A Multicenter, Randomized, Double-blind, Phase 2/3 Study of Ficerafusp Alfa (BCA101) or Placebo in Combination With Pembrolizumab for First-Line Treatment of PD-L1-positive, Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

More details:

Overview

Ficerafusp alfa (BCA101; also referred to in some materials as FMAB2) is an investigational, tumor‑targeted, bifunctional IgG1 antibody designed to simultaneously inhibit EGFR and neutralize TGF‑β within the tumor microenvironment. It is being developed by Bicara Therapeutics across multiple squamous and EGFR‑driven solid tumors, with the most mature data in first‑line HPV‑negative recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) in combination with pembrolizumab. (pmc.ncbi.nlm.nih.gov, ichgcp.net)

Mechanism of action

• Structure: An anti‑EGFR IgG1 fused to the extracellular domain of human TGF‑β receptor II (a “TGF‑β trap”). (pmc.ncbi.nlm.nih.gov)
• Function: Retains EGFR binding, growth‑inhibition, and ADCC while locally sequestering TGF‑β in tumors; in preclinical models it enhanced pro‑inflammatory cytokines, limited iTreg differentiation, rescued NK/CTL function, and reduced EMT/VEGF signaling. (pmc.ncbi.nlm.nih.gov)
• Isoform specificity: Neutralizes TGF‑β1 and TGF‑β3 but not TGF‑β2 in reporter assays. (pmc.ncbi.nlm.nih.gov)

Clinical development

• Ongoing first‑in‑human Phase 1/1b, open‑label study (NCT04429542) evaluating ficerafusp alfa as monotherapy and with pembrolizumab in EGFR‑driven tumors; expansion cohorts include first‑line R/M HNSCC, squamous cell carcinoma of the anal canal (SCAC), and cutaneous SCC (cSCC). (ichgcp.net)
• Updated interim clinical data have been presented at ASCO 2023 and 2025, AACR 2025, and other forums. (ascopubs.org, ir.bicara.com, aacrjournals.org)

Efficacy

Head and Neck SCC (first‑line, HPV‑negative; with pembrolizumab) - ASCO 2025 updated Phase 1/1b expansion (efficacy‑evaluable HPV‑negative n=28): confirmed ORR 54% (64% including unconfirmed), CR 21%, median DOR 21.7 months, median PFS 9.9 months, median OS 21.3 months, 2‑year OS 46%; disease control rate 89%. (biospace.com, onclive.com) - Earlier ASCO 2023 expansion signal: ORR 58% in HPV‑negative vs 17% in HPV‑positive patients (total n=18 evaluable in Stage 1). (ascopubs.org)

Squamous cell carcinoma of the anal canal (post‑chemo; with pembrolizumab) - ASCO GI 2025 Phase 1/1b dose‑expansion (n=28 ICI‑naïve, 1–2 prior chemo lines): confirmed ORR 25% (1 CR, 6 PR), median PFS 2.9 months; 12‑month PFS rate 40.7%. (ir.bicara.com, biospace.com)

Cutaneous SCC (2L+; monotherapy) - AACR 2025 dose‑expansion: ORR 30.4% (7/23), clinical benefit rate 82.6%; median PFS 7.0 months. (aacrjournals.org, biospace.com)

Safety

Across Phase 1/1b cohorts, the combination and monotherapy have shown a generally manageable safety profile consistent with EGFR‑targeted agents plus on‑target TGF‑β effects: - Common treatment‑related AEs (any grade) included acneiform dermatitis/rash (≈57–76%), fatigue (≈30–43%), hypophosphatemia (≈38%), pruritus (≈21–46%), epistaxis (≈30–50%); most were grade 1–2. (ir.bicara.com, biospace.com, ascopost.com, aacrjournals.org) - Selected serious/grade ≥3 events reported include rash, anemia, hemorrhage, pericarditis; infusion reactions were generally low grade. No treatment‑related deaths were reported in cited abstracts. (ascopost.com)

Notes and ongoing plans

• A pivotal Phase 2/3 program in first‑line HPV‑negative R/M HNSCC (ficerafusp alfa + pembrolizumab) has been announced following maturation of the Phase 1/1b dataset. (ir.bicara.com)

