The designation is supported by findings from a phase 1/1b trial (NCT04429542), which demonstrated that in patients with HPV-negative, recurrent/metastatic HNSCC with a PD-L1 CPS of at least 1 (n = 28), the combination of ficerafusp alfa and pembrolizumab generated a confirmed objective response rate (ORR) of 54% and an unconfirmed ORR of 64%.2 Findings presented at the 2025 ASCO Annual Meeting also showed that a tumor shrinkage of at least 80% was reported in 80% of confirmed responders (n = 15). The complete response and disease control rates were 21% and 89%, respectively.
The median time to response with the combination was 1.4 months, and patients achieved a median progression-free survival (PFS) of 9.9 months. The median duration of response (DOR) was 21.7 months, and the 18-month DOR rate was 57%.
At 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%.
“This [breakthrough therapy] recognition highlights the urgent unmet need for patients with HPV-negative recurrent/metastatic HNSCC,” David Raben, MD, chief medical officer of Bicara Therapeutics, stated in a news 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.”
How Was the Phase 1 Investigation of Ficerafusp Alfa Plus Pembrolizumab Designed?
The phase 1/1b trial evaluating ficerafusp alfa as monotherapy and as part of combination therapies for patients with EGFR-driven advanced solid tumors also included an expansion cohort of patients with first-line, recurrent/metastatic, HPV-negative HNSCC who also had a PD-L1 CPS of at least 1.2,3 Patients were allowed to have a primary tumor location of the oropharynx, oral cavity, hypopharynx, or larynx; nasopharynx as a primary tumor location was not permitted.3
In the HNSCC expansion cohort, no prior systemic therapy in the recurrent or metastatic setting was allowed; however, systemic therapy given as part of multimodal treatment in the locally advanced setting was allowed, if completed more than 6 months prior to enrollment. Prior checkpoint inhibitors were allowed only if given in the neoadjuvant setting more than 6 months ahead of study enrollment.
During the dose-expansion phase, patients with HPV-negative, PD-L1–positive, recurrent/metastatic HNSCC received ficerafusp alfa at 1500 mg on days 1, 8, and 15 of each 21-cycle in combination with pembrolizumab at 200 mg on day 1 of each cycle.2
Safety, tolerability, and the incidence of dose-limiting toxicities served as the primary end points of the study. Secondary end points included ORR, clinical benefit rate, PFS, DOR, OS, and pharmacokinetics.
Is Ficerafusp Alfa Being Evaluated in Any Ongoing Trials?
The ongoing phase 2/3 FORTIFI-HN01 trial (NCT06788990) is investigating ficerafusp alfa plus pembrolizumab vs placebo plus pembrolizumab for the first-line treatment of patients with PD-L1–positive, recurrent/metastatic HNSCC.4
In phase 2, patients are being randomly assigned 1:1:1 to 1 of 3 treatment arms:
- Arm A: ficerafusp alfa at 1500 mg once per week plus pembrolizumab at 200 mg once every 3 weeks
- Arm B: ficerafusp alfa at 750 mg once per week plus pembrolizumab at 200 mg once every 3 weeks
- Arm C: placebo once per week plus pembrolizumab at 200 mg once every 3 weeks
Once the optimal biologic dose of ficerafusp alfa is determined in phase 2, phase 3 will evaluate that dosage plus pembrolizumab vs placebo plus pembrolizumab.
References
- 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 13, 2025. https://ir.bicara.com/news-releases/news-release-details/bicara-therapeutics-announces-ficerafusp-alfa-granted
- Chung C, Hanna G, Zandberg D, 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
- Study of safety and tolerability of BCA101 monotherapy and in combination therapy in patients with EGFR-driven advanced solid tumors. Updated August 15, 2025. Accessed October 13, 2025. https://www.clinicaltrials.gov/study/NCT04429542
- 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 13, 2025. https://clinicaltrials.gov/study/NCT06788990
