- Practice Guideline:
- The American Society of Clinical Oncology recommends programmed death ligand 1 (PD-L1) combined positive score (CPS) testing by immunohistochemistry:
- For all patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) to guide first-line immunotherapy selection
- The American Society of Clinical Oncology recommends programmed death ligand 1 (PD-L1) combined positive score (CPS) testing by immunohistochemistry:
- For first-line treatment:
- Pembrolizumab monotherapy is recommended for patients with PD-L1 CPS ≥ 1
- While pembrolizumab plus platinum-based chemotherapy is recommended for those with symptomatic or rapidly progressive disease, regardless of PD-L1 status
- For patients with platinum-refractory recurrent or metastatic HNSCC:
- Either nivolumab or pembrolizumab is appropriate regardless of PD-L1 status:
- Based on improved overall survival compared to standard chemotherapy
- Either nivolumab or pembrolizumab is appropriate regardless of PD-L1 status:
- Pembrolizumab monotherapy is recommended for patients with PD-L1 CPS ≥ 1
- The guideline also notes that tumor mutational burden (TMB) is not routinely used:
- But may be considered in rare cases where PD-L1 CPS is unavailable or for rare head and neck cancers:
- For rare head and neck cancers with high TMB (≥ 10 mutations / megabase):
- Pembrolizumab may be considered
- For rare head and neck cancers with high TMB (≥ 10 mutations / megabase):
- But may be considered in rare cases where PD-L1 CPS is unavailable or for rare head and neck cancers:
- The American Society of Clinical Oncology:
- Does not currently recommend immunotherapy in the curative-intent (locoregionally advanced) setting outside of clinical trials:
- As evidence is insufficient to support its routine use in combination with chemoradiation or as neoadjuvant / adjuvant therapy
- Does not currently recommend immunotherapy in the curative-intent (locoregionally advanced) setting outside of clinical trials:
- The rationale for these recommendations:
- Is based on randomized trials demonstrating survival benefit of immune checkpoint inhibitors in the recurrent / metastatic setting, and the predictive value of PD-L1 CPS for response to anti–PD-1 therapy
- Building on these recommendations:
- Recent clinical trial data and expert reviews:
- Further clarify the evolving role of immunotherapy in head and neck squamous cell carcinoma (HNSCC)
- Recent clinical trial data and expert reviews:
- Immune checkpoint inhibitors (ICIs):
- Specifically anti–PD-1 agents such as pembrolizumab and nivolumab:
- Have become the standard of care for recurrent or metastatic HNSCC:
- With objective response rates in the range of 14% to 22% and durable responses in a minority of patients
- Have become the standard of care for recurrent or metastatic HNSCC:
- The KEYNOTE-048 trial:
- Established the benefit of pembrolizumab, either as monotherapy in PD-L1 positive tumors or in combination with platinum-based chemotherapy:
- As first-line therapy for recurrent / metastatic disease, and this approach is now widely adopted in clinical practice
- Established the benefit of pembrolizumab, either as monotherapy in PD-L1 positive tumors or in combination with platinum-based chemotherapy:
- Specifically anti–PD-1 agents such as pembrolizumab and nivolumab:
- Despite these advances, attempts to incorporate ICIs into the curative-intent setting:
- Such as concurrent administration with chemoradiation or as neoadjuvant / adjuvant therapy:
- Have not demonstrated clear survival benefit and are not standard outside clinical trials
- Early-phase studies of neoadjuvant immunotherapy have shown promising signals of response:
- But larger trials are ongoing to determine their impact on long-term outcomes
- Such as concurrent administration with chemoradiation or as neoadjuvant / adjuvant therapy:
- The use of tumor mutational burden (TMB) as a biomarker remains investigational:
- With PD-L1 combined positive score (CPS) being the primary biomarker guiding immunotherapy selection in routine practice
- In summary, the integration of immunotherapy into the management of HNSCC is most firmly established in the recurrent / metastatic setting, with biomarker-driven selection based on PD-L1 CPS
- The use of ICIs in the curative-intent setting remains investigational, and ongoing research aims to refine patient selection and optimize combination strategies
- References:
- Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline. Yilmaz E, Ismaila N, Bauman JE, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023;41(5):1132-1146. doi:10.1200/JCO.22.02328.
- Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline Q and A. Yilmaz E, Ismaila N, Dabney R, Saba NF, Mell LK. JCO Oncology Practice. 2023;19(4):194-196. doi:10.1200/OP.22.00802.
Current Progress and Future Directions of Immunotherapy in Head and Neck Squamous Cell Carcinoma: A Narrative Review. Sim ES, Nguyen HCB, Hanna GJ, Uppaluri R. JAMA Otolaryngology– Head & Neck Surgery. 2025;151(5):521-528. doi:10.1001/jamaoto.2024.5254. - Immunotherapeutic Strategies in Head and Neck Cancer: Challenges and Opportunities. Liu X, Harbison RA, Varvares MA, Puram SV, Peng G. The Journal of Clinical Investigation. 2025;135(8):e188128. doi:10.1172/JCI188128.
- Immunotherapy, Chemotherapy, or Both: Options for First-Line Therapy for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Ho AL. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023;41(4):736-741. doi:10.1200/JCO.22.01408.
- Treating Head and Neck Cancer in the Age of Immunotherapy: A 2023 Update. Bhatia A, Burtness B. Drugs. 2023;83(3):217-248. doi:10.1007/s40265-023-01835-2.
- Integrating Immunotherapy Into Multimodal Treatment of Head and Neck Cancer. Rao YJ, Goodman JF, Haroun F, Bauman JE. Cancers. 2023;15(3):672. doi:10.3390/cancers15030672.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 