Retrospective cohort study of novel immunotherapy agents in early-phase trials in head and neck squamous cell carcinoma

Immune checkpoint inhibitors (ICIs) have transformed the management of recurrent of metastatic head and neck squamous cell carcinoma (R/M HNSCC), yet most patients eventually develop resistance. Investigational immunotherapy strategies beyond checkpoint blockade are being explored, but their clinical activity and associated biomarkers are poorly defined. A retrospective cohort study at MD Anderson Cancer Center (Houston, TX) evaluated safety, antitumor activity, and biomarkers associated with novel immunotherapy agents is patients with R/M HNSCC treated in early-phase trials between Januari 1, 2015 and May 31, 2025. The sample included 158 patients (median age 60.7 years; range 25.7-84.6; 86.1% male; median 3 prior lines of systemic therapy). Most patients received combination immunotherapy (67.1%), with a median treatment duration of 2.3 months (range 0.1-19.7). Treatment-related adverse events occurred in 53.8%, including grade 3 or higher events in 14.6%. The overall response rate and clinical benefit rate were 7.7% and 16.1%, respectively. Bispecific antibodies were associated with improved clinical benefit whereas TP53, PIK3CA, and CDKN2A/B alterations were associated with reduced benefit. Median progression-free survival was 2.3 months (95% CI 2.0-2.9) and median overall survival was 8.3 months (7.2-11.0). The authors conclude that this retrospective cohort study of heavily pretreated patients with HNSCC treated in early-phase clinical trials found that novel immunotherapy agents may have manageable toxic effects but modest antitumor activity. Bispecific antibodies may have encouraging activity while genomic alterations may help inform treatment stratification.