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 (R/M) head and neck squamous cell carcinoma (HNSCC) despite low response rates. Some patients treated with ICI experience dissociated response (DR), the coexistence 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 their 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 [odds ratio (OR), 16.79; P = 0.004]. Patients with DR had a median progression-free and overall survival of 6.7 and 16.9 months, respectively, similar to subjects with partial response (PR) or stable disease (SD). DR was less favorable when it occurred early, and we identified no instances in which early DR converted to uniform objective response. We demonstrated increased CD8+ T-cell infiltration and decreased signal transducer and activator of transcription 3 (STAT3) signaling in tissue from responding versus nonresponding 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 response (CR) or PR. Early DR as the 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. SIGNIFICANCE: Mixed response or DR is common in patients with R/M HNSCC who receive immune checkpoint inhibition (ICI). Patients with DR have survival outcomes similar to patients with a PR, especially when DR occurs after an initial uniform response to therapy. DR occurring early in treatment is less favorable and unlikely to convert to uniform response later on.