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Cited 6 time in webofscience Cited 6 time in scopus
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A Phase II Trial of Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma Harboring HRAS Mutations

Authors
Lee, Hye WonSa, Jason K.Gualberto, AntonioScholz, CatherineSung, Hyun HwanJeong, Byong ChangChoi, Han YongKwon, Ghee YoungPark, Se Hoon
Issue Date
1-10월-2020
Publisher
AMER ASSOC CANCER RESEARCH
Citation
CLINICAL CANCER RESEARCH, v.26, no.19, pp.5113 - 5119
Indexed
SCIE
SCOPUS
Journal Title
CLINICAL CANCER RESEARCH
Volume
26
Number
19
Start Page
5113
End Page
5119
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/52498
DOI
10.1158/1078-0432.CCR-20-1246
ISSN
1078-0432
Abstract
Purpose: To assess the antitumor activity and safety of tipifarnib, a highly potent and selective farnesyltransferase inhibitor, we performed a phase II clinical trial in patients with advanced and refractory urothelial carcinoma harboring missense HRAS mutations. Patients and Methods: A total of 245 adult patients with previously treated, advanced urothelial carcinoma entered the molecular screening program including HRAS. Those with missense HRAS mutations or STK11:rs2075606 received oral tipifarnib 900 mg twice daily on days 1-7 and 15-21 of 28-day treatment cycles. The primary endpoint was progression-free survival at 6 months (PFS6). Results: Weidentified 16 (7%) missense HRASmutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11:rs2075606 carriers. In 21 patients enrolled in the study, 14 and 7 patients had missense HRAS mutations and STK11:rs2075606, respectively. The most frequently observed adverse events included fatigue (86%) and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as an STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. The overall response rate by intent-totreat analysis was 24% (4 missense and one nonsense frameshift HRAS mutation); no response was observed in patients with urothelial carcinoma with wild- type HRAS tumors. Five responses were observed in 12 evaluable patients of 15 with tumors carrying HRAS mutations. Conclusions: Oral tipifarnib resulted in a manageable safety profile and encouraging antitumor efficacy against treatmentrefractory urothelial carcinoma containing HRAS mutations.
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