Tipifarnib in head and neck squamous cell carcinoma with HRAS mutations

Alan L. Ho, Irene Brana, Robert Haddad, Jessica Bauman, Keith Bible, Sjoukje Oosting, Deborah J. Wong, Myung Ju Ahn, Valentina Boni, Caroline Even, Jerome Fayette, Maria José Flor, Kevin Harrington, Sung Bae Kim, Lisa Licitra, Ioanna Nixon, Nabil F. Saba, Stephan Hackenberg, Pol Specenier, Francis WordenBinaifer Balsara, Mollie Leoni, Bridget Martell, Catherine Scholz, Antonio Gualberto

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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).

Original languageEnglish
Pages (from-to)1856-1864
Number of pages9
JournalJournal of Clinical Oncology
Issue number17
Early online date14 May 2021
Publication statusPublished - 10 Jun 2021
Externally publishedYes


  • head and neck squamous cell carcinoma (HNSCC)
  • cancer
  • oncology
  • HRAS mutations
  • targeted therapies
  • drug-refractory disease
  • tipifarnib


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