e CYP2C9*2 and CYP2C9*3polymorphisms. Erdafitinib exposure was similar in subjects with CYP2C9*1/*2 and *1/*3 genotypesrelative to subjects with CYP2C9*1/*1 genotype (wild type). No data are available in subjectscharacterized by other genotypes (e.g., *2/*2, *2/*3, *3/*3). Simulation suggested no clinically
meaningful differences in erdafitinib exposure in subjects with CYP2C9*2/*2 and *2/*3 genotypes. The
exposure of erdafitinib is predicted to be 50% higher in subjects with the CYP2C9*3/*3 genotype,estimated to be present in 0.4% to 3% of the population among various ethnic groups.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenicity studies have not been conducted with erdafitinib.
Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic inan in vitro micronucleus or an in vivo rat bone marrow micronucleus assay.
Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicitystudy, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea)in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose.
14 CLINICAL STUDIES
14.1 Urothelial Carcinoma with Susceptible FGFR Genetic Alterations
Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to eva luate theefficacy and safety of BALVERSA in patients with locally advanced or metastatic urothelial carcinoma(mUC). Fibroblast growth factor receptor (FGFR) mutation status for screening and enrollment ofpatients was determined by a clinical trial assay (CTA). The efficacy population consists of a cohort ofeighty-seven patients who were enrolled in this study with disease that had progressed on or after at leastone prior chemotherapy and that had at least 1 of the following genetic alterations: FGFR3 genemutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as determined by the CTA performed at a central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN therascreen®
FGFR RGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC forBALVERSA.
Patients received a starting dose of BALVERSA at 8 mg once daily with a dose increase to 9 mg oncedaily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and17; a dose increase occurred in 41% of patients. BALVERSA was administered until diseaseprogression or unacceptable toxicity. The major efficacy outcome measures were objective response rate(ORR) and duration of response (DoR), as determined by blinded independent review committee
(BIRC) according to RECIST v1.1.
The median age was 67 years (range: 36 to 87 years), 79% were male, and 74% were Caucasian. Mostpatients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or1. Sixty-six percent of patients had visceral metastases. Eighty-four (97%) patients received at least oneof cisplatin or carboplatin previously. Fifty-six percent of patients only received prior cisplatin-basedregimens, 29% received only prior carboplatin-based regimens, and 10% received both cisplatin andcarboplatin-based regimens. Three (3%) patients had disease progression following prior platinumcontainingneoadjuvant or adjuvant therapy only. Twen |
