Abstract 3284: Dual blockade of EGFR and TGF-Β with ficerafusp alfa has the potential to overcome resistance mechanisms in 1L R/M HNSCC in combination with pembrolizumab

Abstract Objective: Resistance mechanisms, such as epithelial-mesenchymal transition (EMT) and hypoxia diminish the efficacy of standard treatments in head and neck squamous cell carcinoma (HNSCC), including anti-EGFR and anti-PD-1 therapies. TGF-β is a cytokine involved in these resistance pathways, promoting a mesenchymal tumor phenotype through EMT. TGF-β-expressing cancer-associated fibroblasts (CAFs) are associated with T cell exclusion and resistance to anti-PD-1/PD-L1, while EMT is linked to anti-EGFR resistance. Ficerafusp alfa, a bifunctional antibody targeting EGFR and TGF-β in the tumor microenvironment (TME), showed clinical activity in a Phase 1b study for 1L R/M HNSCC (NCT04429542), particularly among HPV-negative (neg) patients (IJROBP 2024). Analysis of paired biopsies from HPV-neg tumors highlight the effects of ficerafusp alfa in combination with pembrolizumab (P). Methods: Paired tumor biopsies collected from the Ph1b 1L R/M HNSCC cohort (NCT04429542) were analyzed by immunohistochemistry for pSMAD2 and CD8 and for gene expression within regions of the TME by whole genome spatial transcriptomics. Cytokine analysis was performed on pre- and post-treatment plasma samples. Results: Data from paired tumor biopsies demonstrated inhibition of TGF-β signaling within tumor cells and an increase in CD8+ T-cell infiltration (n=7), including in HPV-negative tumors with low PD-L1 (CPS 1-19). Spatial transcriptomics revealed down-regulation of genes and pathways associated with drug resistance including hypoxia and EMT in both tumor and stromal regions (n=8). Up-regulation of immune activation pathways such as interferon-gamma and interferon-alpha was also observed in both tumor and stromal regions. Plasma analyses revealed complete neutralization of TGF-β1 (0.5% of pre-dose at day 21; p<.0001) and increased pro-inflammatory cytokines CXCL9, CXCL10 and IFNG (p<.01) with the ficerafusp alfa combination (n=24). Conclusion: Down-regulation of hypoxia and EMT pathways in both tumor and stromal regions with ficerafusp alfa and P treatment supports the potential role of TGF-β inhibition in preventing the mesenchymal phenotype associated with drug resistance. These findings provide proof of concept that ficerafusp alfa effectively blocks TGF-β signaling in both tumor cells and tumor supporting stromal cells. Association of translational findings with clinical data will be presented. This supports the rationale for combining ficerafusp alfa with P in HPV-negative R/M HNSCC and potentially in other settings where anti-EGFR and anti-PD-1 drug resistance is a factor. Citation Format: Brenda C. O'Connell, Shiv R. Krishn, Pradip Nair, John Kaczmar, Christine H. Chung, Dan Zandberg, Debora J. Wong, David Raben, Rachel Salazar. Dual blockade of EGFR and TGF-Β with ficerafusp alfa has the potential to overcome resistance mechanisms in 1L R/M HNSCC in combination with pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3284.