Tipifarnib Elicits Encouraging Responses in Patients With Recurrent or Metastatic HNSCC

April 27, 2021
Conor Killmurray

Results from the phase 2 study of farnesyltransferase inhibitor tipifarnib showed significant responses in patients with recurrent and/or metastatic head and neck squamous cell carcinoma and demonstrated that variant alle frequency could be a potential biomarker in this patient population.

Researchers saw encouraging signs of efficacy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) with mutant HRAS variant alle frequency (VAF) treated on tipifarnib on a phase 2 clinical trial, according to results published in the Journal of Clinical Oncology.1

Among the 30 patients in the single-arm, open label phase 2 KO-TIP-001 study (NCT02383927) enrollment on tipifarnib was further limited to patients with a mutant HRAS VAF greater than 20%, which was defined as high VAF, after an ad hoc analysis showed efficacy in these patients may be enriched. Twenty-two of the patients had high VAF, but 20 were evaluable for response at the time of data cutoff and researchers recorded an objective response rate (ORR) of 55% (95% CI, 31.5-76.9), meeting the primary end point of the study. The ORR in the intent to treat population (n = 22) was 50% (95% CI, 30.7-69.3).

Twelve patients with high VAF had a VAF greater than 35% (37%-90%) and had an ORR of 58.3%, compared to patients with high VAF less than 35% (23%-33%) who had a 50% ORR. Moreover, 3 patients of the 12 with VAF greater than 35% had an albumin of < 3.5 g/dL with 1 (33.3%) achieving a response. These responses were achieved rapidly, as 8 of 11 patient met the criteria of the first tumor assessment within 8 weeks. Nine patients did not receive a response, however, but all were considered to have stable disease (SD), while 6 patients saw a minor tumor regression.

For this study, patients were initially given tipifarnib at 900 mg orally twice a day on days 1-7 and 15-21 of 28-day cycles. Nine patients required dose reduction to manage toxicities initially, and the treatment was amended to 600 mg twice a day daily in the same cycles moving forward. Tumors were assessed every 8 weeks in the first 6 months and then every 12 weeks until disease progression.

Progression-free survival (PFS) was also found to be statistically significant at a median of 5.6 months (95% CI, 3.6-16.4, P = .0012) on tipifarnib compared to a median PFS of 3.6 months (95% CI, 1.3-5.2) for patients on their last prior therapy. Patients on tipifarnib who experienced a partial response to treatment had a PFS of 9.5 months (95% CI, 5.5-NA) compared to a PFS of 4 months (95% CI, 1.9-NA) in patients with SD. Researchers also observed a significant median overall survival (OS) of 15.4 months (95% CI, 7.0-29.7) for patients on tipifarnib.

“The median OS of 15.4 months with tipifarnib is also longer than historically reported for treatments used in a similar setting (5.1-8.4 months),” researchers wrote. “Another striking observation was the clinical benefit rate for the high–mutant HRAS VAF efficacy evaluable patients were 100% (11 of 20 with PR and 9 of 20 with SD), providing additional evidence for the role of mutant HRAS as an oncogenic driver in these tumors and the ability of (farnesyltransferase inhibitors) to therapeutically target it.”

Secondary endpoints of the study include safety and tolerability, and tipifarnib was considered safe and tolerable in this study. Safety was evaluated in all 30 patients of the trial and the most common treatment-emergent adverse events (TEAEs) in any grade, regardless of their VAF status, were anemia, neutropenia, leukopenia, lymphopenia, and nausea. Three patients had to discontinue treatment due to TEAEs, which included 2 patients who had laryngeal obstruction and 1 patient with respiratory failure. However, the researchers determined these were not related to tipifarnib but the disease itself. At the time of data cutoff, no patient with high VAF discontinued tipifarnib due to adverse events.

The farnesyltransferase inhibitor was previously a part of phase 2 and 3 clinical trials that looked at the targeted therapies use in patients with tumor types that were predilected to have high levels of NRAS and KRAS mutations but results from these trials were not significant. However, for patients with HNSCC, derived xenograft models showed the inhibitor reduced tumor size in HRAS mutant models only.2 HRAS is a driver oncogenic mutation that occurs in 4-8% of patients with HNSCC, which led to researchers wanting to observe an expanded use of the inhibitor in the patient population, as they do not have many other options/

“A review of publicly available HNSCC genomic data from The Cancer Genome Atlas reveals that the VAF threshold of at least 20% would exclude more than one fourth of HRAS mutant tumors and a threshold of at least 35% would apply to < 3% of patients with HNSCC overall,” wrote Alexander T. Pearson, MD, PhD, and Everett E. Vokes, MD, in an editorial in Journal of Clinical Oncology accompanying the study. “The VAF-clinical response correlation is imperfect, with responses observed across the spectrum of HRAS VAFs. Significant enrichment occurs at higher thresholds, but further study should be dedicated to optimize the clinical utility of VAF as a biomarker.”

References

  1. Ho AL, Brana I, Haddad R, et al. Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations. J Clin Oncol. 2021 Mar 22:JCO2002903. doi: 10.1200/JCO.20.02903
  2. Pearson AT, Vokes EE. Is This the Dawn of Precision Oncology in Head and Neck Cancer? J Clin Oncol. 2021 Apr 20:JCO2100569. doi: 10.1200/JCO.21.00569