Mutational Landscape of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma and Association with Immune Checkpoint Inhibitor Outcomes

Purpose: Understanding the mutational landscape of recurrent/ EAGLE: 1.44; 0.99–2.10). In EAGLE, patients with TP53 mutations metastatic head and neck squamous cell carcinoma (R/M HNSCC) had significantly longer OS with durvalumab–tremelimumab veris important in identifying biomarkers to determine which patients sus SoC (P ¼ 0.045). KMT2D mutations were associated with a may benefit from immune checkpoint inhibitors (ICI). trend toward longer OS (HR; 95% confidence interval) versus the Experimental Design: The HAWK (NCT02207530), CON- wild type in HAWK/CONDOR (0.81; 0.56–1.19) and a trend to-DOR (NCT02319044), and EAGLE (NCT02369874) studies ward longer OS with ICIs versus SoC in EAGLE. For both mutaevaluated R/M HNSCC treatment with durvalumab or tions, a European Cooperative Oncology Group performance durvalumab–tremelimumab. Tumor tissue samples pooled from status of 1 was associated with worsened OS, and PD-L1 positivity HAWK/CONDOR (n ¼ 153) and plasma cell–free DNA samples was associated with improved OS. from EAGLE (n ¼ 285) were analyzed to identify somatic alter- Conclusions: This is the first large-scale study to show the ations and association with survival. mutational landscape of R/M HNSCC and its association with Results: The mutational landscape was similar in tissue and clinical outcomes in patients treated with ICIs or SoC. The TP53 plasma. Compared with the wild type, TP53 mutations were as- mutation was a negative prognostic marker; however, treatment sociated with significantly shorter overall survival (OS; HR; 95% with durvalumab–tremelimumab significantly improved survival confidence interval) with standard of care (SoC; EAGLE: 2.12; over SoC. Further investigation of KMT2D as a predictive bio-1.20–3.78) and ICIs (HAWK/CONDOR: 1.49; 1.05–2.12 and marker for immunotherapy in R/M HNSCC is warranted.