FDA Grants Breakthrough Therapy Designation to Tipifarnib in HRAS+ HNSCC

The FDA has granted a Breakthrough Therapy Designation (BTD) to tipifarnib (Zarnestra) for the treatment of patients with recurrent or metastatic HRAS-mutant head and neck squamous cell carcinoma (HNSCC) with variant allele frequency (VAF) ≥ 20% after disease progression on platinum-based chemotherapy, according to a press release from Kura Oncology.¹

“We are very pleased that the FDA has awarded Breakthrough Therapy Designation to tipifarnib, and we appreciate the agency’s affirmation of its potential to treat this devastating disease,” said Troy Wilson, PhD, JD, president, and chief executive officer of Kura Oncology, in a statement.

BTD was granted to tipifarnib after data from the phase 2 RUN-HN clinical trial (NCT02383927) showed a favorable objective response rate (ORR) and survival benefit in patients with metastatic HRAS-mutant HNSCC.

Results were presented during the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting by Alan Loh Ho, MD, PhD, of NYC Health and Hospitals-Bellevue. During his presentation, Ho stated: “We observed compelling clinical activity with tipifarnib in a variety of different HRAS-mutant solid tumor histologies often treated in the second-line and beyond.”

Among all enrolled patients with HRAS-mutant HNSCC (n = 21), the ORR was 42.9% (95% CI, 21.8%-66.0%). In the 17 response-evaluable patients with HRAS-mutant HNSCC, the ORR was 47.1% (95% CI, 23.0%-72.2%). The median duration of response (DOR) in the cohort was 14.67 months (95% CI, 2.1-not evaluable).²

With 1 additional patient in the response evaluable population bringing the cohort to 18 patients, those with high VAF receiving tipifarnib had a median progression-free survival (PFS) of 5.9 months (95% CI, 3.5-19.2). In comparison, patients had a median PFS of 2.8 months (95% CI, 1.1-5.2) on their last line of therapy. Overall survival in this population was a median of 15.4 months (95% CI, 7.0-46.4).

Notably, the robust activity of tipifarnib observed in HRAS-mutant HNSCC was irrespective of prior chemotherapy, immunotherapy, or cetuximab (Erbitux) treatment.

RUN-HN is an ongoing open-label study. Three cohorts are included in the study, which consists of a malignant thyroid tumor group, squamous cell carcinoma HNSCC group, and those with SCCs other than HNSCC. Patients had HRAS-mutant disease in all cohorts and have measurable disease and an ECOG performance status of 0-1 per the eligibility criteria of the trial.

At a starting dose of 900 mg given orally twice daily, the primary end point being explored for patients receiving tipifarnib in the study is ORR. The secondary end points are safety and tolerability, and the study is also assessing DOR and PFS as exploratory end points.

According to the ASCO presentation data, the majority of the patient population of RUN-HN is male (66.7%) who have a median age of 64 years (range, 20-89). The different primary tumor sites of patients in the study included the oral cavity (52.4), pharynx (28.6%), and other (4.8%). Patients had a median of 2 prior treatment regimens (range, 0-6), which included platinum-based chemotherapy (90.5%), immunotherapy (61.8%), and cetuximab (52.4%). The majority of the population was also negative for human papillomavirus (69.2%).

Tipifarnib is described as a potent and highly selective inhibitor of farnesyltransferase, which is a helpful mechanism of action against HRAS mutations. With a BTD, Kura Oncology may submit a rolling application for FDA approval and is eligible for Priority Review designation upon submission of the application. Another BTD benefit is receiving ongoing guidance from the FDA.

“We remain focused on conducting our AIM-HN registration-directed trial and look forward to working closely with the FDA to bring this therapy to patients as soon as possible,” Wilson stated, in the press release.

_References:

_{1. Kura Oncology receives FDA Breakthrough Therapy Designation for tipifarnib in head and neck squamous cell carcinoma. News release. Kura Oncology. February 24, 2021. Accessed February 25, 2021. https://bit.ly/3pRWTtN}

_{2. Ho AL, Hanna GJ, Scholz CR, et al. Preliminary activity of tipifarnib in tumors of the head and neck, salivary gland, and urothelial tract with HRAS mutations. J Clin Oncol. 2020;38(suppl):6504. doi:10.1200/JCO.2020.38.15_suppl.6504}