xRead - An Update on Immunotherapy in Head and Neck Cancer (November 2025)

Clinical Review & Education

JAMA Otolaryngology–Head & Neck Surgery | Review

Current Progress and Future Directions of Immunotherapy in Head and Neck Squamous Cell Carcinoma A Narrative Review

Edward S. Sim, MD; Hoang C. B. Nguyen, MD, PhD; Glenn J. Hanna, MD; Ravindra Uppaluri, MD, PhD

CME at jamacmelookup.com

IMPORTANCE For decades, the 3 therapeutic pillars for head and neck squamous cell carcinoma (HNSCC) have been radiation therapy, chemotherapy, and surgery. In recent years, a fourth pillar, immunotherapy, has shifted the existing paradigm of oncologic care by improving survival outcomes. This narrative review highlights key completed and ongoing clinical trials that have led to new therapeutic approaches and are aiming to further alter the current standard of care. OBSERVATIONS Immunotherapy in HNSCC first saw success in phase 3 clinical trials with immune checkpoint inhibitors (ICIs) for programmed cell death 1 protein in patients with recurrent or metastatic (R/M) disease. However, only approximately 15% to 20% of patients with R/M HNSCC achieve durable responses. Subsequent trials aimed to broaden ICIs to the definitive or curative setting, in combination with established chemoradiation modalities. These studies have yielded disappointing results, raising concerns that concurrent administration of ICI with chemoradiation- or radiation-induced attenuation of immune responses may contribute to lack of efficacy. Therefore, recent studies have attempted to introduce ICI sequentially, either prior to standard of care surgery in the neoadjuvant setting or following definitive treatment in the adjuvant or maintenance setting. These trials have demonstrated mixed results but with promising initial results from early phase neoadjuvant trials demonstrating early signals of response. Further trials are currently underway with various combinatorial approaches in the neoadjuvant and adjuvant settings to assess response rates and survival. CONCLUSIONS AND RELEVANCE The introduction of ICIs has brought a dramatic shift in the treatment landscape of HNSCC. Completed trials have provided new hope for patients, but failures in several settings suggest that further studies based on a biologic understanding of immune responses are required to expand immunotherapeutic approaches.

Author Affiliations: Department of Otolaryngology–Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts (Sim, Nguyen, Uppaluri); Division of Otolaryngology–Head and Neck Surgery, Brigham and Women’s Hospital, Boston, Massachusetts (Sim, Nguyen, Uppaluri); Center for Head and Neck Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (Sim, Nguyen, Hanna, Uppaluri). Corresponding Author: Ravindra Uppaluri, MD, PhD, Dana-Farber Brigham Cancer Center, 450 Brookline Ave, Boston, MA 02215 (ravindra_uppaluri@ dfci.harvard.edu).

JAMA Otolaryngol Head Neck Surg . 2025;151(5):521-528. doi:10.1001/jamaoto.2024.5254 Published online March 6, 2025.

H ead and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world. 1 Despite a de crease in prevalence of heavy tobacco and alcohol con sumption, known risk factors of HNSCC, the incidence of HNSCC has been increasing, likely due to a rise in HNSCC associated with hu man papillomavirus (HPV). 2-5 HPV-associated HNSCC generally has a more favorable prognosis compared with HPV-unrelated dis ease. For both HPV-associated and HPV-unrelated HNSCC, there are no defined screening protocols, and most patients present with locoregionally advanced (LA) disease often requiring multi modal treatment. HNSCC is challenging to treat, in part due to its nature as a di verse and heterogenous group of tumors involving distinct ana tomic sites. Current mainstays of treatment involve definitive ra diotherapy, with or without chemotherapy, or upfront surgery followed by pathology-guided adjuvant radiotherapy with or with out chemotherapy. Therapies targeting critical structures of the head and neck, which are essential for speech, swallowing, taste, and, in general, how a patient interfaces with their surroundings, can yield

devastating functional and cosmetic consequences. Survivors of HN SCC often face significant physical and psychological distress from these treatment-related toxic effects, as reflected in their having the second highest suicide rate among cancer survivors. 6 Despite treat ment, more than half of patients with HNSCC experience locore gional or distant recurrence with a 10- to 13-month median overall survival (OS) for patients with recurrent or metastatic (R/M) disease. 7 There is a great need for therapies that offer better response rates and more favorable safety profiles than those currently available. To address the poor survival and functional outcomes of the current standard of care, new therapies have emerged targeting a tumor’s immune-evasive mechanisms, bringing about a transfor mative shift in the HNSCC treatment landscape. Of these thera pies, immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 protein (PD-1) and its ligand, programmed cell death 1 li gand 1 (PD-L1) have proven effective in reinvigorating the host im mune system, leading to increased survival and reduced adverse ef fects in some patients with R/M HNSCC. 8 Numerous trials have aimed to enhance response rates and extend ICI applications to a broader

(Reprinted) JAMA Otolaryngology–Head & Neck Surgery May 2025 Volume 151, Number 5 521

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