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

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.