Background: HRAS is a proto-oncogene overexpressed and mutated in some human carcinomas. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme for proper HRAS function. Methods: We report data from two phase 2 clinical trials investigating the activity of tipifarnib in HRAS mutant (HRASm) solid tumors: KO-TIP-001 (NCT02383927: Squamous carcinomas [SCC], thyroid and salivary gland tumors, among others) and IST-01 (NCT02535650: Urothelial carcinomas, UC).Primary endpoints were overall response rate (ORR, KO-TIP-001) and progression free survival (PFS) rate at 6 months (IST-01). All pts had RECIST v1.1. measurable disease at study entry. Pts receive a starting dose of tipifarnib of either 600 or 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. Results: Proof of concept was achieved in studies KO-TIP-001 and IST-01. Based on preliminary efficacy results (Ho, et. al, ESMO 2018), KO-TIP-001 was amended to continue enrolling only in Head & Neck SCC (HNSCC) pts (Cohort 2) and other SCC pts (Cohort 3) with tumors carrying high HRASm variant allele frequency (VAF) >20%. As of 17 October 2019, 21 HNSCC pts meeting the high HRASm VAF criteria had been treated with tipifarnib of whom 18 were efficacy evaluable at data cut off. Pts had received a median of 2 prior systemic regimens. Ten objective responses were observed in 18 evaluable pts for an ORR of 56%. No responses were observed on last therapy prior to study entry. PFS on tipifarnib and on prior last therapy were, respectively, 6.1 and 2.8 months. In addition, 13 pts with recurrent/metastatic salivary gland tumors (SGT) were treated in KO-TIP-001 or in extended access programs. One objective response was observed in 12 (8%) evaluable pts and an additional 7 (58%) had stable disease as best response. Median PFS in SGT pts was 7 months. In IST-01, 224 UC pts were screened of whom 16 (7%) carried HRAS mutations and 15 of those were enrolled into the study. Five responses were observed in 12 evaluable UC pts (42%) and 3 additional pts had tumor size reduction. Median PFS was 5.1 months. Conclusions: Encouraging activity of tipifarnib was observed in HRASm solid tumors. Clinical trial information: NCT02383927, NCT02535650.