Merus' Petosemtamab, an investigational IgG1 bispecific antibody, represents a promising therapeutic innovation in Head and neck squamous cell carcinoma (HNSCC). Engineered to target both EGFR and LGR5, petosemtamab exerts its effects through three mechanisms: inhibition of EGFR signaling, induction of EGFR internalization and degradation via LGR5 binding, and immune activation through antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

As of a February 27, 2025 data cutoff from the ongoing phase II trial of petosemtamab in combination with pembrolizumab,in 43 evaluable patients, confirmed overall response rate (ORR) was  63%, and responses observed across PD-L1 levels. In addition to this, median progression-free survival (PFS) was 9 months, and 12-months OS rate was 79%. In 45 patients the combination was generally well tolerated and no significant overlapping toxicities with pembrolizumab were observed. Treatment-emergent adverse events (TEAEs) were reported in 45 patients and G≥3 TEAEs occurred in 60% patients, including 44% patients who experienced treatment-related TEAEs.  Infusion-related reactions occurred in 38% of patients. 

KOL insights: 

“We believe petosemtamab continues to demonstrate substantial clinical activity superior to historical controls, based on the magnitude and consistency of efficacy, not just on one endpoint, but across ORR, PFS and OS in the overall population and within important subgroups of HPV disease and PD-L1 expression levels.” – Expert Opinion

Conclusion: 

In 2024, ~168,000 new cases of head and neck cancer were reported across the 7 major markets, with ~90% being squamous cell carcinomas, many strongly tied to HPV, especially HPV16. Merus's Phase II trial of their bispecific antibody petosemtamab in combination with KEYTRUDA for head and neck cancer showed a “high response rate” and “unprecedented” overall survival rate.  These results outperform historical KEYTRUDA’s findings. This unprecedented  data supports a "best-in-disease" profile, which might lead to an accelerated FDA approval. Patient-reported outcomes further support the regimen’s tolerability, with maintained overall health status and improved gastrointestinal and fatigue-related symptoms during treatment. A global Phase III trial is currently underway to further evaluate this combination in the first-line setting. Apart from Merus, Bicara is also advancing the clinical development of their respective asset into Phase III within head and neck cancer. However, ficerafusp alfa is targeting a more niche patient population by excluding individuals who test positive for human papillomavirus (HPV). At ASCO 2025, Bicara also shared overall survival (OS) statistics for HPV-negative patients, a subgroup that often has worse treatment outcomes than HPV-positive patients. In patients with first-line, PD-L1-positive recurrent or metastatic HNSCC, two-year OS rate was 46%, along with median OS of 21.3 months.