According to DelveInsight, in 2024, the US reported ~71,000 head and neck cancer cases, primarily head and neck squamous cell carcinoma (HNSCC) (~90%) arising from the oral cavity, pharynx, or larynx. Most head and neck cancers are linked to tobacco or HPV (human papillomavirus), though ~80% of recurrent/metastatic (R/M) HNSCCs are HPV-negative and associated with high morbidity, highlighting the need for more effective therapies.

Bicara's Ficerafusp alfa (FICERA), a first-in-class bifunctional antibody targeting EGFR and TGF-β, is designed to overcome resistance in this setting by remodeling the immune-excluded tumor microenvironment and enhancing the durability of anti-tumor responses.

At the March 20, 2025 data cutoff, the combination therapy showed encouraging clinical activity in patients with HPV-negative, relapsed or metastatic HNSCC and PD-L1 CPS ≥1. The confirmed objective response rate (ORR) was 54%.  The ORR (confirmed or unconfirmed) was 64%. Notably, 80% of responders achieved ≥80% tumor reduction, and the disease control rate was 89%.

Responses occurred rapidly, with a median time to response of 1.4 months and a median duration of response (DOR) of 21.7 months. Durable benefit was evident, with 79% of patients maintaining response for ≥6 months, 65% for ≥12 months, and 57% for ≥18 months. Median progression-free survival (PFS) was 9.9 months, and at a median follow-up of 25.2 months, median overall survival (OS) reached 21.3 months, with a 2-year OS rate of 46%. OS outcomes were consistent across PD-L1 subgroups.

The regimen was well tolerated, with no new safety signals. Treatment-emergent adverse events (TEAEs) occurred in 93% of patients; grade 3 and 4 TEAEs were observed in 47% and 3%, respectively. Common ficerafusp alfa–related TEAEs included dermatitis acneiform, pruritus, anemia, hypomagnesemia, fatigue, and other manageable effects, most of which were low grade.

KOL insights: 

“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.” – Expert Opinion

Conclusion:

There was a lot of anticipation around the clinical data of Merus’ bispecific antibody [Petosemtamab (MCLA-158)] and Bicara's bispecific fusion protein (Ficerafusp alfa). Petosemtamab (EGFR x LGR5 Mab) and ficerafusp (EGFR x TGF-β fusion protein) are both EGFR-targeting bispecifics, however differ in secondary targets and structural format. Petosemtamab and ficerafusp targeting first-line PD-L1-positive head and neck cancer in combination with KEYTRUDA. There were slight differences in the target patient population as ficerafusp data was mainly for  HPV-negative patients, and Merus’ Petosemtamab included all-comers (both HPV-positive and negative patients). 

HPV-negative Head and neck cancer patients lack effective treatment options and have worse treatment outcomes if compared with HPV-positive patients. Bicara's data presented at ASCO 2025 in HPV-negative patients, shows an ORR of 54% (n=28), which is comparable or slightly better than Merus’ data (50% ORR (n=8) in HPV-negative). In the phase I/Ib trial, Ficerafusp’ 2-year OS rate was 46% in HPV-negative patients. Recently, Merus announced Phase II clinical results showing that Petosemtamab combined with KEYTRUDA achieved nearly 80% 12-month OS rate, although PD-L1-specific OS data was not split out between HPV subtypes, which was higher than ficerafusp’s 12-month OS of 61% (reported May 22, 2025). Owing to this positive data Merus's stock has soared, and Bicara’s stocks have taken a tumble. 

Even with rising optimism for petosemtamab, there are several distinctions between petosemtamab and ficerafusp that could change the situation. The race for dominance in the first-line market may ultimately depend on outcomes within the HPV-negative single-arm subgroup, where uncertainty remains regarding the OS split of petosemtamab (HPV+ vs. HPV-), while ficerafusp holds an edge. 

Early data show encouraging improvements in PFS, 12-month OS, ORR, and CR rates versus historical benchmarks, with 24-month OS and mature DOR results expected to reinforce clinical benefit. These findings underscore the promise of this combination in establishing a new standard of care across both HPV-positive and HPV-negative first-line HNSCC.  The ongoing FORTIFI-HN01 Phase II/III trial is evaluating this regimen as first-line therapy in PD-L1–positive, HPV-negative R/M HNSCC.