Ficerafusp Alfa Plus Pembrolizumab Shows Robust Activity in Frontline PD-L1+, HPV– HNSCC

By employing a dual-targeted mechanism of action that acts on key drivers of disease growth and proliferation, ficerafusp alfa (BCA101) has the potential to offer an effective frontline treatment option for patients with unresectable, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to Deborah J. Wong, MD, PhD.

In October 2025, the FDA granted breakthrough therapy designation to ficerafusp alfa in combination with pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic or unresectable/recurrent HNSCC whose tumors have a PD-L1 combined positive score of at least 1, excluding human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma.¹ The designation was supported by data from a phase 1/1b trial (NCT04429542).

“The FDA designation of breakthrough status underscores the exciting data that we’ve seen thus far,” Wong said in an interview with OncLive®. “First and foremost, the median overall survival [OS] of 21.3 months is really exciting, [as is] the [confirmed] objective response rate [ORR] of 54% [n = 15 of 28] and the complete response [CR] rate of 21% [n = 6 of 28].”²

In the interview, Wong, a head and neck medical oncologist in the Department of Hematology/Oncology at UCLA Health in Los Angeles, California, explained the mechanism of action of ficerafusp alfa, discussed the notable data that have been reported to date with the agent, and highlighted the ongoing phase 2/3 FORTIFI-HN01 trial (NCT06788990) of ficerafusp alfa or placebo in combination with pembrolizumab in first-line PD-L1–positive recurrent/metastatic HNSCC.³

OncLive: How is the dual-targeted approach of ficerafusp alfa relevant in HPV-negative head and neck cancer?

Wong: We know that [patients with] HPV-negative head neck cancers have a poor prognosis; [these] cancers have EGFR amplification, which drive tumor growth and spread. Furthermore, HPV-negative head and neck cancers also tend to have a very robust TGF-β activation pathway. We know that TGF-β is important in epithelial mesenchymal transition, which [also] facilitates [disease] progression and spread. Dual targeting of EGFR and TGF-β is exciting in the sense that we are now able to block 2 pathways that are critical for growth and spread of head neck cancers, [specifically] HPV-negative head neck cancers.

What were the most clinically meaningful signals from the phase 1b data presented during the 2025 ASCO Annual Meeting?

To assess that, we have to also consider our current standard of care [SOC]. We know that for HPV-negative head and neck cancers, even though pembrolizumab, with or without chemotherapy, is an established SOC, the response [rates] are modest at best. When we look at median OS with pembrolizumab and add an EGFR-targeted antibody to that, the median OS is [approximately] 9 to 10 months. So, we know that HPV-negative head and neck cancers have a particularly poor prognosis and that we don’t have effective agents.

With that in mind, the data evaluating ficerafusp alfa in combination with pembrolizumab were really exciting. We saw a [confirmed] ORR of 54% but, even more dramatically, a CR in over 20% of patients. Beyond that [response] durability was quite impressive, with a median duration of response of [21.7] months and a median OS of 21.3 months. We’re seeing ficerafusp alfa with pembrolizumab doubling the OS [of historical SOC therapies].

How do you anticipate breakthrough therapy designation from the FDA affecting the development timeline of ficerafusp alfa?

[Patients with] HPV-negative head and neck cancers often present with local, regionally recurrent disease and this presents a particularly morbid condition for patients [with] a lot of cancer-related pain and morbidity from the disease itself. Another important outcome [from the phase 1/1b trial] was time response [TTR]. Patients who received this combination had a median TTR of 1.4 months. From a quality of life perspective, if you have a patient with a large, bulky tumor that’s impairing their ability to eat and is causing significant pain, having tumor shrinkage in less than 2 months is another remarkable outcome that’s clinically meaningful.

[Taken together, these phase 1/1b data] support why this is such an exciting combination. Hopefully, the breakthrough designation will help to accelerate the availability of this combination if the phase 2/3 study is positive.

What are the key design characteristics of the phase 2/3 study and what should be monitored in terms of end points and translational biomarkers?

FORTIFI-HN01 is a global, randomized, double-blinded study evaluating pembrolizumab vs ficerafusp alfa and pembrolizumab in a head-to-head trial. This is specifically for patients with treatment-naive, recurrent/metastatic HPV-negative HNSCC that is PD-L1 positive. In the phase 2 portion of the study, 2 doses of ficerafusp alfa will be evaluated in combination with pembrolizumab vs pembrolizumab [alone]. At the conclusion of the phase 2 portion, the optimal biologic dose to be used in the phase 3 study will be determined.

This head-to-head study will be pivotal in determining whether this combination is effective and represents a good treatment option for HPV-negative, recurrent/metastatic HNSCC.

How could the potential FDA approval of ficerafusp alfa change the treatment paradigm for this patient population?

If the study is positive, this will be paradigm-changing for patients with recurrent and metastatic HNSCC. This will represent the new SOC for patients with HPV-negative PD-L1–positive HNSCC.

Are there any other disease areas where dual-targeting of EGFR and TGF-β has shown therapeutic promise?

EGFR expression and TGF-β activation play an important role across multiple different tumor types. Others that come to mind include cutaneous squamous cell carcinoma, some EGFR-driven lung cancers, as well as colorectal cancer. [Since] ficerafusp alfa has dual-targeting of EGFR and TGF-β, it may have applicability in those histologies as well.

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 February 5, 2026. https://ir.bicara.com/news-releases/news-release-details/bicara-therapeutics-announces-ficerafusp-alfa-granted
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. 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 February 3, 2026. Accessed February 6, 2026. https://clinicaltrials.gov/study/NCT06788990