SUMMARY

• Hyperphosphatemia is an expected and transient laboratory abnormality during BALVERSA therapy resulting from increased phosphate reabsorption in the kidneys due to inhibition of fibroblast growth factor receptor (FGFR) in the proximal tubules.^2,4,8,9
• Increases in serum phosphate levels can serve as a pharmacodynamic marker of drug activity in early cycles of BALVERSA therapy.⁴
• Follow dosing and administration guidelines as described within product labeling.
• The recommended starting dose of BALVERSA is 8 mg orally once daily; with individualized uptitration, based on serum phosphate levels, to 9 mg daily if criteria are met.⁵
  • Serum phosphate levels should be assessed between 14 and 21 days after initiating treatment.
  • Uptitrate the dose to 9 mg daily if the serum phosphate level is <9.0 mg/dL, and there is no drug-related toxicity.
  • Phosphate levels should be monitored monthly.
• In the phase 2 BLC2001 study, achieving target serum phosphate levels ≥5.5 mg/dL in early cycles with continuous daily dosing of BALVERSA was associated with increased objective responses rates (ORR) and prolonged progression-free survival (PFS) and overall survival (OS) compared with serum phosphate levels <5.5 mg/dL. In patients with phosphate levels ≥5.5 mg/dL, the most common grade ≥3 treatment-emergent adverse events (TEAEs) except for hyperphosphatemia were skin events, nail events, and central serous retinopathy (CSR).⁶
• Hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, nonuremic calciphylaxis, and vascular calcification has been observed in patients who have received BALVERSA as described in published case reports.^10-12

BACKGROUND

Under normal physiological conditions, fibroblast growth factor 23 (FGF23) binds to the FGFR in the renal proximal tubule, inhibiting renal phosphate reabsorption. FGFR inhibition with erdafitinib blocks the inhibition of reabsorption, resulting in increased reabsorption of phosphate from the proximal tubules which leads to elevated serum phosphate levels.^2,8,9

Increases in phosphate levels during BALVERSA treatment are an expected and transient laboratory abnormality. Hyperphosphatemia can serve as a pharmacodynamic marker of drug activity in early cycles of BALVERSA therapy.⁴

In a phase 1 dose-escalation study¹³ evaluating BALVERSA in patients with advanced solid tumors, dose-dependent elevations in serum phosphate were observed in all patients starting at 4 mg daily. Data from this phase 1 study in conjunction with pharmacokinetic-pharmacodynamic modeling indicated that an increase in serum phosphate of at least 35% over baseline level correlated with the best antitumor response relative to safety. Given the median phosphate level of 3.6 mg/dL at baseline in the phase 1 study, investigators estimated that an increase of ≥50% would correspond to a target absolute phosphate level of approximately 5.5 mg/dL (which is also 35% over the phosphate upper limit of normal). Therefore, a pharmacodynamic objective to reach a serum phosphate threshold of ≥5.5 mg/dL was established in the context of acceptable safety.⁴

The observed increases in serum phosphate were dose- and exposure-dependent peaked after about 14 days of treatment (prior to uptitration),⁴ which represents the approximate time to reach steady state concentrations of erdafitinib.⁵ Phosphate levels appear to normalize in most patients after 3 to 4 cycles of treatment⁴ which is thought to be due, in part, to a number of compensatory physiological mechanisms in response to elevated phosphate levels.¹⁴

BLC2001 Study

BLC2001^7,15 is a phase 2 multicenter, open-label study evaluating the use of BALVERSA in 99 patients with locally advanced and unresectable or metastatic urothelial carcinoma (UC) who had prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/FGFR3 fusion) and who had progressed during or following ≥1 line of prior systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy (n=87), or were chemotherapy -naïve due to cisplatin ineligibility (n=12). Patients had tumor tissues with 1 of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C OR 1 of the following FGFR gene fusions: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7.¹⁶ The efficacy and safety analyses were described in patients who received an initial BALVERSA dose of 8 mg once daily, with uptitration to 9 mg once daily if serum phosphate levels assessed by day 14 were below the target of 5.5 mg/dL and there were no treatment-related adverse events.

On cycle 1 day 14, 35% of patients had phosphate levels ≥5.5 mg/dL which subsequently increased to 61% on cycle 1 day 28. Response to BALVERSA according to serum phosphate levels obtained within the first 3 months of treatment are shown in the table below. ORR per investigator assessment, the primary endpoint, complete response rate, and disease control rate were higher among patients with serum phosphate obtained within first 3 months of treatment of ≥5.5 mg/dL compared with patients with serum phosphate <5.5 mg/dL.⁶

Among patients who had phosphate levels <5.5 mg/dL and uptitrated to 9 mg on cycle 1 day 14, the ORR was 48.8% (n=20) versus 22.2% (n=2) among patients who did not uptitrate due to adverse events.⁶

Median PFS and OS were prolonged in patients with serum phosphate levels ≥5.5 mg/dL compared with patients with serum phosphate <5.5 mg/dL as shown in the table below.

In patients with phosphate levels ≥5.5 mg/dL, the most common grade ≥3 TEAEs, except for hyperphosphatemia, were skin events, nail events, and CSR. A summary of the grade ≥3 TEAEs are shown in the table below. One patient experienced a grade 5 loss of consciousness; however, it was determined to be unrelated to BALVERSA treatment.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DERWENT Drug File(and/or other resources, including internal/external databases) was conducted on 02 April 2025.