ficerafusp alfa (BCA101)

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.

P1, N=292, Recruiting, Bicara Therapeutics | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

Stage 1 of this dose expansion cohort of BCA101+P shows encouraging anti-tumor activity with additive potential, particularly among HPV-neg pts; and the combination is well tolerated among this R/M HNSCC population. Further investigation is warranted. Study funded by Bicara Therapeutics and conducted in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

These results support clinical development of BCA101, either as a monotherapy or in combination with immune checkpoint therapy.

Co-targeting of EGFR and TGF-β directly impacts tumor progression while enhancing the immunogenicity of tumors. Patients with multiple solid tumor types (CRC, pancreatic, HNSCC, SqNSCLC, and others) were treated with escalating doses of either single agent BCA101 or in combination with anti-PD-1 (pembrolizumab) enrolled on NCT04429542 trial... Increased abundance of circulating HLA-DR+ monocytes following treatment indicated polarization towards a more positive, Th1-like systemic immune state. We observed enhanced immunogenicity of tumors as assessed by a targeted IO transcriptomic analysis. The results of the pathway analysis were supported by IHC on post-treatment biopsies from a subsequent cohort showing enhanced CD8+ T cell infiltration and stable, or reduced expression of TAM marker CD163.

P1, N=292, Recruiting, Bicara Therapeutics | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Dec 2022 --> Dec 2023

All 4 responders have been on study >4 months; including 1 confirmed PR in a HNSCC pt refractory to anti-PD-1 therapy and cetuximab...Conclusions BCA101 is well tolerated and clinically active as a SA and in combination with PD-1 blockade with a predictable PK/PD profile. Expansion cohorts for HNSCC, SCAC and cutaneous SCC are currently ongoing and results will be updated and further presented at the congress.

Two of 3 responders have been on study >4 months; including 1 confirmed PR in a HNSCC pt refractory to anti-PD-1 therapy and cetuximab... BCA101 is well tolerated and clinically active as a SA and in combination with PD-1 blockade with a predictable PK/PD profile. A recommended dose of 1500 mg both as SA and in combination has advanced to the part B expansion phase for pts with HNSCC, SCAC, and cutaneous SCC.

BCA101 is well tolerated at biologically active doses . BCA101 is now being tested in combination with the PD-1 antibody pembrolizumab in patients with SCCHN and anal carcinoma.