Tipifarnib in head and neck squamous cell carcinoma with HRAS mutations

Ho, Alan L. and Brana, Irene and Haddad, Robert and Bauman, Jessica and Bible, Keith and Oosting, Sjoukje and Wong, Deborah J. and Ahn, Myung Ju and Boni, Valentina and Even, Caroline and Fayette, Jerome and Flor, Maria José and Harrington, Kevin and Kim, Sung Bae and Licitra, Lisa and Nixon, Ioanna and Saba, Nabil F. and Hackenberg, Stephan and Specenier, Pol and Worden, Francis and Balsara, Binaifer and Leoni, Mollie and Martell, Bridget and Scholz, Catherine and Gualberto, Antonio (2021) Tipifarnib in head and neck squamous cell carcinoma with HRAS mutations. Journal of Clinical Oncology, 39 (17). pp. 1856-1864. ISSN 0732-183X (https://doi.org/10.1200/JCO.20.02903)

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PURPOSE Mutations in the HRAS (mHRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M mHRAS HNSCC. METHODS We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for mHRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with mHRAS variant allele frequency (VAF) data, enrollment was limited to those with a mHRAS VAF of $ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. RESULTS Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%). CONCLUSION Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist (NCT02383927).