BALVERSA Erdafitinib 4 mg Tablet, Film Coated, 28-count — NDC 59676-040-28 (Billing 59676-0040-28)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.

12.2Pharmacodynamics Cardiac Electrophysiology Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval. Serum Phosphate FGFR inhibition by BALVERSA increases serum phosphate level [see Dosage and Administration (2.3) and Drug Interactions (7.1) ].

12.3Pharmacokinetics Following administration of BALVERSA 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum plasma concentration (C max ), area under the curve (AUC tau ), and minimum plasma concentration (C min ) were 1,399 ng/mL (51%), 29,268 ng∙h/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeat once daily dosing of BALVERSA, erdafitinib exposure (C max and AUC) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose).

Steady state was achieved after 2 weeks with once daily dosing with a mean accumulation ratio was 4-fold. Absorption Median time to achieve peak plasma concentration (t max ) was 2.5 hours (range: 2 to 6 hours). Effect of Food No clinically meaningful differences in erdafitinib exposure was observed following administration of BALVERSA with a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat).

Distribution The mean apparent volume of distribution of erdafitinib was 29 L. Erdafitinib protein binding was 99.7% in patients, primarily to alpha-1-acid glycoprotein. Elimination The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h.

The mean effective half-life of erdafitinib was 59 hours. Metabolism Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20%, respectively.

Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites. Excretion Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged). Specific Populations No clinically meaningful effects on erdafitinib exposure were observed based on age (21–92 years), sex, race (White, Hispanic or Asian), body weight (36–166 kg), mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, or mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m²).

Limited data are available in patients with severe (Child-Pugh C) hepatic impairment and in patients with severe renal impairment. The pharmacokinetics of erdafitinib in patients with renal impairment requiring dialysis is unknown. Drug Interaction Studies Clinical Studies Effect of Other Drugs on Erdafitinib Moderate CYP2C9 Inhibitors Erdafitinib mean ratios for C max and AUC inf were 121% and 148%, respectively, when BALVERSA was co-administered with fluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, relative to BALVERSA administered alone.

Strong CYP3A4 Inhibitors Erdafitinib mean ratios for C max and AUC inf were 105% and 134%, respectively, when BALVERSA was co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to BALVERSA alone. CYP3A4/2C9 Inducers Erdafitinib mean ratios for C max and AUC inf were 78% and 45%, respectively, when BALVERSA was co-administered with carbamazepine (a strong CYP3… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.

12.3Pharmacokinetics Following administration of BALVERSA 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum plasma concentration (C max ), area under the curve (AUC tau ), and minimum plasma concentration (C min ) were 1,399 ng/mL (51%), 29,268 ng∙h/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeat once daily dosing of BALVERSA, erdafitinib exposure (C max and AUC) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose).

Steady state was achieved after 2 weeks with once daily dosing with a mean accumulation ratio was 4-fold. Absorption Median time to achieve peak plasma concentration (t max ) was 2.5 hours (range: 2 to 6 hours). Effect of Food No clinically meaningful differences in erdafitinib exposure was observed following administration of BALVERSA with a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat).

Distribution The mean apparent volume of distribution of erdafitinib was 29 L. Erdafitinib protein binding was 99.7% in patients, primarily to alpha-1-acid glycoprotein. Elimination The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h.

The mean effective half-life of erdafitinib was 59 hours. Metabolism Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20%, respectively.

Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites. Excretion Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged). Specific Populations No clinically meaningful effects on erdafitinib exposure were observed based on age (21–92 years), sex, race (White, Hispanic or Asian), body weight (36–166 kg), mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, or mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m²).

Limited data are available in patients with severe (Child-Pugh C) hepatic impairment and in patients with severe renal impairment. The pharmacokinetics of erdafitinib in patients with renal impairment requiring dialysis is unknown. Drug Interaction Studies Clinical Studies Effect of Other Drugs on Erdafitinib Moderate CYP2C9 Inhibitors Erdafitinib mean ratios for C max and AUC inf were 121% and 148%, respectively, when BALVERSA was co-administered with fluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, relative to BALVERSA administered alone.

Strong CYP3A4 Inhibitors Erdafitinib mean ratios for C max and AUC inf were 105% and 134%, respectively, when BALVERSA was co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to BALVERSA alone. CYP3A4/2C9 Inducers Erdafitinib mean ratios for C max and AUC inf were 78% and 45%, respectively, when BALVERSA was co-administered with carbamazepine (a strong CYP3A4 and weak CYP2C9 inducer) relative to BALVERSA alone. Effect of Erdafitinib on Other Drugs CYP3A4 Substrates: No clinically meaningful effect on the exposure of midazolam (a CYP3A4 substrate) was observed following coadministration with BALVERSA.

