Building on updated data from the phase 1 KEYNOTE-E28 trial (NCT04429542), the phase 2/3 FORTIFI-HN01 trial (NCT06788990) will evaluate ficerafusp alfa (BCA101) plus pembrolizumab (Keytruda) vs pembrolizumab plus placebo for the treatment of patients with PD-L1–positive, recurrent or metastatic human papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC), according to Kevin Harrington, MBBS, MRCP, FRCR, FRCP, PhD, DIC.

“The aim of [the FORTIFI-HN01 trial] is to establish a new standard of care for the treatment of patients with relapsed, metastatic head and neck cancer,” Harrington explained in an interview with 

®. “This study is already actively recruiting, and we are keen on seeing the results of this study when they come to light.”

During the interview, Harrington highlighted early efficacy data with ficerafusp alfa, contextualized findings from the phase 3 KEYNOTE-048 trial (NCT02358031), and detailed key objectives of the FORTIFI-HN01 trial. He also discussed other therapies within the HPV-negative HNSCC landscape, including petosemtamab(MCLA-158), amivantamab-vmjw (Rybrevant), and ficlatuzumab (AV-299).

Harrington is a professor of Biological Cancer Therapies at The Institute of Cancer Research, as well as the joint head of the Division of Radiotherapy and Imaging, and a consultant clinical oncologist at The Royal Marsden NHS Foundation in London, United Kingdom.

: What data have defined the disease landscape in HPV-negative HNSCC?

: In the context of relapsed and metastatic disease, [we’re] trying to build upon the initial success of the KEYNOTE-048 study. We’re trying to push beyond the current indications, which are either for single-agent pembrolizumab or pembrolizumab plus chemotherapy. Now, the greatest degree of clinical trial activity is evaluating chemotherapy-free options. Essentially, pembrolizumab plus other agents, including other immunotherapy drugs, and more recently [we’ve seen] a great deal of interest in using EGFR-targeted strategies, with [several] agents actively in clinical trials that are progressing into randomized phase 2 and phase 3 trials.

What data stood out to you from the KEYNOTE-E28 trial with ficerafusp alfa plus pembrolizumab that were 

presented at the 2025 ASCO Annual Meeting

There are a number of aspects of ficerafusp alfa, which demand attention and are particularly compelling in terms of the possibility that this could represent an advance in the field of treating [patients with] relapsed and metastatic HNSCC. And if [the data are] positive in that context [the agent could] come forward into the curative setting of newly diagnosed HNSCC.

[Ficerafusp alfa] is a bifunctional antibody that can bind the EGFR on the surface of malignant cells. We know that head and neck cancer, especially HPV-negative cancers, express those receptors in high numbers. [Furthermore], the other functionality of the antibody is that it can bind transforming growth factor beta [TGFβ] within the tumor microenvironment,. Now this targeted binding within the microenvironment of TGFβ, which is a major player, both in immune evasion, but also in the generation of a dense fibroblastic stroma around and within the tumors, represents an important potential therapeutic opportunity. Specifically, we have a drug that can potentially reduce the fibrotic density of the tumor, reduce the immunosuppressive microenvironment within the tumor, and allow access of immune cells, particularly for affected CD8-positive T cells, into those tumor nests within the tumor mass itself.

At the same time, [ficerafusp alfa] can, in combination with its immunotherapy partner, pembrolizumab, in this case, take the brakes off the immune response and allow those antitumor immune responses to evolve through those CD8 T cells, being able to permeate within the tumor. We have a treatment that facilitates [tumor] penetration of the immune response while at the same time maintaining its strength and efficacy. For those reasons, this is really a very compelling therapeutic combination.

What are some of the key efficacy findings from the study?

, we looked at data that were presented from the phase 1b study of ficerafusp alfa in combination with pembrolizumab in patients with newly diagnosed recurrent, metastatic disease in the first-line setting. The highlights of that study are that we saw quite a high overall response rate [ORR]. We saw very deep and durable responses to treatment, and patients had prolonged overall survival [OS] with those treatments. It was a relatively limited number of patients in the study. [The study included] patients with first-line recurrent, metastatic HPV-negative disease, and a group of patients who had large tumors. We saw that a significant number of patients had tumors that were greater than 5 cm, and some of them had [tumors] even greater than 7 cm in diameter. Those are poor prognosis lesions, and although patients had those relatively adverse tumor features, we saw an ORR of 54%. Of the patients who responded, 80% achieved a greater than 80% reduction in the sum of the tumor diameters.

 Those responses were durable, and the median progression-free survival [PFS] was 9.9 months. Importantly, the responses occurred early, so the median time to response was only 1.4 months. Essentially, what we have is almost all the things that would tick the boxes, both for investigators working with these drugs and for patients who desire a response. [These include] rapid responses, depth of response, durability of response, and a very significant chance of evolving such a response. This was all achieved with manageable toxicity and is very compelling in terms of the further development of this drug.

How do the data stack up against expectations and show the ability to fulfill an unmet need?

It’s worth considering the historical data, initially from the KEYNOTE-048 study, as well as real-world data from the Flatiron database in the United States. Within the United Kingdom, a real-world data set demonstrated that for [patients with] HPV-negative disease treated in a real-world context with single-agent pembrolizumab, so the control arm in any randomized trial, what we’re looking at is a median OS of 9.2 months.

 What we’re seeing already in the preliminary data with ficerafusp alfa in an HPV-negative population, many of whom have very bulky tumors, is a median PFS that is already in advance of that number. The OS data that were presented as part of the ASCO presentation is very close to 2 years for the median OS.

We also saw [with respect to] PD-L1 combined positive score [CPS] that the median OS data look as good in the patients with a CPS between 1 and 19, as those with a score of 20 and above. This has been an unmet need. Patients with a low CPS value treated with single-agent pembrolizumab have tended to do less well than patients with higher CPS values when treated with the KEYNOTE-048 [regimen]: single-agent pembrolizumab. We’re [now] seeing a combination regimen that can potentially deliver excellent response rates, durable PFS, and we’re beginning to see data suggesting the OS is going to look favorable as well.

All of these [aspects] are lining up to demand that we test this in a randomized phase 3 trial, with the hope and even the expectation that we may see a significant improvement. We may be looking at a new combination that may exceed the baseline achievable with single-agent pembrolizumab.

Regarding further development of ficerafusp alfa, please describe the rationale, design, and objectives of the FORTIFI-HN01 trial.

FORTIFI-HN01 is a randomized clinical trial in which we will test ficerafusp alfa in combination with pembrolizumab vs pembrolizumab [plus placebo] as the standard of care [(SOC) in recurrent, metastatic HNSCC].

 The aim is that this will be a registrational study looking to establish a new SOC for the treatment of patients with relapsed, metastatic HNSCC. The study will enroll patients with recurrent disease from the main sub-sites in the head and neck region, [including] the oral cavity, oropharynx, hypopharynx, and larynx. Patients will need to have a positive PD-L1 CPS greater than or equal to 1. Critically, this study will exclude patients who have HPV-positive oropharyngeal carcinoma, and this differentiates it from studies such as the phase 3 LiGeR-HN1 trial [NCT06525220]with petosemtamab. [Patients are randomly assigned] 2:1 between the combination of ficerafusp alfa and pembrolizumab vs pembrolizumab [alone].

In the initial phases of the study, in line with the FDA’s Project Optimus, 2 different dose levels of ficerafusp alfa are being tested. [This includes] the 1500-mg and the 750-mg weekly dosing. That allows us to select a dose for the larger part of the trial, and hopefully to use an effective drug dose with minimization of toxicity. Patients will be treated with a schedule that includes weekly ficerafusp alfa and pembrolizumab every 3 weeks. The expected total patient population is going to be [approximately 650] with co-primary end points of ORR and OS. This study is already actively recruiting, and we are keen to see the results of this study when they come to light.

Where do other agents factor into the investigational landscape of recurrent and/or metastatic HNSCC?

Petosemtamab is a bispecific antibody targeting both EGFR and LGR5, [and we’re] looking to develop this drug in the first-line setting in relapsed, metastatic disease, [and in] the second- and third-line settings in the LiGeR-HN1 and LiGeR-HN2 [NCT06496178]trials, respectively. In the first-line LiGeR-HN1 trial, there is a randomization between petosemtamab plus pembrolizumab and pembrolizumab. It’s important to emphasize that these trials include both HPV-negative and HPV-positive patient populations.

That’s a stark difference from the FORTIFI-HN01 study, looking at the role of ficerafusp alfa. In the second- and third-line settings the LiGeR-HN2trial is looking to compare petosemtamab with current standards of care in patients [who received] prior treatment, with platinum chemotherapy, and with prior immunotherapy exposure. This is a population of patients who will be randomly assigned either to petosemtamab as a single agent or to investigator’s choice of a range of drugs, including agents such as taxanes, cetuximab [Erbitux], methotrexate, and other chemotherapy drugs, including capecitabine [Xeloda], for instance. That study is looking to establish a new standard of care in patients who have not received EGFR-targeted therapy, either in the first line or as part of their radical treatment. It’s an interesting study, and we can hopefully expect to see each of these studies read out in the relatively near future.

Are there any other agents or approaches emerging to help improve outcomes in the HPV-negative population?

In the HPV-negative population, other [agents] are worth highlighting, such as amivantamab, another bispecific antibody that targets EGFR and c-MET. This looks like a compelling agent that has already demonstrated activity in non–small cell lung cancer and is now transitioning into HNSCC. The phase 1/2 OrigAMI-4 study [(NCT06385080) is evaluating whether] this agent has activity both as a single agent and potentially in combination with other partner therapies—this is a drug to keep an eye on for the future.

It's also worth emphasizing another agent that targets the EGFR pathway: ficlatuzumab. This is an antibody that binds HGF, the ligand for the c-MET receptor, and that is being tested in the second- and third-line settings for patients with HPV-negative disease. This approach is being tested with ficlatuzumab plus cetuximab vs cetuximab [plus placebo] as the SOC in the phase 3 FIERCE-HN trial [NCT06064877], which is actively recruiting.

Beyond cetuximab, a seminal component of the original EXTREME trial [NCT00122460] regimen,now we have several new, reinvigorated approaches to targeting EGFR. I’m very hopeful all of these may show that we have activity against this disease.

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. 

. 2025;43(suppl 16):6017. doi:10.1200/JCO.2025.43.16_suppl.6017

Vasiliadou I, Grose D, Wilson C, et al. The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK. 

. 2024;155(5):883-893. doi:10.1002/ijc.34963

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. 

. 2025;43(suppl 16):TPS6113. doi:10.1200/JCO.2025.43.16_suppl.TPS6113

Articles

Kevin Harrington, MBBS, MRCP, FRCR, FRCP, PhD, DIC, discusses ficerafusp alfa for the treatment of patients with HPV-negative head and neck cancer. 

Phase 2/3 Trial Further Evaluates Ficerafusp Alfa With Pembrolizumab in HPV– Head and Neck Cancer

Dr Chung on the Potential Role for Ficerafusp Alfa Plus Pembrolizumab in the HPV-Negative HNSCC Paradigm

"This patient population needs better treatments. When we combined ficerafusp alfa with pembrolizumab, the ORR was 54%, and greater than 80% of responders [achieved] a reduction in their tumors of 80% [or greater. These data show that the combination] really produces deep as well as durable responses."

