Tipifarnib Shows ‘Encouraging Activity’ For HRAS-Mutated HNSCC

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: A potent and selective inhibitor of farnesyltransferase has shown some activity in a phase II clinical trial of head and neck squamous cell carcinoma (HNSCC) patients with recurrent or metastatic disease positive for a HRAS mutation and no curative therapeutic options. 

The KO-TIP-001 basket trial of tipifarnib initially aimed to recruit thyroid tumour patients and those with other types of solid tumours with a HRAS mutation but following an “initial sign of activity”, the protocol was amended to focus the phase II study in patients with head and neck tumours and HRAS mutant variant allele frequency (VAF) of at least 35% or a VAF of 20% plus a serum albumin level of at least 3.5 g/dL. 

In addition, the initial tipifarnib dose of 900 mg twice daily every second week was reduced to 600 mg to improve tolerability, explained presenting author Alan Loh Ho, from Memorial Sloan Kettering Cancer Center in New York, USA, at the virtual 2020 ASCO Annual Meeting. 

Overall, 21 patients aged a median of 64 years were enrolled with cancer of the oral cavity (52.4%), pharynx (28.6%), larynx (14.3%) or other head and neck sites (4.8%), with 30.7% of participants positive for human papillomavirus. The patients had received a median of two prior treatments, most commonly platinum chemotherapy (90.5%), immunotherapy (61.9%) or cetuximab (52.4%). 

The primary endpoint of the objective response rate (ORR) was 42.9% in the intention-to-treat group, rising to 50.0% among the 17 HNSCC patients who were evaluated for response plus one additional patient from an expanded access programme. The median duration of response was 14.7 months in this latter group of 18 patients. 

“Outcomes we observed with tipifarnib appeared to be superior to those that these patients achieved with prior lines of therapy”, the investigator commented, reporting nine partial responses and nine cases of stable disease versus one partial response and six stable disease responses with the last line of therapy. 

Progression-free survival (PFS) was a median of 5.9 months with tipifarnib in the 18 patients and this compared with 2.8 months achieved with their previous treatment regimen. And overall survival (OS) was a median of 15.4 months in this group, the investigator said. 

“These data represent very encouraging antitumour activity for tipifarnib in high HRAS-mutant VAF recurrent [or] metastatic head and neck cancer patients with a very high response rate [and] durable responses”, Alan Loh Ho said, adding that the KO-TIP-007 trial is now recruiting HNSCC patients with high HRAS-mutant VAF to evaluate tipifarnib further. 

The presenter also reported outcomes for seven HRAS-mutated salivary gland tumour patients in cohort 2 of the basket trial and six other salivary gland cancer patients who received tipifarnib at the 900 or 600 mg dose through an expanded access programme. 

Of the 12 patients with RECIST-evaluable disease, there was one partial response and seven cases of stable disease for between 3 and 13 months, with a median PFS of 7 months and OS of 18 months. At time of reporting, one patient had an ongoing partial response at 14 months. 

Finally, Alan Loh Ho described the outcome of 21 patients with HRAS-mutated urothelial carcinoma or a STK11 mutation associated with a poor outcome; this patient population was chosen because STK11 encodes for a farnesylated protein. 

The ORR in this cohort was 24%, with all responses reported in the HRAS-mutated patients and no tumour regression among those wild-type for the mutation. Median PFS was 4.7 months. 

“We observed very compelling activity with tipifarnib in a variety of different HRAS mutant salivary tumour histologies often treated in a second line and beyond”, the presenter concluded. But he emphasized that further work is required to understand the clinical biomarkers for tipifarnib response and resistance between tumour types. 

Reference 

Ho AL, Hanna GJ, Scholz C, et al. Preliminary activity of tipifarnib in tumors of the head and neck, salivary gland and uorothelial tract with HRAS mutations. J Clin Oncol; 38: suppl; abstr 6504. DOI: 10.1200/JCO.2020.38.15_suppl.6504