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Tipifarnib for Patients With Advanced HRAS-Mutant Head and Neck Cancer and High Variant Allele Frequency


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In a phase II trial reported in the Journal of Clinical Oncology, Ho et al found that tipifarnib produced a high response rate among patients with recurrent or metastatic head and neck squamous cell carcinoma with HRAS mutations and high variant allele frequency.

As stated by the investigators, “Mutations in the HRAS proto-oncogene occur in 4% to 8% of patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function.”

Study Details

In the study, 30 patients with HRAS-mutant disease from sites in the United States, Korea, and Europe were enrolled between September 2015 and April 2020. Patients received oral tipifarnib at 600 or 900 mg twice daily on days 1 to 7 and 15 to 21 of 28-day cycles.

After an ad hoc analysis in the first 16 patients with HRAS variant allele frequency data, enrollment was limited to patients with variant allele frequency of ≥ 20% (high). The primary endpoint was objective response rate on Response Evaluation Criteria in Solid Tumors version 1.1 among patients with high variant allele frequency. Data cutoff was in April 2020.

Responses

Of 22 patients with high variant allele frequency, 20 were evaluable for response at the time of data cutoff. Objective responses (all partial responses) were observed in 11 patients (55%, 95% confidence interval [CI] = 31.5%–76.9%). Response was observed in 7 (58.3%) of 12 patients with variant allele frequency ≥ 35% and in 4 (50.0%) of 8 with variant allele frequency < 30%.

Response was achieved at first tumor assessment at 8 weeks in 8 of 11 responders. Responses were observed in five of six patients started at 600 mg twice daily. Stable disease was achieved as best response in the remaining nine patients; among the nine patients with stable disease, three remained on treatment for approximately 7 months. Among 11 with partial response, 7 remained on treatment for ≥ 6 months.

Median progression-free survival was 5.6 months (95% CI = 3.6–16.4 months), as compared to 3.6 months (95% CI = 1.3–5.2 months) on last prior therapy. Median progression-free survival was 9.5 months (95% CI = 5.5 months–not estimable) among patients with response and 4.0 months (95% CI = 1.9 months–not estimable) among those with stable disease. Median overall survival was 15.4 months (95% CI = 7.0–29.7 months).

Adverse Events

Among all 30 patients receiving tipifarnib in the study, the most common adverse events were hematologic and gastrointestinal. The most common grade ≥ 3 adverse events were anemia (37%); lymphopenia (13%); and neutropenia, leukopenia, hypercalcemia, hypokalemia, hypophosphatemia, pneumonia, and nausea (10% each).

Adverse events led to discontinuation of treatment in three patients, due to laryngeal obstruction in two and respiratory failure in one; none was considered related to treatment. As of data cutoff, no patients with high variant allele frequency had discontinued treatment due to an adverse event. No tipifarnib-related deaths were observed.

The investigators concluded, “Tipifarnib demonstrated encouraging efficacy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma with HRAS mutations for whom limited therapeutic options exist.”

Alan L. Ho, MD, PhD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Kura Oncology. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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