Bauman, Jessica R.

TPS2618 Background: Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are requisite for localization to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. Tipifarnib has demonstrated robust activity in HRAS mutant head and neck squamous cell carcinoma (HNSCC) and HRAS mutant squamous non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) models resistant to standard therapies. Methods: This is a multi-institutional, open-label Phase II trial evaluating the efficacy and safety of tipifarnib for pts with HRAS mutant solid tumors. Pts must have either unresectable, locally advanced or metastatic non-hematological malignancies that harbor a missense HRAS mutation. The primary endpoint of the study is overall response rate. Secondary endpoints include safety and tolerability, PFS, duration of response. Two cohorts (N = 18 each) are enrolling, each being evaluated with a Simon two-stage design. Cohort 1 is for patients with malignant thyroid tumors of any histology. Cohort 2 was originally designated for pts with any other solid tumor. The prespecified activity goal for the first stage of accrual in Cohort 2 was met. Based on data observed in the first stage of this group, enrollment to the second stage of Cohort 2 has been limited to HRAS mutant HNSCC since August 2016. Enrolled patients are treated with tipifarnib 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. Clinical trial information: NCT02383927.

Abstract Background: HRAS is a proto-oncogene that is mutated in head and neck, bladder, thyroid, and salivary gland tumors, among others. While discovered over 40 years ago, no specific therapies have yet been developed targeting mutant HRAS. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme requisite for HRAS activation. Over 5,000 patients (pts) have been treated with tipifarnib; although responses have been documented in several tumor indications, the mechanisms of response are still poorly understood. Tipifarnib has demonstrated robust activity in HRAS mutant patient derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and squamous non-small cell lung cancer that are resistant to standard therapies. This Phase 2 study (NCT02383927) was conducted to test the hypothesis that inhibition of mutant HRAS oncogenic activity with tipifarnib could translate to objective responses in HNSCC pts driven by the HRAS oncogene. Methods: The study was originally designed to enroll pts into 2 single-arm study cohorts: Cohort 1 (thyroid cancer) and Cohort 2 (other solid tumors), each one with a 2-stage design (11+7 evaluable pts) to determine overall response rate (ORR) as the primary objective. This design has 80% power to detect a difference between 10% and 30% ORR at one-sided significance level of 0.087. Two objective responses were needed to be observed in the first stage for each cohort to proceed to stage 2. The study is considered positive if at least 4 responses are observed in one of the 2 cohorts (N=18 each, stages 1 and 2 combined). The prespecified activity goal for the first stage of accrual in Cohort 2 was met and based on data observed in the first stage of this Cohort, ongoing enrollment to the second stage of Cohort 2 was limited to HRAS mutant HNSCC. For enrollment, pts must have an HRAS mutant, locally advanced/unresectable and/or metastatic solid tumor malignancy and RECIST v1.1 measurable disease. Tipifarnib is given at 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Response assessments are conducted every 8 weeks. Results: As of August 30, 2017, 28 pts have been enrolled. Tipifarnib was generally well tolerated with myelosuppression, gastrointestinal disturbances (nausea, vomiting and diarrhea) and fatigue constituting the most common adverse events (≥30% of pts, all grades). Twenty four pts are currently evaluable for efficacy: 10 in Cohort 1 and 14 in Cohort 2. Stage 1 enrollment continues in Cohort 1. The primary objective was met for Cohort 2 prior to completing full enrollment, with 4 confirmed responses observed out of 14 evaluable pts. Notably, of the 6 pts in Cohort 2 with HNSCC currently evaluable for efficacy, 4 (67%) achieved a confirmed partial response. Three of these pts remain on treatment in cycles 3, 5, and 19, and one subject discontinued at Cycle 21. Two (33%) pts had disease stabilization as best response (4 cycles, ongoing and 7 cycles). Importantly, 4 of these pts were refractory to prior therapies, including regimens containing immunotherapy (pembrolizumab, nivolumab) or cetuximab +/- chemotherapy. None of the 6 HNSCC patients experienced an objective partial response on their last prior therapy. Conclusions: These data suggest that HRAS mutant HNSCC pts may be refractory to standard therapies but can derive prolonged clinical benefit from tipifarnib treatment. Based on the encouraging activity of tipifarnib in pts with HNSCC with HRAS mutations, enrollment continues in this cohort. Citation Format: Alan Ho, Nicole Chau, Deborah J. Wong, Maria E. Cabanillas, Jessica Bauman, Marcia S. Brose, Keith Bible, Valentina Boni, Irene Brana, Charles Ferte, Caroline Even, Francis Burrows, Linda Kessler, Vishnu Mishra, Kelly Magnuson, Catherine Scholz, Antonio Gualberto. Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A10.