Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. PATIENTS AND METHODS: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. RESULTS: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. CONCLUSIONS: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Physicochemical stability of crystalline sugars and their spray-dried forms: dependence upon relative humidity and suitability for use in powder inhalers.

Lactose, trehalose, sucrose, and mannitol were purchased in crystalline form and fractionated by sieving. Coarse (125-212 microns) and fine (44-74 microns) free-flowing fractions were selected as typical of drug carriers in dry-powder inhalers. In addition, one batch of each sugar was spray-dried to form a respirable powder (> 50% [w/w], < 5 microns). Both fractions and the spray-dried powders were characterized before and after storage for 30 days at < 23%, 23%, 52%, 75% and 93% relative humidity (RH) at 25 degrees C. Moisture uptake was determined by thermogravimetric analysis (TGA) validated by Karl Fischer titration. Sieve fractions (before storage at different RHs) and spray-dried materials (before and after storage) were further characterized by differential scanning calorimetry (DSC) and x-ray powder diffraction (XRPD). All crystalline sieve fractions (except sucrose at 93% RH) were stable at 25 degrees C and showed insignificant moisture uptake when exposed to each relative humidity for 30 days. Sucrose dissolved in sorbed moisture at 93% RH. Spray-dried lactose, sucrose, and trehalose, which were collected in the amorphous form, showed moisture uptake, without recrystallization, when held for 30 days at 23% RH. These sugars recrystallized as sintered masses and became undispersible at > or = 52% RH. Spray-dried mannitol was apparently 100% crystalline when collected directly from the spray-dryer; it did not show humidity-induced changes. The physicochemical behavior of each sugar form is discussed as it relates to the sugar's suitability as a powder-inhaler excipient, with both conventional and protein drugs.