Tipifarnib in Head and Neck Squamous Cell Carcinoma With <i>HRAS</i> Mutations.

Abstract

Mutations in the <i>HRAS</i> (m<i>HRAS</i>) 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 <i>HRAS</i> function. We evaluated the efficacy of tipifarnib in patients with R/M m<i>HRAS</i> HNSCC. We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m<i>HRAS</i> malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m<i>HRAS</i> variant allele frequency (VAF) data, enrollment was limited to those with a m<i>HRAS</i> 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. 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%). Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with <i>HRAS</i> mutations for whom limited therapeutic options exist (NCT02383927).