Tipifarnib showed promising clinical activity in patients with recurrent and/or metastatic, HRAS-mutant head and neck squamous cell carcinoma whose disease had progressed after prior therapy.
Tipifarnib showed promising clinical activity in patients with recurrent and/or metastatic, HRAS-mutant head and neck squamous cell carcinoma (HNSCC) whose disease had progressed after prior therapy, according to results from a phase 2, open-label, single-arm KO-TIP-001 trial (NCT02383927) published in the Journal of Clinical Oncology.1
Among the 20 response-evaluable patients with a variant allele frequency (VAF) of 20% or higher (high VAF) treated on study, 11 met RECIST v1.1 criteria for confirmed partial response (PR), which translated to an objective response rate (ORR) of 55% (95% CI, 31.5%-76.9%). Tipifarnib resulted in a significant improvement in median progression-free survival (PFS) over last prior therapy received, at 5.6 months (95% CI, 3.6-16.4) and 3.6 months (95% CI, 1.3-5.2), respectively. Moreover, the median overall survival (OS) with tipifarnib was 15.4 months (95% CI, 7.0-29.7).
“We are encouraged by the compelling efficacy and safety profile of tipifarnib in patients with recurrent or metastatic HRAS-mutant HNSCC,” Alan Ho, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center and principal investigator of this trial, stated in a press release.2 “Importantly, these patients experienced limited benefit on prior therapies, including immunotherapies, which demonstrates the high unmet need for this disease. These data also reinforce the relevance of genomic testing for HRAS mutations to identify patients who could potentially benefit from tipifarnib treatment.”
Despite recent advances in immunotherapy, the prognosis for patients with advanced HNSCC remains poor, and the development of biomarker-directed therapies in the recurrent and metastatic settings has been limited. Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function and has demonstrated durable anticancer activity in previous studies. In February 2021, the FDA granted a breakthrough therapy designation to tipifarnib for use in patients with recurrent or metastatic HRAS-mutated HNSCC with high VAF based on data from this trial that were presented during the 2020 ASCO Virtual Scientific Program.
This trial enrolled patients with incurable solid tumors that harbored missense HRAS mutations; it was divided into 2 stages. The first stage was comprised of 3 cohorts, patients with thyroid cancer, those with non-thyroid solid tumors, and those with squamous cell carcinoma other than HNSCC. The second stage of the trial included those in cohort 2 who had HNSCC only; the cohort was expanded to further characterize safety and tolerability indications of interest.
A total of 31 patients were split into 2 subsets: those with HRAS VAF of 20% or greater and serum albumin level of 3.5 g/dL or greater or HRAS of 35% or greater (n = 22), and those with a HRAS VAF of 20% or less or 20% to 35% with a serum albumin of 3.5 g/dL or less (n = 9).
To be eligible for enrollment on the trial, patients had to have HRAS-mutant disease with a VAF greater than 20%, measurable disease per RECIST v1.1 criteria that was relapsed/refractory to prior therapy, as well as an ECOG performance status of 0 or 1. Patients who had previously been treated with a farnesyltransferase inhibitor, who had a history of coronary heart disease, or who had uncontrolled brain, leptomeningeal, or epidural metastases were excluded.3
Initially, oral tipifarnib was given to patients with HNSCC at a twice-daily dose of 900 mg on days 1 through 7 and 15 through 21 of 28-day cycles, based on data from 2 prior trials that established the safety of this schedule. However, of the first 15 patients dosed, 9 needed a dose reduction to manage adverse effects (AEs). As such, the median dose of tipifarnib by cycle 2 day 1 was 600 mg, given twice daily. The trial protocol was then amended to begin the agent at 600 mg twice daily to improve tolerability of tipifarnib and allow patients to continue on treatment for a longer period of time.
The primary end point of the trial was investigator-assessed ORR, while secondary end points included safety and tolerability. PFS, duration of response (DOR), overall survival, and feasibility of molecular analyses using next-generation sequencing were also evaluated as exploratory end points.
Among the 22 patients with high-VAF HNSCC, the median age was 63 years (range, 20-89), and the majority were male (68.2%). The primary location of the tumor was the oral cavity in 45.5% of patients (n = 10), and patients received a median of 2 prior treatments, which included platinum-based chemotherapy (90.9%), immunotherapy (63.9%), and cetuximab (Erbitux; 50%).
Additional results revealed that the ORR for the intent-to-treat population (n = 22) was 50% (95% CI, 30.7%-69.3%). Among the 20 evaluable high-VAF patients, those with a VAF of greater than 35% had an ORR of 58.3% vs 50% of t hose with a VAF that was less than 35%. Three of 12 patients with a VAF greater than 35% had an albumin of less than 3.5 g/dL with 1 (33.3%) experiencing response to the agent. Notably, responses were rapid, with 8 of 11 patients who met PR criteria experiencing response at the time of their first tumor assessment.
Moreover, 7 of 11 patients who achieved PRs ended up discontinuing treatment because of disease progression. Of the 9 patients who did not respond to tipifarnib, all achieved a best response of stable disease and 6 experienced minor tumor regression. Three of 9 patients who had disease stability received treatment for about 7 months, while 7 patients with PR continued treatment for at least 6 months.
Of the 11 patients who received immunotherapy as their last prior line of treatment, 7 experienced a PR and 4 achieved disease stability with tipifarnib. In the 8 patients who had a prior line of treatment that was not immunotherapy, 3 experienced PRs and 4 had stable disease.
The PFS benefit with tipifarnib proved to be greater in the patients who experienced a PR vs those who achieved stable disease, at 9.5 months (95% CI, 5.5-NA) vs 4.0 months (95% CI, 1.9-NA), respectively.
Safety was evaluated in 30 patients who were treated with tipifarnib. The most commonly reported treatment-emergent AEs (TEAEs) of any grade, irrespective of VAF or albumin cutoff, were hematologic, and included anemia, neutropenia, leukopenia, and lymphopenia. Gastrointestinal effects, such as nausea, were also reported.
Three patients reported TEAEs that led to discontinuation of tipifarnib: 2 patients had laryngeal obstruction and 1 had respiratory failure; however, these effects were not determined to be related to the study treatment. No treatment-related deaths were reported, and at data cutoff, no high-VAF participants had discontinued treatment due to AEs.
Tipifarnib will continue to be evaluated in the phase 2 AIM-HN/SEQ-HN trial (NCT03719690) in patients with HRAS-mutated HNSCC.
"We are pleased to see our data from the phase 2 RUN-HN trial of tipifarnib published in the Journal of Clinical Oncology for review by the broader clinical community,” Troy Wilson, PhD, JD, president and chief executive officer of Kura Oncology, added in the release. "The highlighted data from the RUN-HN trial comes on the heels of our breakthrough therapy designation from the FDA and we continue to advance the ongoing AIM-HN registration-directed trial in patients with HRAS-mutant HNSCC, for whom there is an urgent unmet need.”