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

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Overview

Ficerafusp alfa (also known as BCA101; other code names include FmAb2/FMAB2) is an investigational, bifunctional antibody being developed by Bicara Therapeutics for EGFR-expressing solid tumors, with lead development in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). A pivotal Phase 2/3 trial (FORTIFI‑HN01) in first‑line, PD‑L1–positive, HPV‑negative R/M HNSCC began enrolling in 2025. Early‑phase expansion cohorts have also explored activity in squamous cell carcinoma of the anal canal (SCAC) and cutaneous SCC. (ir.bicara.com)

Mechanism of action

Ficerafusp alfa is an anti‑EGFR IgG1 monoclonal antibody fused to the extracellular domain of TGF‑β receptor II, functioning as a tumor‑targeted TGF‑β “trap.” In preclinical studies it: - Binds EGFR, inhibits proliferation and retains ADCC - Neutralizes TGF‑β in the tumor microenvironment, reduces SMAD signaling, and decreases iTreg differentiation - Enhances cytokine production and augments antitumor activity, including in combination with anti‑PD‑1 therapy

These data support dual blockade of tumor‑intrinsic EGFR signaling and TGF‑β–mediated immunosuppression. (aacrjournals.org)

Efficacy

Head and neck squamous cell carcinoma (R/M, first‑line; ficerafusp alfa + pembrolizumab) - ASCO 2023 interim expansion cohort (stage 1; CPS ≥1; n=18 evaluable): ORR 44% overall; 58% in HPV‑negative subgroup; acneiform rash common; no treatment‑related deaths. (ascopubs.org) - Updated 2025 oral presentation (CPS ≥1; HPV‑negative efficacy subset n=28): ORR 54% confirmed (64% including 3 unconfirmed); CR 21%; median PFS 9.9 months; median DOR 21.7 months; median OS 21.3 months; 2‑year OS 46%. (Company report of ASCO 2025 dataset; pivotal FORTIFI‑HN01 subsequently initiated.) (ir.bicara.com)

Squamous cell carcinoma of the anal canal (post‑chemotherapy; ficerafusp alfa + pembrolizumab) - ASCO GI 2025 phase 1/1b dose‑expansion: among 22 evaluable patients, ORR 32% (95% CI 13.9–54.9), disease control rate 64%; 12‑month PFS rate 36%. (ascopubs.org)

Note: Results above are from early‑phase, single‑arm cohorts and should be interpreted cautiously until randomized data are available (e.g., FORTIFI‑HN01). (ir.bicara.com)

Safety

Across early studies, the combination with pembrolizumab showed a tolerable profile with class‑consistent toxicities: - Most common treatment‑related adverse events (all grades): acneiform rash (≈50–76%), fatigue (≈43%), hypophosphatemia (≈38%), epistaxis/pruritus in SCAC. Grade ≥3 TRAEs included anemia (~19% in SCAC cohort) and acneiform rash (~12%). Discontinuations for TRAEs were infrequent (≤8% reported). (ascopubs.org)

Further reading

• Cancer Research (peer‑reviewed): BCA101 is a tumor‑targeted bifunctional fusion antibody that simultaneously inhibits EGFR and TGF‑β signaling to durably suppress tumor growth. (aacrjournals.org)
• ASCO 2023 abstract (HNSCC, 1L): Dose expansion results of BCA101 with pembrolizumab. (ascopubs.org)
• ASCO GI 2025 abstract (SCAC): Ficerafusp alfa + pembrolizumab preliminary expansion results. (ascopubs.org)
• Pivotal trial information (FORTIFI‑HN01, Phase 2/3, 1L R/M HNSCC). (clinicaltrials.ucbraid.org)
• Company communications summarizing ASCO 2025 HNSCC updates (efficacy and survival metrics). (ir.bicara.com)

ClinicalTrials registration for the ongoing Phase 1/1b program: NCT04429542 (monotherapy and combinations, including HNSCC and SCAC cohorts). (clinicaltrials.ucsd.edu)

Last updated: Oct 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.