ficerafusp alfa (BCA101)

P2, N=32, Not yet recruiting, Dana-Farber Cancer Institute

Recent advances highlight a rapid surge in positive immunotherapy trials across different head and neck cancer entities, with clinical benefit observed both when immune checkpoint inhibitors are moved earlier in the disease course and when they are combined with agents targeting resistance mechanisms or enabling more precise drug delivery to tumors.

P2/3, N=191, Recruiting, Bicara Therapeutics Inc.

Cetuximab, a chimeric IgG1 monoclonal antibody anti-EGFR, is the only EGFR-targeted agent approved for HNSCC and has shown efficacy in both locally advanced (in platinum-unfit patients) and recurrent/metastatic (R/M) settings...Irreversible pan-HER tyrosine kinase inhibitors (e.g., afatinib, dacomitinib), dual-target bispecific antibodies such as duligotuzumab (EGFR/HER3), petosemtamab (EGFR/LGR5) or ficerafusp alfa (EGFR/TGF-β) have led to promising preclinical and early-phase clinical activity...While EGFR remains a valid therapeutic target, future efforts must focus on biomarker-driven patient selection and combination strategies to enhance efficacy and durability of response. Ongoing trials will further define the role of emerging anti-EGFR agents and their integration into HNSCC treatment algorithms.

Although EGFR is a common target in squamous cancers, anti-EGFR monotherapies have shown modest success due to existing or acquired activation of other oncogenic pathways and tumor heterogeneity. A bifunctional fusion protein ficerafusp alfa in combination with pembrolizumab represents a potential solution to overcome resistance in early phase clinical investigation.

Ficerafusp alfa exhibited a manageable safety profile and clinical activity as monotherapy and in combination with pembrolizumab, with exposure increasing proportionally at anticipated therapeutic doses.

P2/3, N=650, Recruiting, Bicara Therapeutics

While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy.

P1, N=292, Recruiting, Bicara Therapeutics | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

This resistance is rescued by a combination of the G12Ci with BCA101 but not cetuximab...Conclusions Preclinical results show that BCA101 has the potential to increase the efficacy of G12Ci along with the ability to mitigate G12Ci-induced acquired resistance in lung and colon cancer cell lines. This study provides a rationale to combine BCA101 with G12Ci in G12C mutant lung or colon cancer patients.

Conclusions BCA101+P exhibits encouraging anti-tumor activity particularly among HPV(-) pts, and the combination is well tolerated among this R/M HNSCC population. Further investigation is warranted.

In addition, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab...The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy.