A Phase II Trial of Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma HarboringHRASMutations
| Autor: | Byong Chang Jeong, Hyun Hwan Sung, Antonio Gualberto, Se Hoon Park, Ghee Young Kwon, Hye Won Lee, Han Yong Choi, Catherine Scholz, Jason K. Sa |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty Mutation Metastatic Urothelial Carcinoma business.industry Farnesyltransferase inhibitor STK11 medicine.disease_cause Frameshift mutation 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Internal medicine Medicine Missense mutation Tipifarnib HRAS business medicine.drug |
| Zdroj: | Clinical Cancer Research. 26:5113-5119 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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