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Tipifarnib Demonstrates Encouraging Efficacy in Patients with Recurrent and/or Metastatic HNSCC with HRAS Mutations

Results from the KO-TIP-001 study with farnesyltransferase inhibitor in patients with head and neck squamous cell carcinoma
21 Apr 2021
Anticancer agents & Biologic therapy;  Head and neck cancers;  Translational research

In a phase II study conducted in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) with mutant HRAS variant allele frequency ≥20%, treatment with tipifarnib produced an objective response rate (ORR) of 55%, median progression-free survival (PFS) of 5.6 months and a median overall survival (OS) of 15.4 months. The safety profile of tipifarnib was tolerable and manageable. The study findings are published by Dr Alan L. Ho of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues on 20 April 2021 in the Journal of Clinical Oncology.

The authors wrote in the background that since the approval of the anti-epidermal growth factor antibody cetuximab more than a decade ago, development of targeted therapies in HNSCC has been stymied by the limited number of druggable targets and the aggressiveness of drug-refractory disease.

Phase II and III clinical studies failed to show significant efficacy of farnesyltransferase inhibitors in tumour types predicted to be enriched for NRAS and KRAS mutations, ending the development as a pan–RAS-targeted strategy.

In HNSCC patient–derived xenograft models, farnesyltransferase inhibitor therapy induced regressions only in HRAS mutant models. In HNSCC, HRAS is a driver oncogenic mutation that occurs in approximately 4-8% of patients and defines a predominantly HPV-negative biologic subset characterised by enrichment for wild-type TP53, Caspase-8 mutations, and low copy number alterations.

On the basis of these insights, the study team developed a clinical study to revisit farnesyltransferase inhibitor as a therapeutic strategy to target mutant HRAS in human malignancies. Tipifarnib is a first-in-class non-peptidomimetic quinolinone that binds and potently inhibits farnesyltransferase. Its prior clinical development consisted of more than 70 clinical studies in solid and haematologic malignancies, however conducted without genetic selection.

A single-arm, open-label phase II, KO-TIP-001 study was developed to evaluate the ORR of tipifarnib in patients with incurable HRAS mutant solid tumours. The study team enrolled 30 patients with R/M HNSCC; one additional patient was treated on an expanded access programme. After an ad hoc analysis of the first 16 patients with HNSCC with mutant HRAS variant allele frequency data, enrolment was limited to those with a mutant HRAS variant allele frequency of ≥20%. The primary endpoint was ORR. Secondary endpoints 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. Of the 22 patients with HNSCC with high variant allele frequency, 20 were evaluable for response at the time of data cut-off.

The ORR for evaluable HNSCC patients with variant allele frequency was 55% (95% confidence interval [CI] 31.5 to 76.9). Median PFS 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 OS 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 anaemia (37%) and lymphopenia (13%).

The authors wrote that main caveats of this study include the non-randomised, open-label design and the small sample size. However, the efficacy signal observed is impressive for a targeted therapy in a biomarker-selected HNSCC patient cohort and supports continued investigation of tipifarnib.

A pivotal AIM-HN and SEQ-HN Study evaluating the efficacy and safety of tipifarnib in HRAS mutant HNSCC (AIM-HN) and the impact of HRAS mutations on HNSCC therapies (SEQ-HN) is currently ongoing.

Alexander T. Pearson and Everett E. Vokes of the The University of Chicago wrote in accompanied editorial that clinical responses in this study represent potentially impactful change in clinical HNSCC research. It is novel because of a limited number of current successful targeting strategies for RAS family alterations and few targeted treatment strategies in HNSCC. The ideal patients for tipifarnib treatment will likely become more apparent as more data are collected. They also wrote that the development of targeted therapies in HNSCC has been slow and they hope that these results will help to further justify increased clinical genomic testing and drive translational investigations.

The study was supported by research funding from Kura Oncology.

Reference

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