Breakthrough Clinical Results
Merus announced positive Phase II data for its bispecific antibody petosemtamab in combination with Keytruda (pembrolizumab) for first-line treatment of head and neck squamous cell carcinoma (HNSCC). The data showed a nearly 80% overall survival rate at 12 months and a confirmed overall response rate of 63% in 43 patients. Analysts are optimistic about the potential for petosemtamab to become a standard of care, with some suggesting potential for accelerated approval. Merus plans to present these findings at the 2025 ASCO annual meeting and is conducting two Phase III trials.
Key Highlights
- Nearly 80% overall survival rate at 12 months in Phase II trial.
- 63% confirmed overall response rate in the Phase II trial.
- Analysts predict petosemtamab could become the standard of care for first-line HNSCC.
- Potential for accelerated approval based on promising data.
Incidence and Prevalence
Global Incidence and Prevalence of Head and Neck Squamous Cell Carcinoma (HNSCC)
Head and neck squamous cell carcinoma (HNSCC) represents a significant global health burden. According to the latest PubMed data:
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HNSCC is the sixth most frequent cancer worldwide, comprising almost 50% of all malignancies in some developing nations.
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Overall, head and neck squamous cell carcinoma accounts for more than 550,000 cases annually worldwide.
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In the United States, specifically, 30,000 new cases and 8,000 deaths are reported each year.
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Head and neck cancers rank in the leading sixth place in terms of incidence globally, and the incidence continues to rise, with mortality rates remaining at high levels.
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About 90% of head and neck cancers are squamous cell carcinomas (SCCs).
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Some sources indicate that head and neck cancer is the 10th most common cancer in the world, constituting 5-8% of total cancer burden in Europe and America.
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Cutaneous squamous cell carcinoma (CSCC) makes up the seventh most common type of cancer worldwide, with most of these cancers occurring on the head and neck.
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The overall 5-year survival rate is 50%, which is among the lowest of the major cancers.
These statistics highlight the significant global impact of HNSCC and emphasize the need for continued research, early detection, and improved treatment strategies to address this prevalent form of cancer.
Emerging End Points
Emerging Key Endpoints for Head and Neck Squamous Cell Carcinoma (HNSCC)
EGFR Inhibition and Resistance Mechanisms
Cetuximab remains the first and only FDA-approved EGFR-targeted agent for HNSCC. Despite ubiquitous EGFR expression in HNSCC tumors, clinical responses to cetuximab are limited and modest. Combinations of cetuximab with chemotherapy or radiation improves overall survival. The field is advancing with novel molecular agents that inhibit alternative targets to overcome anti-EGFR resistance. Tyrosine kinase inhibitors Gefitinib and Erlotinib have produced response rates of 11% and 4% respectively, with prolonged disease control rates when used with chemotherapy.
Biomarkers for Treatment Response
Significant progress has been made in identifying biomarkers that predict treatment outcomes. Long-PFS patients are characterized by basal subtype traits including strong EGFR signaling phenotype and hypoxic differentiation, while short-PFS patients present with strong activation of RAS signaling. Mass spectrometry profiling has been used to predict outcome in HNSCC patients after EGFR inhibitor treatment. BMI1 (B cell-specific Moloney murine leukemia virus integration site 1) is emerging as an important biomarker of cancer stem cells (CSCs).
PD-L1 Expression and Immunotherapy
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have emerged as frontline treatment for HNSCC. PD-L1 expression by immunohistochemistry determines eligibility for immunotherapy. Two scoring systems are widely used: the Combined positive score (CPS) and tumor proportion score (TPS) to evaluate PD-L1 expression. Research has shown that PD-L1 expression in cytology samples demonstrates high concordance with paired histologic samples, offering potential for less invasive assessment.
Novel Combination Approaches
Innovative combination therapies are showing promise. CD47 inhibition promotes cetuximab-triggered antibody-dependent cellular phagocytosis (ADCP). The combination of CD47-SIRPĪ± blockade and cetuximab demonstrates strong anticancer activity in vivo. CD47-SIRPĪ± blockade enhances ADCP through CD11b/CD18-ICAM1-mediated intercellular adhesion. Additionally, gene therapy and immunotherapy are emerging as promising strategies to improve efficacy and reduce toxicity in HNSCC treatment.
Cancer Stem Cell Targeting
Cancer stem cells (CSCs) represent a critical treatment target, as they possess self-renewal characteristics capable of tumor initiation, progression, invasion, metastasis, tumor recurrence and resistance to therapy. Current therapies are relatively ineffective against CSCs. These cells have been isolated from solid tumors using various surface markers including CD34, CD133, CD24, CD44, CD29, and CD31. The field is moving toward therapies that specifically target tumor markers for CSCs, which would constitute a significant advancement toward definitive cancer therapy.
