Durable response to tipifarnib in a patient with refractory head and neck cancer with a HRAS mutation: A case report

Introduction: Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy, particularly in the recurrent or metastatic setting after progression on multimodality therapy. Activating health reimbursement arrangement (HRAS) mutations occur in approximately 4–8% of HNSCC and represent a potentially actionable target. Tipifarnib, an oral farnesyltransferase inhibitor, has demonstrated promising activity in HRAS-mutant tumors but is not commercially available despite prior Breakthrough Therapy designation. Case Report: We report the case of a 48-year-old woman with recurrent, treatment-refractory oral cavity squamous cell carcinoma who experienced a dramatic and durable response to tipifarnib. Following initial treatment, she developed rapid locoregional recurrence requiring tracheostomy. Her disease progressed through multiple lines of therapy. Comprehensive next-generation sequencing of recurrent tumor tissue revealed an HRAS mutation. Given lack of response to prior checkpoint inhibitors, compassionate use of tipifarnib was initiated. The patient experienced a near-complete response within two months and achieved a complete response by 12 months and continues to remain disease free almost two years after therapy initiation with excellent functional recovery and manageable toxicity limited primarily to neutropenia. Conclusion: This case highlights the transformative potential of precision oncology in refractory HNSCC. Broader access to HRAS-targeted therapies and prospective validation of molecular predictors are urgently needed to improve outcomes in this molecularly defined subset.