A Phase II Trial of Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma Harboring HRAS Mutations

Hye Won Lee, Jason K. Sa, Antonio Gualberto, Catherine Scholz, Hyun Hwan Sung, Byong Chang Jeong, Han Yong Choi, Ghee Young Kwon, Se Hoon Park

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27 Citations (Scopus)


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: We identified 16 (7%) missense HRAS mutations (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-to-treat 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 treatment-refractory urothelial carcinoma containing HRAS mutations.

Original languageEnglish
Pages (from-to)5113-5119
Number of pages7
JournalClinical Cancer Research
Issue number19
Publication statusPublished - 2020 Oct 1

Bibliographical note

Funding Information:
This work was supported by Samsung Medical Center (Seoul, Korea) Research Fund (OTX0002441) and in part by Kura Oncology, Cambridge, MA, USA. Study drug (tipifarnib) was kindly provided by Kura Oncology.

Publisher Copyright:
©2020 American Association for Cancer Research.

ASJC Scopus subject areas

  • General Medicine


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