Study Design Parameters
Key Clinical Trials for Head and Neck Squamous Cell Carcinoma (HNSCC)
Study Design Parameters
Neoadjuvant Immunochemotherapy Trial (Study 2)
- Patient population: 21 patients with HNSCC who underwent radical surgery and cervical lymph node dissection
- Treatment protocol: Pembrolizumab (PD-1 inhibitor) plus cetuximab (EGFR inhibitor) with chemotherapy
- Time period: January 2021 to June 2024
- Location: RenJi Hospital
- Biomarkers analyzed: Pre-treatment peripheral lymphocyte count, monocyte count, and platelet to lymphocyte ratio (PLR)
ctDNA Analysis in Recurrent/Metastatic HNSCC (Study 3)
- Design: Retrospective analysis of 60 patients with R/M HNC
- Technology: Guardant360, a 70-gene ctDNA NGS platform for blood samples
- Patient population: Primarily oropharyngeal squamous cell carcinoma (n=21), plus salivary gland (n=8) and thyroid (n=4)
Genetic Study in HNSCC Patients Receiving RT/chemoRT (Study 8)
- Design: Retrospective analysis of 122 non-resectable HNSCC patients
- Time period: 1992-2006
- Treatment groups: RT (N=38) or chemoRT (N=84)
- Genetic markers: Six SNPs analyzed on tumor DNA (ERCC1, ERCC2, ERCC5, XRCC1, TP53, MDM2)
Genetic Relationships Study (Study 9)
- Methodology: Low-coverage whole genome sequencing and target enrichment sequencing
- Primary markers: Copy number alterations (CNAs) and mutations in HNSCC driver genes
- Study design: Analysis of genetic relationships between paired primary tumors and local relapses after chemoradiotherapy
General Selection Criteria for HNSCC Trials
- Randomization: Studies were randomized in a 1:1 ratio in some trials (e.g., TMC vs TMC-I trial)
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Inclusion criteria:
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Randomized controlled trials where >50% of participants had primary tumors in oral cavity or oropharynx
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Trials comparing addition of chemotherapy to other treatments
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Trials comparing two or more chemotherapy regimens
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Adult patients with recurrent or newly diagnosed advanced HNSCC
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Eastern Cooperative Oncology Group performance status of 0-1 for some trials
Trial Endpoints
Primary Endpoints
- Study 2: Major pathological response (MPR)
Secondary Endpoints and Measurements
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Study 2:
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Overall response rate (ORR)
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Complete response (CR) rate
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Pathological complete response (pCR)
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Safety assessments: Adverse events (most common was anemia at 61.9%)
Study 8 Endpoints:
- RT-related toxicity assessment (acute, early, and late toxicities)
- Toxicity measurement focusing on dysphagia, mucositis, epithelitis, xerostomia, dermatitis, fibrosis, and osteoradionecrosis
Study Findings
Immune Checkpoint Inhibitors Meta-analysis
- Anti-PD1/PDL1 monotherapy significantly improved overall survival in the total population (HR 0.87, 95% CI 0.79-0.95, p=0.003)
- Significant improvement in PD-L1 high expression patients (HR 0.71, 95% CI 0.55-0.90, p=0.006)
- Significantly lower incidence of treatment-related adverse events compared to standard of care
RESGEX Study Findings
- Comparison of tomuzotuximab versus cetuximab (both anti-EGFR antibodies) with chemotherapy
- Median progression-free survival: 6.5 months (tomuzotuximab) versus 6.2 months (cetuximab) (p=0.86)
- Median overall survival: 11.6 months (tomuzotuximab) versus 13.8 months (cetuximab) (p=0.96)
- p16-positive patients had significantly longer OS compared to p16-negative patients (HR 1.860, p=0.02)
Nimotuzumab Real-World Study
- Significant overall survival benefit (HR=0.46, 95% CI: 0.26-0.82, p=0.008) when combined with chemoradiation compared to chemoradiation alone in nasopharyngeal carcinoma
Drug used in other indications
Based on the provided context, there is no specific information available about petosemtamab and Keytruda (pembrolizumab) being trialled for indications other than Head and neck squamous cell carcinoma (HNSCC). The context does not contain any data about petosemtamab clinical trials, petosemtamab and Keytruda combination trials, or intervention models for such trials.