Afatinib and Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ALPHA Study): A Phase II Study with Biomarker Analysis
Mené sur 29 patients atteints d'un carcinome épidermoïde de la tête et du cou de stade métastatique ou récidivant, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité d'un traitement combinant afatinib et pembrolizumab
Purpose: Epidermal growth factor receptor (EGFR) pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in pre-clinical models, but how EGFR inhibition affects tumor antigen presentation during anti-PD-1 monotherapy in humans remains unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor (TKI), would improve outcomes in patients treated with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) by promoting antigen presentation and immune activation in the tumor microenvironment. Experimental Design: The ALPHA study (NCT03695510) was a single-arm, Phase II study with Simon's 2-stage design. Afatinib and pembrolizumab were administered to patients with platinum-refractory, recurrent, or metastatic HNSCC. The primary endpoint was the objective response rate (ORR). The study applied gene expression analysis using a NanoString PanCancer Immune Profiling Panel and next-generation sequencing using FoundationOne CDx. Results: From January 2019 to March 2020, the study enrolled 29 eligible patients. Common treatment-related adverse events were skin rash (75.9%), diarrhea (58.6%), and paronychia (44.8%). Twelve patients (41.4%) had an objective partial response to treatment. The median progression-free survival was 4.1 months, and the median overall survival was 8.9 months. In a paired tissue analysis, afatinib-pembrolizumab was found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity. Unaltered methyl-thioadenosine phosphorylase (MTAP) and EGFR amplification may predict the clinical response to the therapy. Conclusions: Afatinib may augment pembrolizumab therapy and improve the ORR in HNSCC patients. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment.