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.

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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

Articles

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.

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