Christine Chung, MD, program lead of Head and Neck Oncology; Research Department Chair of Head and Neck-Endocrine Oncology; chair of the Department of Head and Neck-Endocrine Oncology; and program leader of Head and Neck Oncology at Moffitt Cancer Center, discussed the potential role for ficerafusp alfa (BCA101) plus pembrolizumab (Keytruda) in the larger treatment paradigm for human papillomavirus (HPV)–negative recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), particularly those with a PD-L1 combined positive scores (CPS) of at least 1.

, interim findings from the phase 1/1b KEYNOTE-E28 trial (NCT04429542) showed a confirmed objective response rate (ORR) of 54% with the combination among 28 patients with HPV-negative, recurrent or metastatic HNSCC and CPS of 1 or greater. The ORR,including both confirmed and unconfirmed responses, was 64%, with a complete response rate of 21%. Notably, 80% of responders experienced at least 80% tumor shrinkage, and the disease control rate reached 89%. These results suggest not only a high frequency of responses but also substantial depth of response, according to Chung.

Chung emphasized that standard first-line therapy for patients in this population with a PD-L1 CPS of 1 or greater currently consists of pembrolizumab monotherapy. However, clinical outcomes remain suboptimal, particularly among patients with HPV-negative disease. For example, in a prior phase 2 trial (NCT03370276) combining cetuximab (Erbitux) and nivolumab (Opdivo) in this subgroup, the median overall survival (OS) was only 10.7 months in patients with a CPS of 20 or higher. In contrast, ficerafusp alfa plus pembrolizumab yielded a median duration of response of 21.7 months and a median OS of 21.3 months in KEYNOTE-E28.

Ficerafusp alfa is a bifunctional fusion protein designed to simultaneously target EGFR and TGF-β signaling while enhancing immune activation through PD-1 blockade, Chung explained. She noted that this dual-targeted approach may account for the improved efficacy, offering both deeper and more durable responses in a patient population that needs more effective therapeutic options.

Given the activity observed in KEYNOTE-E28, Chung suggested that the combination of ficerafusp alfa and pembrolizumab could represent a meaningful advance in the first-line treatment landscape for HPV-negative HNSCC. Additional studies will be needed to validate these findings in larger, randomized cohorts, but the interim data highlight a potential new standard of care for this high-risk patient population, Chung concluded.

Videos

Christine Chung, MD, contextualizes efficacy data with ficerafusp alfa plus pembrolizumab within the larger treatment paradigm for HPV-negative HNSCC.

The combination of ficerafusp alfa (BCA101) and pembrolizumab (Keytruda) elicited responses when used as a frontline regimen in patients with human papillomavirus (HPV)–negative recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to updated interim data from the phase 1/1b KEYNOTE-E28 trial (NCT04429542) presented during the 

At a data cutoff date of March 20, 2025, the confirmed objective response rate (ORR) in patients with HPV-negative, relapsed or metastatic HNSCC that had a PD-L1 combined positive score (CPS) of at least 1 (n = 28) was 54%. The ORR (confirmed or unconfirmed) was 64%, which comprised a complete response rate of 21%.

Notably, 80% of those who responded experienced at least 80% tumor shrinkage. The disease control rate with the regimen was 89%.

The median time to response was 1.4 months, and the median duration of response (DOR) was 21.7 months. Moreover, 79% of patients continued to respond for at least 6 months, 65% for at least 12 months, and 57% for at least 18 months. The median progression-free survival (PFS) was 9.9 months. At a median follow-up of 25.2 months, the median overall survival (OS) was 21.3 months; the 2-year OS rate was 46%. In those with a CPS ranging from 1 to 19, the median OS was 22.0 months; in those with a CPS of 20 or higher, the median OS was 20.6 months.

“Ficerafusp alfa plus pembrolizumab is a promising first-line regimen in HPV-negative, recurrent/metastatic head and neck cancer that demonstrates high [ORR], deep and durable responses, and prolonged OS,” Christine H. Chung, MD, of Moffitt Cancer Center, said in a presentation of the data.

