Tipifarnib Shows Promising Disease Control Rate in HRAS-Mutant Salivary Gland Carcinoma

A study published in Cancer demonstrated that tipifarnib resulted in modest clinical activity with a promising disease control rate in patients with HRAS-mutant, recurrent, metastatic salivary gland carcinoma who developed disease progression within the last 6 months.

The study is the first of its kind to report modest, promising clinical activity with tipifarnib in this patient population.

“In the absence of a dedicated clinical trial for this rare orphan disease, we launched an international, multicenter effort to pool together an unprecedented number of patients with HRAS-mutant [salivary gland carcinoma] who were treated with tipifarnib; to the best of our knowledge, the current study is the largest targeted therapy experience for this molecular subset performed to date,” the authors wrote.

The cohort study included 8 centers and was conducted from May 2015 to June 2019. In the current prospective, nonrandomized, multicenter, international study, the median follow-up was 22 months (range, 6-55 months). Individuals with HRAS-mutant relapsed, metastatic salivary gland carcinoma, of any histology, and disease progression within the last 6 months were enrolled and dosed with tipifarnib orally twice daily.

Overall, 13 patients with relapsed, metastatic salivary gland carcinoma were included in the study, and all had received 1-3 regimens of prior systemic therapy. Only 1 objective response was observed, though an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Moreover, 5 of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months.

Q61R was the most commonly activating HRAS mutation noted (7 of 13 patients; 54%), however gene variant and allele frequency were not associated with outcomes. The median progression-free survival (PFS) was 7 months (95% CI, 5.9-10.1 months), and the median overall survival (OS) was 18 months (95% CI, 9.6- 22.4 months) with approximately 58.6% of patients alive at 1 year.

Even further, survival with tipifarnib was comparable regardless of HRAS mutant variant or co-occurring PIK3CA alterations. Additionally, no participants had to discontinue treatment due to toxicity.

“These findings with tipifarnib compare favorably with other molecularly targeted therapies that have been investigated in trials of patients with advanced [salivary gland carcinoma] that were performed without molecular selection,” the authors wrote. “These efforts have highlighted the intrinsic value of molecular selection and profiling even for rare diseases, not only to identify effective new therapies but also to delineate potential mechanisms of acquired resistance that can suggest new directions for clinical investigation.”

Notably, this study was limited by a small sample size, heterogeneous starting doses of tipifarnib, and some variation in imaging schedules. However, patients in the current study with HRAS-mutant salivary gland carcinoma experienced a 1-year OS rate of 58.6% compared with prior studies of subgroups of patients with aggressive salivary gland carcinoma, which have reported 1-year OS rates of 66% to ≥80%.

“It is important to note that this initial observation strongly recommended that novel approaches to optimizing the inhibition of HRAS signaling, including drug combinations with tipifarnib, could translate into even greater clinical activity for patients with HRAS-mutant [salivary gland carcinoma],” the authors wrote.

Reference:

Hanna GJ, Guenette JP, Chau NG, et al. Tipifarnib in Recurrent, Metastatic, HRAS-Mutant Salivary Gland Cancer. Cancer. doi:10.1002/cncr.33036.