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

Abstract

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