Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations
Open accessAbstract
PURPOSE: Mutations in the HRAS (m HRAS) 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 m HRAS HNSCC. METHODS: We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m HRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m HRAS variant allele frequency (VAF) data, enrollment was limited to those with a m HRAS 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 ).
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A phase II study of tipifarnib in HRAS-mutant head and neck squamous cell carcinoma showed an objective response rate of 55%, PFS of 5.6 months, and median OS of 15.4 months.
“A phase II study of tipifarnib in HRAS-mutant head and neck squamous cell carcinoma showed an objective response rate of 55%, PFS of 5.6 months, and median OS of 15.4 months [81].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [81]
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Drugging KRAS: Current perspectives and state-of-art review
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- Authors
- Ho, A. L., Brana, I., Haddad, R., Bauman, J., Bible, K., Oosting, S., Wong, D. J., Ahn, M.-J., Boni, V., Even, C., Fayette, J., Flor, M. J., Harrington, K., Hong, D. S., Kim, S.-B., Licitra, L., Nixon, I., Saba, N. F., Hackenberg, S., Specenier, P., Worden, F., Balsara, B., Leoni, M., Martell, B., Scholz, C., & Gualberto, A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Vall D'Hebron Institute of Oncology, Barcelona, Spain
- Dana-Farber Cancer Institute (US)
- Fox Chase Cancer Center (US)
- Mayo Clinic (US)
- University Medical Center Groningen (NL)
- Ronald Reagan UCLA Medical Center (US)
- Samsung Medical Center (KR)
- START Madrid-CIOCC, Madrid, Spain
- Institut Gustave Roussy (FR)
- Centre Leon Berard, Lyon, France
- Hospital Virgen del Rocio, Sevilla, Spain
- Institute of Cancer Research (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Asan Medical Center (KR)
- University of Milan (IT)
- Beatson West of Scotland Cancer Centre (GB)
- Winship Cancer Institute (US)
- Universitätsklinikum Würzburg (DE)
- Antwerp University Hospital (BE)
- U-M Rogel Cancer Center (US)
- Kura Oncology (United States) (US)
- Corresponding author
- Ho, Alan L.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2021-06-10
- Volume
- 39
- Issue
- 17
- Pages
- 1856-1864
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC8189627
- OpenAlex
- W3137170664
- Cited by
- 208
- References
- 37
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 55 · 2023: 35 · 2022: 41 · 2021: 14
- FWCI
- 31.69
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-09-28)
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
- Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- tipifarnib, head and neck squamous cell carcinoma, HRAS mutation, farnesyltransferase inhibitors, recurrent or metastatic cancer, variant allele frequency, objective response rate, progression-free survival, overall survival, anemia, lymphopenia
- MeSH terms
- Squamous Cell Carcinoma of Head and Neck, Proto-Oncogene Mas, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Female, Head and Neck Neoplasms, Humans, Male, Middle Aged, Quinolones, Proto-Oncogene Proteins p21(ras), Mutation, Missense, Young Adult
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