We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial....Clinical response to alpelisib of a patient with HNSCC harboring the noncanonical PIK3CA mutation Q75E….The patient was treated for a total of 12 months with single-agent alpelisib until his disease progressed, and he was switched to durvalumab...He is currently alive with stable disease on durvalumab, approximately 2 years after completing alpelisib monotherapy.