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Afatinib and Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ALPHA Study): A Phase
Hsiang-Fong Kao1,2,3, Bin-Chi Liao1,2, Yen-Lin Huang4,5
1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Purpose:
EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen presentation during anti-PD-1 monotherapy in humans remain unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor, 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.
Patients And Methods:
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 were found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity. Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict the clinical response to the therapy.
Conclusions:
Afatinib may augment pembrolizumab therapy and improve the ORR in patients with HNSCC. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment.
Insights
Afatinib combined with pembrolizumab improved objective response rates in head and neck squamous cell carcinoma patients. This combination therapy enhanced antigen presentation and immune activation within the tumor microenvironment.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) pathway inhibition shows potential in enhancing anti-programmed cell death protein 1 (PD-1) responses in preclinical settings.
- The effect of EGFR inhibition on tumor antigen presentation during anti-PD-1 monotherapy in human cancers remains largely unknown.
- Head and neck squamous cell carcinoma (HNSCC) is a complex malignancy where immune evasion plays a significant role.
Purpose of the Study:
- To investigate the efficacy of combining afatinib, an irreversible EGFR tyrosine kinase inhibitor, with pembrolizumab, an anti-PD-1 therapy.
- To determine if this combination improves outcomes in patients with recurrent or metastatic HNSCC.
- To explore the impact of afatinib on antigen presentation and immune activation within the tumor microenvironment during anti-PD-1 therapy.
Main Methods:
- The ALPHA study was a single-arm, Phase II clinical trial (NCT03695510).
- Patients with platinum-refractory, recurrent, or metastatic HNSCC received afatinib and pembrolizumab.
- Gene expression analysis (NanoString PanCancer Immune Profiling Panel) and next-generation sequencing (FoundationOne CDx) were employed.
Main Results:
- The study enrolled 29 patients between January 2019 and March 2020.
- The objective response rate (ORR) was 41.4% (12 patients).
- Median progression-free survival was 4.1 months, and median overall survival was 8.9 months.
- Afatinib-pembrolizumab treatment upregulated genes associated with antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity.
- Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict clinical response.
Conclusions:
- Combination therapy with afatinib and pembrolizumab demonstrated potential to augment anti-PD-1 treatment efficacy in HNSCC.
- The observed enhancement in antigen presentation machinery suggests a mechanism for improved therapeutic outcomes.
- Further investigation is warranted to validate these findings and explore predictive biomarkers.
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