seven percent of the patients achieved a partial response according to RECIST1.1, and 59% achieved a partial metabolic response as compared with 22% and 70% in a similar study run by the EORTCSafety and tolerability were as expected regarding the toxicity profile of afatinib. Up to 12% of patients in Arm A stopped afatinib early because of toxicity, which might impact the results of translational analyses because of the lack of sufficient drug exposure. Importantly, all reported AEs were manageable and did not delay the planned definitive surgery, the latter representing a major concern with window-of-opportunity trialsIn comparison with the TCGA cohortWe identified higher metabolic response to afatinib in patients with low pre-treatment HER4 activity. This result is not in line with what has been observed in preclinical model. A xenograft model of HNSCC identified a At the cellular level, pharmacodynamic analyses on the TME elucidated B cells changes in response to afatinib which may rely on the (re)activation of a tumor-targeting immune responseOur study has several limitations. First, mean tumor reduction was lower than anticipated and correlative biomarkers analyses were based instead on metabolic response, which was not a predefined primary endpoint. In addition, no adjustment for multi-test were carried out, thus rendering biomarkers analyses mainly exploratory. Second, the specificity of FDG-PET scan to predict afatinib efficacy is unknown. In some pre-clinical and clinical studies, however, metabolic responses to targeted therapies have been shown to correlate with residual tumor cellularity, tumor shrinkage, and improved time to progressionOverall, we found that short course of preoperative afatinib induced a high rate of metabolic response without delaying the planned definitive surgery in treatment-naïve HNSCC patients selected for primary curative surgery. Baseline expression of pHER4, pERK1/2 and pRB1 together with B cells enrichment and NF-kappa B signaling activation correlated with metabolic response to afatinib. Although exploratory, these phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy. More mechanistic studies are needed to reliably establish the link between B cells enrichment, NF-kappa B signaling activation and sensitivity to HER family blockers in HNSCC.