In recent years, programmed death-1 (PD-1) immune checkpoint inhibitors have fundamentally transformed the treatment landscape for head and neck cancers, particularly recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

From the initial approvals of Pembrolizumab and Nivolumab to the rapid emergence of domestically developed PD-1 antibodies and the expansion of perioperative immunotherapy, PD-1 blockade has become an essential component of comprehensive HNSCC management.

Drawing upon recently published clinical studies, presentations at international oncology conferences, and the latest developments in global drug research, DengYueMed provides a comprehensive overview of currently available PD-1 therapies for head and neck cancer, highlighting globally approved products, pivotal clinical trials, and future research directions.

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What Are PD-1 Inhibitors?

Programmed Death-1 (PD-1) is an immune checkpoint receptor expressed on activated T lymphocytes. When PD-1 binds to its ligand PD-L1, which is frequently overexpressed on tumor cells, T-cell activity is suppressed, allowing cancer cells to evade immune surveillance.

PD-1 inhibitors block the PD-1/PD-L1 signaling pathway, restoring the immune system’s ability to recognize and eliminate malignant cells. As a result, PD-1 blockade has become one of the most successful immunotherapeutic strategies in modern oncology.

In HNSCC, PD-1 inhibitors are now widely used in several clinical settings, including:

• Recurrent or metastatic HNSCC
• Locally advanced PD-L1-positive disease
• First-line treatment combined with platinum-based chemotherapy
• Second-line immunotherapy following disease progression
• Neoadjuvant and adjuvant perioperative treatment (approved for selected indications)

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Why Have PD-1 Inhibitors Changed the Treatment Landscape of HNSCC?

Conventional treatment options primarily include:

• Surgery
• Radiotherapy
• Chemotherapy
• EGFR-targeted therapy (such as cetuximab)

Although these approaches have improved outcomes for many patients, survival remains poor for those with recurrent or metastatic disease.

Several biological characteristics make HNSCC particularly suitable for immunotherapy:

• Relatively high immunogenicity
• HPV-positive tumors possess a more active immune microenvironment
• High PD-L1 expression in many patients
• Abundant immune-cell infiltration within tumors

These characteristics provide a strong biological rationale for PD-1 blockade.

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Globally Approved PD-1 Drugs for Head and Neck Cancer

1. Pembrolizumab (Keytruda)

Developer

Merck (MSD)

Approved indications include:

• PD-L1-positive recurrent or metastatic HNSCC
• First-line therapy combined with platinum chemotherapy
• Perioperative treatment for selected patients with resectable locally advanced HNSCC

Pembrolizumab established a new global standard of care following the landmark KEYNOTE-048 study.

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2. Nivolumab (Opdivo)

Developer

Bristol Myers Squibb (BMS)

The pivotal CheckMate-141 study demonstrated:

• Improved overall survival (OS)
• Higher objective response rate (ORR)
• Better tolerability than chemotherapy
• Improved quality of life

Nivolumab remains a preferred second-line treatment recommended by major international guidelines.

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3. Toripalimab (Tuoyi®)

Developer

Junshi Biosciences

Toripalimab has received approval in China for selected HNSCC indications and has also obtained U.S. FDA approval for specific indications, becoming one of the first Chinese-developed PD-1 antibodies approved in the United States.

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4. Penpulimab (Annike®)

Developer

Akeso / SinoMab

Penpulimab has been approved for nasopharyngeal carcinoma and selected head and neck cancer indications, expanding therapeutic options within the PD-1 inhibitor class.

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Landmark Clinical Trials

KEYNOTE-048

KEYNOTE-048 established pembrolizumab as the standard first-line therapy for recurrent or metastatic HNSCC.

Major findings included:

• Improved overall survival for PD-L1-positive patients
• Broader benefit when combined with chemotherapy
• Adoption into NCCN and international treatment guidelines

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CheckMate-141

Among platinum-refractory patients, nivolumab demonstrated:

• Significant improvement in overall survival
• Lower incidence of severe adverse events
• Durable long-term survival benefit

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Combination Therapy Is the Future

Current research increasingly focuses on combination strategies.

PD-1 + Chemotherapy

The current standard first-line treatment for many patients.

PD-1 + EGFR Targeted Therapy

Potentially enhances immune activation while overcoming resistance.

PD-1 + Antibody-Drug Conjugates (ADCs)

Active areas include:

• HER3 ADCs
• TROP2 ADCs
• B7-H3 ADCs

These combinations are among the hottest areas of oncology research.

PD-1 + Radiotherapy

Radiotherapy induces immunogenic cell death, potentially enhancing responses to PD-1 blockade.

Perioperative Immunotherapy

Neoadjuvant and adjuvant PD-1 therapy may reduce recurrence risk and move immunotherapy into earlier disease stages.

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Future Development Trends

Future research is expected to focus on:

• More accurate predictive biomarkers
• PD-1 plus ADC combinations
• PD-1 plus bispecific antibodies
• Cancer vaccines
• Cellular therapies
• ctDNA-guided treatment
• Artificial intelligence
• Multi-omics precision medicine
• Large global Phase III clinical trials

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Conclusion

PD-1 inhibitors have become a cornerstone of systemic therapy for head and neck squamous cell carcinoma.

From Pembrolizumab and Nivolumab to newer agents such as Toripalimab, PD-1 therapies continue to expand into new indications and improve outcomes for patients worldwide.

Meanwhile, combination strategies involving antibody-drug conjugates (ADCs), bispecific antibodies, radiotherapy, and perioperative immunotherapy are rapidly reshaping the future of HNSCC treatment.

As immunotherapy continues to evolve, more personalized and biomarker-driven treatment strategies are expected to further improve survival and quality of life for patients with head and neck cancer.

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Medical Disclaimer

This article is intended for educational and informational purposes only and should not be considered medical advice, diagnosis, or treatment recommendations. Patients should consult qualified oncology specialists before making any treatment decisions.