Dataset Information

Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations.

ABSTRACT:

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).

SUBMITTER: Ho AL

PROVIDER: S-EPMC8189627 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Tipifarnib in Head and Neck Squamous Cell Carcinoma With <i>HRAS</i> Mutations.

Ho Alan L AL Brana Irene I Haddad Robert R Bauman Jessica J Bible Keith K Oosting Sjoukje S Wong Deborah J DJ Ahn Myung-Ju MJ Boni Valentina V Even Caroline C Fayette Jerome J Flor Maria José MJ Harrington Kevin K Kim Sung-Bae SB Licitra Lisa L Nixon Ioanna I Saba Nabil F NF Hackenberg Stephan S Specenier Pol P Worden Francis F Balsara Binaifer B Leoni Mollie M Martell Bridget B Scholz Catherine C Gualberto Antonio A

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20210322 17

<h4>Purpose</h4>Mutations in the <i>HRAS</i> (m<i>HRAS</i>) 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 <i>HRAS</i> function. We evaluated the efficacy of tipifarnib in patients with R/M m<i>HRAS</i> HNSCC.<h4>Methods</h4>We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m<i>HRAS</i> malignancies; one add ...[more]

PMID: 33750196

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Project description:PurposeIn head and neck squamous cell carcinoma (HNSCC), HRAS mutation is a new actionable oncogene driver. We aimed to evaluate HRAS mutational variants, comutation profile, and survival outcomes of this molecularly defined population.MethodsWe leveraged four deidentified patient data sets with HRAS-mutant HNSCC, MD Anderson Cancer Center, Kura Oncology, Inc trial, Foundation Medicine, and American Association for Cancer Research GENIE v.12. Patient demographic information and clinical courses were extracted, when available, in addition to HRAS mutation type and co-occurring mutations. Survival outcomes were analyzed (Kaplan-Meier method).ResultsTwo hundred forty-nine patients with HRAS-mutant HNSCC were identified from the four data sets. Median age ranged from 55 to 65 years, with a higher frequency in male patients (64%); the majority of HRAS-mutant HNSCC occurred in human papillomavirus-negative HNSCC. HRAS mutation patterns were similar across data sets; G12S was the most common (29%). Treatment responses to tipifarnib were not codon-specific. Compared with wild-type, significantly co-occurring mutations with HRAS were Casp8 (Fisher's exact test, P < .00013), TERT (P < .0085), and NOTCH1 (P < .00013). Analysis of clinical courses from the MD Anderson Cancer Center and Kura Oncology, Inc data sets demonstrated poor clinical outcomes with a high rate of recurrence following primary definitive treatment (50%-67% relapse < 6 months) and short disease-free survival (4.0 months; 95% CI, 1.0 to 36.0) and overall survival (OS; 15.0 months; 95% CI, 6.0 to 52.0). Use of tipifarnib in this data set demonstrated improved OS (25.5 months; 95% CI, 18.0 to 48.0).ConclusionOncogenic mutations in HRAS occur in 3%-4% of HNSCC, with G12S being the most frequent. Without targeted therapy, patients with HRAS-mutant HNSCC had poor clinic outcomes; observable trend toward improvement in OS has been noted in cohorts receiving treatments such as tipifarnib. The comutation pattern of HRAS-mutant in HNSCC is distinct, which may provide insight to future therapeutic combination strategies.