Here we describe two cases of metastatic squamous cell carcinoma of the head and neck, discussed at the molecular tumour board of the Profiling Orphan Neoplasms for Treatment Election (PONTE) project, part of the International Cancer Genome Consortium Accelerating Research in Genomic Oncology (ICGC ARGO). These patients had variability in response to immunotherapy due to biological heterogeneity of head and neck squamous cell carcinoma, highlighting the importance of complete molecular characterisation—including PD-L1 expression, tumour mutational burden, and microsatellite instability—to accurately predict treatment response in patients with these tumours.