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Ho AL , Brana I , Haddad R , Bauman J , Bible K , Oosting S , Wong DJ , Ahn MJ , Boni V , Even C , Fayette J , Flor MJ , Harrington K , Kim SB , Licitra L , Nixon I , Saba NF , Hackenberg S , Specenier P , Worden F , Balsara B , Leoni M , Martell B , Scholz C , Gualberto A
Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations
J Clin Oncol. 2021 Jun 10;39(17) :1856-1864
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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).
1527-7755 Ho, Alan L Orcid: 0000-0002-6885-3742 Brana, Irene Orcid: 0000-0002-1068-9601 Haddad, Robert Orcid: 0000-0003-1413-0079 Bauman, Jessica Bible, Keith Orcid: 0000-0003-3042-5969 Oosting, Sjoukje Wong, Deborah J Ahn, Myung-Ju Boni, Valentina Orcid: 0000-0002-8675-0018 Even, Caroline Fayette, Jerome Flor, Maria José Harrington, Kevin Orcid: 0000-0002-6014-348x Kim, Sung-Bae Orcid: 0000-0001-5588-8332 Licitra, Lisa Orcid: 0000-0003-0623-4118 Nixon, Ioanna Saba, Nabil F Orcid: 0000-0003-4972-1477 Hackenberg, Stephan Specenier, Pol Worden, Francis Balsara, Binaifer Leoni, Mollie Martell, Bridget Scholz, Catherine Gualberto, Antonio Orcid: 0000-0002-6590-839x Journal Article United States J Clin Oncol. 2021 Mar 22:JCO2002903. doi: 10.1200/JCO.20.02903.