Management approaches for recurrent or metastatic head and neck squamous cell carcinoma after anti-PD-1/PD-L1 immunotherapy.

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally. For patients with recurrent or metastatic (R/M) HNSCC, immunotherapy represents an important advance in clinical practice as an effective and widely used first-line treatment. However, drug resistance following immunotherapy is an emerging problem and, despite the success of immunotherapy in R/M HNSCC, a proportion of patients will become immunotherapy resistant. The mechanisms of immunotherapy resistance are not yet fully understood and subsequent treatment options are limited. Therefore, there is an unmet need for effective and well tolerated treatments for patients who develop immunotherapy-resistant HNSCC. In this review, we address these challenges by summarizing the current definitions of immunotherapy resistance (primary and acquired resistance) as well as knowledge of the mechanisms of resistance to immunotherapy in R/M HNSCC. We then review available clinical data on treatment strategies, including rechallenge with immunotherapy, chemotherapy ± cetuximab, other targeted treatments, antibody-drug conjugates, and bispecific antibodies. We also investigate future research directions by reviewing ongoing clinical trials. Our review shows that the optimal therapeutic strategy for patients with R/M HNSCC remains unclear. While many therapies have reported promising preliminary results, prospective clinical trials are required to support their adoption in clinical practice. In particular, it appears that immunotherapy and antibody-drug conjugates have high potential in this setting. Our review also highlights the importance of further investigation of the mechanisms underlying immunotherapy-resistant R/M HNSCC, to inform selection of optimal therapeutic strategies on an individual patient basis and improve patient outcomes.