Tipifarnib shows promise in refractory HRAS-mutant urothelial carcinoma
Treatment with tipifarnib appears to be safe with favourable efficacy in patients with treatment-refractory urothelial carcinoma harbouring HRAS mutations, according to the results of a phase II trial.
In total, 21 adult patients (median age, 64 years) with mutated advanced urothelial carcinoma received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-day treatment cycles. The patients had received a median of two prior systemic chemotherapy, with two of them having been exposed to immune checkpoint inhibitors (SMC-15 and -20).
Of the patients, 14 had missense HRAS mutations and seven were STK11:rs2075606 carriers. Four patients (19 percent) achieved the primary endpoint of progression-free survival (PFS) at 6 months: three with missense HRAS mutations and one who was an STK11 carrier had HRAS frameshift insertions at H27fs and H28fs, which rendered a nonsense HRAS mutation.
The overall response rate was 24 percent (four patients with missense and one patient with nonsense frameshift HRAS mutation). Tipifarnib did not produce a response in any of the patients with wild-type HRAS tumours.
Over a median follow-up of 28 months, the median PFS was 4.7 months (95 percent confidence interval [CI], 2.5–5.6) while the median overall survival was 6.1 months (95 percent CI, 5.0–7.2).
A total of 97 tipifarnib cycles (median, 3; range, 1 to 18) were delivered. At the final analysis, only two patients remained on treatment. The most frequent reason for discontinuation was disease progression (n=14).
All patients developed a treatment-related adverse event (TRAE), with 14 (67 percent) experiencing higher-grade TRAE. Commonly reported adverse events included fatigue (86 percent) and haematologic toxicities.