Dissociated response to immune checkpoint inhibition in head and neck squamous cell carcinoma is common and exhibits distinct clinical outcomes.

Immune checkpoint inhibition (ICI) constitutes the first-line therapy for relapsed/metastatic head and neck squamous cell carcinoma (HNSCC) despite low response rates. Some patients treated with ICI experience dissociated response (DR), the co-existence of responding and progression lesions. DR prevalence and prognostic impact in HNSCC are unknown. We retrospectively identified 112 patients treated with ICI at our institution and evaluated disease characteristics, survival outcomes, and response. Tissue specimens were used to assess the tumor microenvironment (TME). DR occurred in 19% of our patient cohort. DR was more likely in patients with disease involving the cervical lymph nodes (OR 16.79, p=0.004). Patients with DR had median progression-free and overall survival of 6.7 and 16.9 months, respectively, similar to subjects with partial response or stable disease. DR was less favorable when it occurred early, and we identified no instances where early DR converted to uniform objective response. We demonstrated increased CD8+ T cell infiltration and decreased STAT3 signaling in tissue from responding versus non-responding patients. Tumors from patients with DR had low T cell infiltration and reduced STAT3. In conclusion, DR during ICI therapy in HNSCC is common and associated with favorable prognosis, especially in patients who initially have a complete or partial response. Early DR as best response is less beneficial and unlikely to convert to a true response; change in therapy should be considered for these patients. Response patterns may be related to organ-specific differences in the TME.