On April 12, 2019, erdafitinib was granted accelerated approval for patients with locally advanced or metastatic urothelial carcinoma with susceptible fibroblast growth factor receptor 3 (FGFR3) or FGFR2 genetic alterations, when the disease has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.^1,2

Patients should be selected for therapy based on a U.S. Food and Drug Administration (FDA)-approved companion diagnostic for erdafitinib. The FDA simultaneously approved the therascreen FGFR RGQ RT-PCR Kit for use as a companion diagnostic for this indication.

Supporting Efficacy Data

Approval was based on findings in a cohort of 87 patients enrolled in the multicenter single-arm BLC2001 study (ClinicalTrials.gov identifier NCT02365597).² Patients had locally advanced or metastatic urothelial carcinoma that had progressed on or after at least one prior chemotherapy regimen and had certain FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR2/FGFR3 gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7).

Patients received erdafitinib at a starting dose of 8 mg once daily with a dose increase to 9 mg daily in those with serum phosphate levels below the target of 5.5 mg/dL between days 14 and 17. Overall, the starting dose was increased to 9 mg daily in 41% of the patients. Erdafitinib was given until disease progression or unacceptable toxicity.

Patients had a median age of 67 years (range = 36–87 years), 79% were male, 74% were white, 92% had a baseline Eastern Cooperative Oncology Group performance status of 0 or 1, and 66% had visceral metastases. Prior anti–programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) therapy had been received by 24% of patients.

The objective response rate determined by blinded independent review committee by Response Evaluation Criteria in Solid Tumors, version 1.1, was 32.2% (95% confidence interval [CI] = 22.4%–42.0%), with a complete response in 2.3% of patients. Responses were observed in 44.6% of 64 patients with FGFR3 point mutations, 11.1% of 18 patients with FGFR3 fusions, and 0% of 6 patients with FGFR2 fusions.

The median duration of response was 5.4 months (95% CI = 4.2–6.9 months). Responders included patients who had previously not responded to anti–PD-L1 or anti–PD-1 treatment.

How It Works

Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3, and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2.

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.

How It Is Used

After patient selection based on an FDA-approved companion diagnostic, the recommended starting dose is 8 mg orally once daily, with a dose increase to 9 mg once daily based on serum phosphate levels and tolerability at 14 to 21 days. The dose can be increased to 9 mg once daily if the serum phosphate level is < 5.5 mg/dL and there are no ocular disorders or grade ≥ 2 adverse reactions at 14 to 21 days. Phosphate levels should be monitored monthly for hyperphosphatemia.

Recommended dose reductions for adverse reactions are carried out sequentially from 9 mg/d to 8 mg, 6 mg, 5 mg, and 4 mg daily or from 8 mg to 6 mg, 5 mg, and 4 mg daily. Treatment should be stopped if further dose reduction is required.

Product labeling provides specific dose-modification instructions for hyperphosphatemia, central serous retinopathy/retinal pigment epithelial detachment, and grade 3 or 4 adverse reactions. The package insert also provides specific instructions for

avoiding adverse drug interactions with the following agents: strong CYP2C9 or CYP3A4 inhibitors (eg, amiodarone, diltiazem; consider alternative agents or monitor closely for adverse reactions); strong CYP2C9 or CYP3A4 inducers (eg, carbamazepine, rifampin; avoid concomitant use with erdafitinib); moderate CYP2C9 or CYP3A4 inducers (eg, ritonavir, rifampicin; increase erdafitinib dose up to 9 mg); serum phosphate level–altering agents (eg, theophylline, acyclovir; avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period); CYP3A4 substrates (eg, clomipramine, atorvastatin; avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices); OCT2 substrates (eg, norepinephrine, prazosin; consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability); and P-gp substrates (eg, colchicine, digoxin; separate erdafitinib administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices).

Safety Profile

The most common adverse events of any grade in the BLC2001 study were increased phosphate levels, stomatitis, fatigue, increased creatinine levels, diarrhea, dry mouth, onycholysis, increased alanine aminotransferase, increased alkaline phosphatase levels, decreased sodium levels, decreased appetite, decreased albumin levels, dysgeusia, decreased hemoglobin levels, dry skin, decreased aspartate aminotransferase levels, and decreased magnesium levels. Grade 3 or 4 adverse events occurred in 67% of patients, with the most common being onycholysis, stomatitis, and palmar-plantar erythrodysesthesia syndrome. The most common grade 3 or 4 laboratory abnormalities were decreased sodium levels and decreased phosphate levels. Serious adverse events occurred in 41% of patients, including eye disorders in 10%. Adverse events led to dosage interruption in 68% of patients and dose reduction in 53% of patients. Adverse events led to treatment discontinuation in 13% of patients and to death in 1 patient.

Erdafitinib carries warnings/precautions for ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment; hyperphosphatemia; and embryofetal toxicity. Monthly ophthalmologic examinations should be performed during the first 4 months of treatment, every 3 months thereafter, and at any time for visual symptoms. Erdafitinib should be withheld if central serous retinopathy/retinal pigment epithelial detachment occurs and permanently discontinued if it does not resolve within 4 weeks or if it is grade 4 in severity.

Increases in phosphate levels are a pharmacodynamic effect of erdafitinib. Patients should be monitored for hyperphosphatemia and undergo dose modifications when required. Patients receiving erdafitinib therapy should be advised not to breastfeed. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm635910.htm. Accessed May 7, 2019.

2. Janssen Pharmaceuticals: Balversa (erdafitinib) tablets prescribing information, April 23, 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/212018s000lbl.pdf. Accessed May 7, 2019.