Tipifarnib Produced Positive Efficacy Data for Treatment of HNSCC With HRAS Mutations


The phase 2 trial showed that tipifarnib was effective for patients with metastatic head and neck squamous cell carcinoma who have limited therapeutic options available.

Tipifarnib (Zarnestra) showed encouraging efficacy data for patients with recurrent and/or metastatic HRAS-mutant head and neck squamous cell carcinoma (HNSCC) who have limited therapeutic options available to them, according to a study published in the Journal of Clinical Oncology.

This single-arm, open-label phase 2 trial (NCT02383927) investigated tipifarnib’s ability to target mutations in the HRAS (mHRAS), which occur in 4% to 8% of patients with HNSCC.

“This study evaluated the efficacy of the farnesyltransferase inhibitor tipifarnib in patients with recurrent and/or metastatic head and neck squamous cell carcinoma with HRAS mutations, a unique subset of the disease with high unmet needs,” wrote the investigators.

A total of 30 patients with HNSCC were enrolled in the single-arm trial, of whom 20 had high variant allele frequency (VAF) evaluable at the time of data cutoff. In this cohort, the overall response rate (ORR) was 55% (95% CI, 31.5%-76.9%).

For median progression-free survival (PFS), that number was 5.6 months (95% CI, 3.6-16.4) for patients who received tipifarnib compared with 3.6 months (95% CI, 1.3-5.2) for patients on last prior therapy. Median overall survival (OS) for this patient population was 15.4 months (95% CI, 7.0-29.7).

Common treatment-emergent adverse events observed in the cohort of 30 patients with HNSCC due to tipifarnib were anemia (37%) and lymphopenia (13%).

“This report describes encouraging antitumor activity with tipifarnib in a heavily pretreated cohort of patients with high–mHRAS VAF, refractory and/or metastatic HNSCC with an unprecedented ORR of 55% as compared with the approximately 15% historical response rate of other standard therapies developed in the platinum-refractory setting, including cetuximab [Erbitux], nivolumab [Opdivo], and pembrolizumab [Keytruda],” wrote the investigators.

The trial’s primary end point was ORR, with key secondary end points including safety and tolerability. The cohort of eligible patients received either 600 or 900 mg of tipifarnib orally twice daily on days 1 through 7 and 15 through 21 of 28-day cycles.

Some limitations of the research include the nonrandomized, open-label style, and small sample size of the patient population. Regardless, the research team explains that the efficacy data within is impressive for a targeted therapy in a biomarker-selected HNSCC patient population.

Further investigation is needed to validate these data, with the AIM-HN and SEQ-HN Study (NCT03719690) launched to evaluate the efficacy and safety of tipifarnib in this group of patients and the impact of HRAS mutations on HNSCC therapeutic options.

“For tipifarnib, the meaningful efficacy signal in patients with treatment-refractory mHRAS HNSCC was discovered only after (1) revisiting the FTI class with a trial design focused on testing the unique vulnerability of mHRAS disease, (2) the recognition that confirmation of the HNSCC signal would be most efficiently accomplished by enriching for higher VAF in enrollment, and (3) changing the tipifarnib dose to improve tolerability,” wrote the investigators.


Ho AL, Brana I, Haddad R, et al. Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations. J Clin Oncol. March 22, 2021. doi:10.1200/JCO.20.02903

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