Ficerafusp Alfa/Pembrolizumab Receives FDA BTD in Front-Line HNSCC

The FDA has granted breakthrough therapy designation (BTD) to ficerafusp alfa (BCA101) in combination with pembrolizumab (Keytruda) as a first-line therapy for patients with metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC) expressing PD-L1 with a combined positive score (CPS) of at least 1, according to a press release from the developer, Bicara Therapeutics.¹

The full indication excludes patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma.

“This recognition highlights the urgent unmet need for patients with HPV-negative [recurrent/metastatic] HNSCC,” stated David Raben, MD, chief medical officer of Bicara Therapeutics, in the press release.¹ “It also 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.”

Multiple phase 1/1b dose cohorts evaluated ficerafusp alfa plus pembrolizumab in patients with front-line HPV negative recurrent or metastatic HNSCC, providing support for the FDA’s decision; most recently, results from an expansion cohort of an open-label, multicenter phase 1/1b trial (NCT04429542) were shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.²

Additionally, the global, double-blind, placebo-controlled randomized phase 2/3 FORTIFI-HN01 trial (NCT06788990) evaluating approximately 650 patients with recurrent or metastatic HNSCC is underway, and the design was shared at the 2025 ASCO Annual Meeting.³

Phase 1/1b Expansion Cohort

The confirmed and unconfirmed overall response rates (ORR) were 54% (n = 15/28) and 64% (n = 18/28). Of confirmed responders, 80% (n = 12/15) achieved at least 80% tumor shrinkage; the complete response (CR) rate was 21%, and the disease control rate was 89%. The median time to response was 1.4 months. The median progression-free survival (PFS) was 9.9 months.

Of the 15 confirmed responders, the median duration of response (DOR) was 21.7 months; the DOR rate was 79% at 6 months or more, 65% at 12 months or more, and 57% at 18 months or more.

With a median follow-up of 25.2 months, the median overall survival (OS) was 21.3 months, and the 2-year OS rate was 46%. In patients with a CPS between 1 and 19, the median OS was 22.0 months compared with 20.6 months in those with a CPS of 20 or higher.

The trial enrolled 30 patients with frontline recurrent, HPV-negative HNSCC who had a CPS of at least 1, and a primary site of disease in the oral cavity, oropharynx, larynx, or hypopharynx. All patients received ficerafusp alfa at 1500 mg intravenously on days 1, 8, and 15, and pembrolizumab at 200 mg intravenously on day 1, every 21 days.

The median age of patients was 63 years, 63% were male, and 63% had an ECOG performance status of 1. The most common primary site of disease was the oral cavity (47%), 50% each had a CPS from 1 to 19 and 20 or higher, and 47% had locoregional and distant metastatic disease.

The combination demonstrated a favorable safety profile and no new safety signals. Any-grade treatment-emergent adverse events (TEAEs) related to ficerafusp alfa occurred in 93% of patients, with 47% being grade 3 and 3% being grade 4. The most common TEAEs of any grade were dermatitis acneiform (77%), pruritus (53%), anemia (43%), hypomagnesemia (43%), and fatigue (37%); of grade 3, the most common were anemia (20%), dermatitis acneiform (13%), and fatigue (3%).

Phase 2/3 FORTIFI-HN01 Study

The trial enrolled patients with frontline recurrent or metastatic HNSCC, excluding those with HPV-positive oropharyngeal squamous cell carcinoma, who have a CPS of at least 1. Additional enrollment criteria include an age of 18 years or more, no prior systemic therapy in the recurrent or metastatic setting, primary tumor located in the oral cavity, hypopharynx, larynx, or oropharynx, and an ECOG performance status of 0 or 1.

Patients were randomly assigned, in a 1:1:1 ratio, to one of 3 trial arms during the phase 2 portion of the trial, which will continue until 10 to 20 patients per arm have at least 12 weeks of follow-up. In arm A, patients received 1500 mg of ficerafusp alfa weekly plus 200 mg of pembrolizumab every 3 weeks; in arm B, patients received 750 mg of ficerafusp alfa weekly plus 200 mg of pembrolizumab every 3 weeks; and in arm C, patients received placebo weekly or 200 mg of pembrolizumab every 3 weeks. In the phase 3 portion of the trial, after investigators have decided on a dose between arm A and arm B, all patients in arms A and B will receive the same dosage.

The dual primary end points of the phase 3 portion of the trial are ORR at the interim analysis and OS at the final analysis.

“BTD provides external validation of the importance of ficerafusp alfa’s best-in-disease potential, and solidifies the foundation for our ongoing pivotal trial, FORTIFI-HN01,” said Claire Mazumdar, PhD, MBA, chief executive officer of Bicara Therapeutics.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/3dk932dh
2. Chung CH, Hanna GJ, Zandberg DP, et al. Ficerafusp alfa with pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: updated results from an expansion cohort of an open-label, multicenter, phase 1/1b trial. J Clin Oncol. 2025;43(suppl 16):6017. doi:10.1200/JCO.2025.43.16_suppl.6017
3. Ferrarotto R, Kaczmar JM, Spigel DR, et al. 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: the FORTIFI-HN01 study. J Clin Oncol. 2025;43(suppl 16):TPS6113. doi:10.1200/JCO.2025.43.16_suppl.TPS6113