Tipifarnib in Head and Neck Squamous Cell Carcinoma WithHRASMutations

Abstract

PURPOSE Mutations in the HRAS (m HRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M m HRAS HNSCC. METHODS We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m HRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m HRAS variant allele frequency (VAF) data, enrollment was limited to those with a m HRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. RESULTS Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%). CONCLUSION Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist ( NCT02383927 ).

Targeted Therapy of Papillary Thyroid Cancer: A Comprehensive Genomic Analysis

“…At this time, it is unclear if drugs targeting NRAS, HRAS, or KRAS (BI1701963 targeting KRAS and Tipifarnib targeting HRAS) will have any relevance for PTC in the future. Ho et al (30) reported stable disease in 9 of 11 HRAS-mutated thyroid cancer patients treated with Tipifarnib; however, they focus on head and neck squamous cell carcinoma in their report and the specific histology of the thyroid cancer patients is not included. Given the predominance of RAS mutations in RAI avid as opposed to RAI-refractory DTC reported in the literature (31), this pathway might be less relevant for the treatment of RAI-R disease.…”

Emerging strategies to target RAS signaling in human cancer therapy

“…A Structure of RAS proteins, including the effector lobe (aa 1-86), allosteric lobe (aa , and HVR (aa 167-188/189). Switch I (aa [30][31][32][33][34][35][36][37][38][39][40] and switch II (aa [60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] are located in the effector lobe and function in effector binding and GEF or GAP binding. The HVR domain contributes to RAS binding to cell membranes.…”

“…However, FTase inhibitors (FTIs) exhibited disappointing results in clinical trials [114] toward to pancreatic cancer, which mainly possess KRAS mutation [65][66][67], and subsequent research revealed KRAS and NRAS gained alternative modifications by geranylgeranyltransferases (GGTase) in cells treated with FTIs [68]. Noteworthily, tipifarnib, a FTase inhibitor, exhibited encouraging efficiency in cancer harboring HRAS mutation [69,70]. Although simultaneous inactivation of FTase and GGTase exhibited tumorigenesis inhibition in mouse models [71,72], the toxicity associated with GGTIs limited their utility, thus reducing the benefit of targeting KRAS through combined FTase and GGTase inhibition [73].…”

Stem Cell Technology in Regenerative Medicines and Cancer Treatment: Towards Revolution in Clinical Success

“…The activity of HRAS is synchronized by the enzyme farnesyltransferase. Tipifarnib inhibits this enzyme and results in decreasing HRAS expression and tumor growth diminished but until tipifarnib in trial phases [37][38][39]. Many therapies are in trial phases, some are in use but these therapies are not completely treating cancer.…”