The early-phase trial enrolled patients with first-line recurrent or metastatic HNSCC who were negative for HPV. Patients could have had cancer in the oral cavity, oropharynx, larynx, or hypopharynx. They were required to have a CPS of at least 1.

Study participants were given 1500 mg of ficerafusp alfa on days 1, 8, and 15 plus 200 mg of pembrolizumab on day 1 every 21 days.

When looking at demographics and baseline characteristics in the safety set (n = 30), the median age was 63 years (range, 31-84), and most were male (63%) and had an ECOG performance status of 1 (63%). Primary sites of disease included oropharynx (27%), oral cavity (47%), hypopharynx (13%), and larynx (13%). Half of patients had a CPS ranging from 1 to 19, and half had a CPS of 20 or higher. Thirty percent of patients had locoregional-only disease, and 47% had locoregional and distant metastatic disease. Sum of target lesions was over 50 mm (47%) or over 70 mm (27%) in diameter.

The combination had a favorable toxicity profile, with no new safety signals. Any treatment-emergent adverse effects (TEAEs) were experienced by 93% of patients; grade 3 TEAEs occurred in 47% of patients, and grade 4 TEAEs were recorded in 3%.

The most common TEAEs reported in at least 20% of patients that were related to ficerafusp alfa included dermatitis acneiform (all grade, 77%; grade 3, 13%), pruritus (53%; 0%), anemia (43%; 20%), hypomagnesemia (43%; 0%), fatigue (37%; 3%), dry skin (30%; 0%), hypophosphatemia (27%; 0%), hypokalemia (27%; 0%), stomatitis (23%; 0%), and nausea (20%; 0%).

Looking at the Limitations and Next Steps

“These results are from a multicenter, single-arm, dose-expansion cohort with 2-year follow-up of all patients,” Chung noted regarding limitations of the data.

The phase 2/3 FORTIFI-HN01 study (NCT06788990) is now enrolling patients with HPV-negative, recurrent or metastatic HNSCC to further assess the benefits of ficerafusp alfa plus pembrolizumab as first-line treatment.

Chung CH, Hanna GJ, Zandberg DP, et al. Ficerafusp alfa with pembrolizumab in patients recurrent or metastatic head and neck squamous cell carcinoma: updated results from an expansion cohort of an open-label, multicenter, phase 1/1b trial. 

. 2025;43(suppl 16_:6017. doi:10.1200/JCO.2025.43.16_suppl.6017

Bicara Therapeutics demonstrates deep and durable responses with ficerafusp alfa plus pembrolizumab in 1L HPV-negative R/M HNSCC at ASCO 2025. News release. Bicara Therapeutics, Inc. June 1, 2025. Accessed June 1, 2025. https://ir.bicara.com/news-releases/news-release-details/bicara-therapeutics-demonstrates-deep-and-durable-responses

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 May 30, 2025. Accessed June 1, 2025. https://clinicaltrials.gov/study/NCT06788990

The combination of ficerafusp alfa and pembrolizumab shows promise as a first-line treatment for HPV-negative recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Interim data from the KEYNOTE-E28 trial revealed a confirmed objective response rate of 54% and a disease control rate of 89%. The median duration of response was 21.7 months, with a median progression-free survival of 9.9 months and overall survival of 21.3 months. The regimen demonstrated a favorable safety profile, with manageable treatment-emergent adverse effects. Further investigation is ongoing in the phase 2/3 FORTIFI-HN01 study.

Ficerafusp alfa plus pembrolizumab elicited deep responses in HPV-negative recurrent or metastatic head and neck cancer.

Going Beyond Immunotherapy in HPV-Negative Head and Neck Squamous Cell Carcinoma | Supplements and Featured Publications

Phase 2/3 Trial Further Evaluates Ficerafusp Alfa With Pembrolizumab in HPV– Head and Neck Cancer

Dr Chung on the Potential Role for Ficerafusp Alfa Plus Pembrolizumab in the HPV-Negative HNSCC Paradigm

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