Breakthrough Clinical Results

Merus N.V. announced positive interim data from a Phase 2 trial of petosemtamab in combination with pembrolizumab for first-line treatment of PD-L1+ recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). The data, presented at ASCO 2025, showed a 63% overall response rate in 43 evaluable patients, with a 79% overall survival rate at 12 months and a median progression-free survival of 9 months. The combination was generally well-tolerated. These results suggest petosemtamab may become a new standard of care if approved.

Incidence and Prevalence

Global Incidence and Prevalence of Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide according to multiple references. The disease accounts for 2.5% of all new cancer cases and 1.9% of all cancer deaths annually on a global scale.

In the United States specifically, HNSCC represents approximately 2% of all cancers and 2% of cancer deaths. A total of 75,000 cases of head and neck cancer were diagnosed in 2001 in the United States, with 30,000 deaths recorded that same year.

Approximately 90-90% of all head and neck cancers are represented by squamous cell carcinoma. More specifically, more than 90% of oral cancers (occurring in the mouth, lip, and tongue) are oral squamous cell carcinoma (OSCC).

The incidence rate of oral cancer varies widely throughout the world, with an evident prevalence in South Asian countries. OSCC is associated with a high death rate of around 50% in some regions of the world.

Recent trends show that incidence is rising in several sites: - Thyroid (up 52%) - Bone (43%) - Soft tissues (20%) - Salivary (20%) - Tongue (16%) - Tonsil (12%) - Nose (12%)

Conversely, incidence is falling in other sites: - Lip (down 58%) - Hypopharynx (35%) - Cervical esophagus (32%) - Oropharyngeal mucosa (26%) - Larynx (26%)

Despite falls in alcohol consumption and a reduction in smoking, the incidence rate of new disease continues to rise. Notably, the incidence of HPV-related OSCC appears to be on the rise while HPV-unrelated OSCC tends to have stabilized in the past decades.

Economic Burden

Recent Studies

Recent Studies on Head and Neck Squamous Cell Carcinoma

Key Clinical Trials and Interventions

Cetuximab Studies

• The Bonner trial investigated Cetuximab (Erbitux) combined with radiotherapy, demonstrating improved overall survival, progression-free survival, and time to local recurrence in locally advanced HNSCC.
• Cetuximab significantly improves survival of patients with locally advanced or metastatic HNSCC.
• For recurrent/metastatic HNSCC, cetuximab with platinum-based chemotherapy showed superior outcomes compared to chemotherapy alone in terms of overall survival, progression-free survival, and response rate.

• Cetuximab has received FDA approval for:

• Locally advanced HNSCC with radiotherapy

• Recurrent/metastatic HNSCC

• Notable limitations include low reactivity and serious side effects.

EGFR Expression Studies

• A multi-country study across Australia, Hong Kong, Singapore, and Taiwan found EGFR expression in 88.4% (152/172) of HNSCC cases.
• Research in Pakistan identified 45.2% (52 cases) positive and 8.7% (10 cases) focal positive for EGFR expression.

• Stronger EGFR expression correlated significantly with:

• T4 tumors (p=0.017)

• Later clinical stages (p=0.016)

• A significant association was observed between EGFR expression and both tumor stage and disease-free survival.

Innovative Combination Approaches

• A combination of gold nanoparticles (AuNPs) + cetuximab + radiotherapy demonstrated:

• Marked reduction in HSC-3 cell numbers

• Decreased proliferation

• Enhanced apoptosis in vitro

• Reduced tumor volume in xenograft models

• AuNPs showed no toxic effects on normal tissues while sensitizing tumors to radiotherapy.

Alternative EGFR Inhibitors

• Gefitinib (250mg or 500mg daily) failed to increase median overall survival or objective response rate when compared to weekly methotrexate.

• Other agents investigated in HNSCC studies include:

• Panitumumab

• Zalutumumab

• Nimotuzumab

• Erlotinib

• Lapatinib

Resistance Mechanisms

• The EGFRvIII allele frequency was found to be under 1% in HNSCC patients.
• EGFR R521K was present in 42% of patients, though preclinical differences did not translate to significant changes in progression-free survival or overall survival.

Drug used in other indications

Based on the provided context, there is no specific information available about Petosemtamab and Pembrolizumab being trialed together for indications other than Head and neck squamous cell carcinoma.

The context does mention Pembrolizumab (without Petosemtamab) being tested in various cancer types:

• Non-small-cell lung cancer (42.1% of trials)
• Melanoma (26.3% of trials)
• Gastric or gastro-oesophageal junction cancer (10.5% of trials)
• Urothelial cancer (5.3% of trials)
• Renal-cell carcinoma (5.3% of trials)

Additionally, Pembrolizumab in combination with lenvatinib (not Petosemtamab) has been tested in:

• Renal cell carcinoma with 70% objective response rate
• Gastric cancer with 69% objective response rate
• Melanoma with 48% objective response rate
• Endometrial cancer with 38-53% objective response rate
• Hepatocellular carcinoma with mPFS 9.3 months, mOS 22.0 months

The context does not contain any information about Petosemtamab being used in any clinical trials, nor does it provide information about the intervention models for trials involving Petosemtamab and Pembrolizumab together.