OCT2 Substrates : No clinically meaningful effect on the exposure of metformin (an OCT2 substrate) was observed following coadministration with BALVERSA. In Vitro Studies CYP Substrates Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.

Transporters Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2.

Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant conc… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval. Serum Phosphate FGFR inhibition by BALVERSA increases serum phosphate level [see Dosage and Administration (2.3) and Drug Interactions (7.1) ].

14 CLINICAL STUDIES

14.1Urothelial Carcinoma with Susceptible FGFR3 Genetic Alterations The efficacy of BALVERSA was evaluated in Study BLC3001 (NCT03390504) Cohort 1, a randomized, open-label, multicenter study in which 266 patients with advanced urothelial cancer harboring selected FGFR3 alterations were randomized 1:1 to receive BALVERSA (8 mg with titration up to 9 mg) versus chemotherapy (docetaxel 75 mg/m 2 once every 3 weeks or vinflunine 320 mg/m 2 once every 3 weeks) until unacceptable toxicity or progression. Randomization was stratified by region (North America vs.

Europe vs. rest of world), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2) and visceral or bone metastases (yes vs. no). All patients needed to have had disease progression after 1 or 2 prior treatments, at least 1 of which included a PD-1 or PD-L1 inhibitor.

FGFR3 genetic alterations were identified from tumor tissue in a central laboratory by the QIAGEN therascreen ® FGFR RGQ RT-Polymerase Chain Reaction (PCR) kit in 75% of patients while the remainder (25%) were identified by local next generation sequencing (NGS) assays. The major efficacy outcome measures were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) assessed by investigator using RECIST (Response Evaluation Criteria in Solid Tumors) Version 1.1. The median age was 67 years (range: 32 to 86 years) and 71% were male; 54% were White, 29% Asian, 0.4% Black, 0.4% multiple races, 16% not reported; 2% were Hispanic/Latino; and baseline ECOG performance status was 0 (43%), 1 (48%), or 2 (9%).

Eighty-one percent of patients had FGFR3 mutations, 17% had fusions, and 2% had both mutations and fusions. Ninety-five percent of patients had pure transitional cell carcinoma (TCC) and 5% had TCC with other histologic variants. The primary tumor location was the upper tract for 33% of subjects and lower tract for 67%; 74% of patients had visceral or bone metastases.

Eighty-eight percent of patients received platinum-containing chemotherapy previously. PD-1 or PD-L1 inhibitor therapy was received only in the neoadjuvant or adjuvant setting in 7% of patients. Statistically significant improvements in OS, PFS, and ORR were demonstrated for BALVERSA compared with chemotherapy.

Table 9 and Figures 1 and 2 summarize the efficacy results for BLC3001 Cohort 1. Table 9: Efficacy Results for Study BLC3001 Cohort 1 BALVERSA N=136 Chemotherapy N=130 All p-values reported are 2-sided and compared with 0.019 of the allocated alpha for the interim analysis. ORR = confirmed objective response (CR + PR) CI = Confidence Interval Overall Survival (OS) Number of events (%) 77 (56.6%) 78 (60.0%) Median Based on Kaplan-Meier estimates , months (95% CI) 12.1 (10.3, 16.4) 7.8 (6.5, 11.1) Hazard ratio Based on an unstratified Cox proportional hazard model (95% CI) 0.64 (0.47, 0.88) p-value Based on an unstratified log-rank test 0.0050 Progression-free survival (PFS) Number of events (%) 101 (74.3%) 90 (69.2%) Median , months (95% CI) 5.6 (4.4, 5.7) 2.7 (1.8, 3.7) Hazard ratio (95% CI) 0.58 (0.44, 0.78) p-value 0.0002 Objective response rate (ORR) ORR (95% CI) 35.3% (27.3, 43.9) 8.5% (4.3, 14.6) p-value p-value is estimated using Cochran-Haenszel (CMH) test with ECOG performance status (0 or 1 vs 2) as a stratification factor. <0.001 Complete response, CR (%) 5.1% 0.8% Partial response, PR (%) 30.1% 7.7% Figure 1: Kaplan-Meier Plot of Overall Survival (Study BLC3001 Cohort 1) Figure 2: Kaplan-Meier Plot of Progression-free Survival (Study BLC3001 Cohort 1) Figure 1 Figure 2 Study BLC3001 Cohort 2 Study BLC3001 (NCT03390504) Cohort 2 was a multicenter, open-label, randomized study in 351 patients with locally advanced or metastatic urothelial carcinoma with selected FGFR3 alterations who received 1 prior line of systemic therapy and no prior PD-1 or PD-L1 inhibitor.

Patients were randomized 1:1 to receive BALVERSA (8 mg with titration up to 9 mg) or pembrolizumab 200… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 in an 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 toxicity study, 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.