Tipifarnib produced responses in patients with head-and-neck squamous-cell carcinoma (HNSCC).
Major Finding: Tipifarnib produced responses in patients with head-and-neck squamous-cell carcinoma (HNSCC).
Concept: In patients with an HRAS-mutation variant-allele frequency of ≥ 20%, the objective response rate was 55%.
Impact: This trial shows that farnesyltransferase inhibitors may be worth investigating in HRAS-mutant cancers.
Activating mutations affecting any of the RAS genes (KRAS, NRAS, and HRAS) are common oncogenic drivers in human cancers, including head-and-neck squamous-cell carcinoma (HNSCC). Targeting mutant RAS proteins has proven difficult, and inhibitors of farnesyltransferase—which covalently adds a farnesyl group to C terminus of the RAS proteins and others to enable their localization to the plasma membrane and subsequent activation of downstream signaling—have not shown strong efficacy signals in clinical trials. Hypothesizing that this may be explained by the preclinical observation that KRAS and NRAS but not HRAS can be alternatively prenylated by enzymes other than farnesyltransferase, Ho and colleagues conducted a phase II trial investigating the use of the farnesyltransferase inhibitor tipifarnib in 31 patients with HRAS-mutant recurrent or metastatic HNSCC. After an ad hoc analysis suggested that patients whose tumors had high variant-allele frequency (VAF) HRAS mutations may have a greater chance of disease response, only patients with HRAS mutations at a VAF of 20% (high-VAF patients) or greater were enrolled; in total, 22 high-VAF patients participated in the trial. Among the 20 high-VAF patients whose disease was evaluable for efficacy, the overall response rate was 55%, all responses were partial responses, and the median overall survival and progression-free survival were 15.4 months and 5.6 months, respectively. Of the 30 patients for whom safety was evaluable, the most common treatment-emergent adverse events of any grade were hematologic abnormalities (including anemia, neutropenia, leukopenia, and lymphopenia) and gastrointestinal symptoms (including nausea). In summary, the results of this trial demonstrate that tipifarnib shows signs of efficacy in HRAS-mutant HNSCC, particularly for patients with high mutant-HRAS VAF, and suggest that tipifarnib may also be worth investigating for other tumor types with high mutant-HRAS VAF.
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