Further reading

• Preclinical/mechanistic paper (open access): BCA101 inhibits EGFR and neutralizes TGF‑β1/3; tumor‑targeted activity and immune effects. (pmc.ncbi.nlm.nih.gov)
• ASCO 2023 abstract in R/M HNSCC (dose‑expansion signals). (ascopubs.org)
• ASCO Post coverage summarizing early HNSCC activity and safety. (ascopost.com)
• ASCO 2025 oral presentation notice and abstract details for HNSCC update. (ir.bicara.com)
• ASCO GI 2025 SCAC results (Phase 1/1b expansion). (ir.bicara.com)
• AACR 2025 cSCC monotherapy expansion abstract. (aacrjournals.org)
• Trial registry (NCT04429542) with design and arms. (ichgcp.net)

Scientific citations above include peer‑reviewed journals (Cancer Research), ASCO/AACR abstracts, and meeting reports. Company disclosures are used where peer‑reviewed/abstract details are not yet published. (pmc.ncbi.nlm.nih.gov, ascopubs.org, aacrjournals.org, ir.bicara.com, ichgcp.net)

Last updated: Sep 2025

Inclusion Criteria:

* Age ≥18 years on the day the Informed Consent Form is signed.

* Histologically or cytologically confirmed R or M HNSCC. Eligible primary tumor locations are oral cavity, hypopharynx, larynx or oropharynx (with documented HPV-negative disease if presenting with OPSCC). Note: primary tumor location of paranasal sinuses and nasopharynx, any histology are excluded.

* No prior systemic therapy administered in the R or M setting; and completed systemic therapy \>6 months prior if given as part of multimodal treatment for locoregionally advanced disease in the adjuvant or definitive setting.

* Archival tumor tissue or willing to undergo pretreatment biopsy at Screening if archival tissue is insufficient or unavailable.

* PD-L1 CPS ≥1 (by PD-L1 IHC 22C3 pharmDx assay).

* Measurable disease based on RECIST 1.1.

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

* Adequate organ function, as defined in the protocol.

Exclusion Criteria:

* Disease suitable for local therapy administered with curative intent.

* Prior treatment with anti-TGFβ therapy.

* Prior therapy with an anti-EGFR antibody (exception: radio sensitizing agents and multimodal treatment for locoregionally advanced disease).

* Prior history of Grade ≥2 intolerance or hypersensitivity reaction to anti-EGFR therapy or other murine proteins.

* Prior therapy with an immune checkpoint inhibitor completed within 6 months prior to study treatment initiation.

* Progressive disease \<6 months from completion of curative intent systemic therapy for locoregionally advanced HNSCC.

* Life expectancy less than 3 months.

* Known active central nervous system metastases, history of spinal cord compression from tumor involvement, a history of carcinomatous meningitis, or leptomeningeal disease are excluded.

* Current active major bleeding, or a recent major bleeding episode within 4 weeks prior to enrollment.

* Subject participated in another clinical study or received treatment with another investigational drug must wait at least 5 half-lives of the treatment received or 4 weeks (whichever is shorter) following prior therapy.

* Active autoimmune disease requiring systemic treatment in the past 2 years.

* Subjects with chronic hepatitis B virus (HBV) infection with active disease who meet the criteria for anti-HBV therapy and are not on a suppressive antiviral therapy prior to initiation of study treatment.

* Subjects with a known history of hepatitis C virus (HCV) who have not completed curative antiviral treatment or have an HCV viral load above the limit of quantification at Screening.

* Known history of human immunodeficiency virus (HIV).

* Receipt of any organ transplantation, including autologous and allogeneic stem cell transplantation, with the exception of transplants that do not require immunosuppression.

* Known to be diagnosed and/or treated for any other additional malignancy within 2 years prior to randomization with the exception of the following: curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, and curatively resected in situ cervical cancer, and curatively resected in situ breast cancer, and low-risk early stage prostate cancer.

* Any condition requiring systemic treatment with either corticosteroids (\>10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 7 days prior to the first dose of study treatment, except for topical, intranasal, intrabronchial, or ocular steroids.

* Use of a live or live attenuated vaccine within 4 weeks prior to Screening.

Other Inclusion/Exclusion criteria may apply as defined in the protocol.