Ficerafusp Alfa Earns FDA Breakthrough Therapy Designation for HPV-Negative R/M HNSCC

The US FDA has granted breakthrough therapy designation (BTD) to the bifunctional antibody ficerafusp alfa (BCA101) in combination with pembrolizumab (Keytruda) for the first-line treatment of human papillomavirus (HPV)-negative, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).¹

BTD expedites the development and review of drugs that intend to treat serious conditions, and which show preliminary clinical advantages over available therapies on clinically significant end points.² This BTD, granted to Bicara Therapeutics, enables the sponsor to receive more intensive guidance on drug development, with the intention of generating evidence to support approval.

“[This recognition] reinforces our conviction that depth and durability of response, driven by ficerafusp alfa’s ability to synergize with pembrolizumab and enable tumor penetration, are key to achieving long-term clinical benefit,” said David Raben, MD, chief medical officer of Bicara Therapeutics, in a press release.¹

What Is the Clinical Rationale for the Agent?

As one of the most common subtypes of head and neck cancers, HPV-negative HNSCC is a condition characterized by severe morbidities, poor prognosis, and limited options for management and treatment. This unmet need calls for novel therapies that elicit durable antitumor responses that can improve patient quality of life and outcomes.

Ficerafusp alfa is an investigational first-in-class bifunctional antibody that combines an epidermal growth factor receptor (EGFR)-directed monoclonal antibody with a domain that binds to transforming growth factor beta (TGF-β). The agent functions to drive tumor penetration through a dual-targeted approach, targeting 2 clinically validated pathways in the tumor microenvironment.

What Data Support This Designation?

This BTD is supported by positive data from a phase 1/1b study (NCT04429542) evaluating the safety and preliminary efficacy of ficerafusp alfa as monotherapy and in combination with pembrolizumab in several tumor types.³ This study consisted of a dose-escalation phase (part A) and dose-expansion phase (part B), with the following patients eligible:

1. Part A: Patients with EGFR-driven advanced solid tumors that are refractory to standard of care or for whom standard of care is not available, including HNSCC or squamous cell carcinoma of the anal canal (SCCAC).
2. Part B:
   1. Monotherapy: Patients with cutaneous squamous cell carcinoma (CSCC).
   2. Combination therapy:Patients with HPV-negative R/M HNSCC, squamous carcinoma of the anal canal (SCAC), and squamous non–small cell lung cancer (SqNSCLC).
   3. Randomized to either monotherapy or combination therapy: Patients with colorectal cancer (CRC).

Data from this study, presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated deep, durable responses, with a median duration of response of 21.7 months and a median overall survival of 21.3 months. The agent was also found to be safe and well tolerated in patients.

Continued investigation of ficerafusp alfa’s efficacy in HPV-negative R/M HNSCC is underway in an ongoing global, randomized, phase 2/3 pivotal trial, FORTIFI-HN01 (NCT06788990), which began enrolling patients earlier in 2025.⁴

“BTD … solidifies the foundation for our ongoing pivotal trial, FORTIFI-HN01,” said Claire Mazumdar, PhD, MBA, chief executive officer of Bicara Therapeutics, in a press release.¹ “We look forward to working closely with the FDA to bring this therapy to patients as quickly as possible.”

REFERENCES:

1. Bicara Therapeutics Announces Ficerafusp Alfa Granted Breakthrough Therapy Designation by U.S. FDA for 1L HPV-Negative R/M HNSCC. News release. Bicara Therapeutics. October 13, 2025. Accessed October 14, 2025. https://tinyurl.com/3a23bexu

2. Breakthrough Therapy. FDA. Updated January 4, 2018. Accessed October 14, 2025. https://tinyurl.com/2fw9bnn7

3. Study of Safety and Tolerability of BCA101 Monotherapy and in Combination Therapy in Patients With EGFR-driven Advanced Solid Tumors. ClinicalTrials.gov. Updated August 15, 2025. Accessed October 14, 2025. https://www.clinicaltrials.gov/study/NCT04429542

4. FORTIFI-HN01: A Study of Ficerafusp Alfa (BCA101) or Placebo in Combination With Pembrolizumab in First-Line PD-L1-pos, R or M HNSCC (FORTIFI-HN01). ClinicalTrials.gov. Updated October 7, 2025. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT06788990