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

Clin Cancer Res. 2020 Oct 1;26(19):5113-5119. doi: 10.1158/1078-0432.CCR-20-1246. Epub 2020 Jul 7.


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.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Aged
  • Carcinoma / drug therapy*
  • Carcinoma / genetics
  • Carcinoma / pathology
  • Drug-Related Side Effects and Adverse Reactions / classification
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neoplasm Metastasis
  • Progression-Free Survival
  • Protein Serine-Threonine Kinases / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Quinolones / administration & dosage*
  • Quinolones / adverse effects
  • Urothelium / drug effects*
  • Urothelium / metabolism
  • Urothelium / pathology


  • Quinolones
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • tipifarnib