SUMMARY

• Hyperphosphatemia is an expected and transient laboratory abnormality during BALVERSA therapy due to renal tubular fibroblast growth factor receptor (FGFR) inhibition.¹
  • 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.^2-4
• Refer to the product labeling for monitoring and dose modifications for elevated phosphate levels.
• THOR (BLC3001/NCT03390504) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of BALVERSA vs chemotherapy (docetaxel or vinflunine) or pembrolizumab in patients with metastatic or unresectable urothelial carcinoma (UC) and selected FGFR gene alterations that has progressed during or after 1 or 2 prior lines of therapy.^5,6
  • In an analysis of results from cohort 1 (n=266), the safety profiles were reported to be consistent with the known safety profiles of BALVERSA and chemotherapy. In the safety population, any grade and grade ≥3 hyperphosphatemia was reported in 108 (80%) and 7 (5.2%) patients in the BALVERSA arm. No hyperphosphatemia events were reported in the chemotherapy arm.
• BLC2001 (NCT02365597) is a phase 2, open-label, multicenter study of BALVERSA in 99 patients with locally advanced and unresectable or metastatic UC and prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 fusion).^7,8
  • In the final analysis, the safety profile remained similar to that in the primary analysis, with no new safety signals reported with a longer follow-up. The most common TRAEs and treatment-emergent adverse events (TEAEs) included hyperphosphatemia (any grade), which was reported in 74.3% and 78% of patients treated with BALVERSA, respectively. No incidences of grade 4 or 5 treatment-related or treatment-emergent hyperphosphatemia were reported.
• Hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis, and vascular calcification has been observed in patients who have received BALVERSA as described in published case reports.^9-11
• Serum phosphate concentrations should be assessed between 14 and 21 days after initiating treatment with BALVERSA.¹
  • Uptitrate the dose to 9 mg daily as soon as possible if that serum phosphate concentration is <9.0 mg/dL, and there is no drug-related toxicity.
  • If the phosphate level is 9.0 mg/dL or higher, follow the relevant dose modifications within the product labeling. Phosphate concentrations should be monitored monthly.
• Interventions investigators in the BLC2001 study and THOR study were instructed to perform to manage elevated phosphate concentrations are provided in Table: Management of Elevated Phosphate Levels in the BLC2001 Study and Table: Management of Elevated Phosphate Levels in the THOR Study.^5,12
  • Dietary phosphate may require restriction in patients receiving BALVERSA.¹² In general, plant-based foods have lower phosphorous levels compared to processed foods and animal-based foods.¹³ Examples of high phosphorus foods include: dairy products, protein-rich foods, phosphorus food additives, and beverages such as dark colas, beer, and cocoa/chocolate drinks. Additional information on dietary phosphorus, including infographics and patient handouts, may be found at http://www.kidney.org/atoz/content/phosphorus.^14,15
  • Because many foods may contain significant amounts of phosphorus/phosphates, consulting a nutrition professional (eg, a registered dietician nutritionist [RDN]) for individualized dietary planning and education may be an important part of an interdisciplinary treatment plan.¹⁵
  • For persistently elevated phosphate concentrations, adding a non-calcium containing phosphate binder (eg, sevelamer carbonate) may be considered.¹²

CLINICAL Data

To provide the most relevant information, the summary below is limited to information from the pivotal phase 3 (THOR/BLC3001; cohort 1) and phase 2 (BLC2001) studies in patients with locally advanced or metastatic UC and selected FGFR gene alterations.

THOR Study

THOR is an ongoing study evaluating the efficacy and safety of BALVERSA vs standard of care chemotherapy (docetaxel or vinflunine) or pembrolizumab in patients with metastatic or unresectable UC and selected FGFR gene alterations that has progressed during or after  1 or 2 prior lines of therapy.^5,6

In cohort 1, 266 patients were randomized 1:1 to receive an uptitration regimen of BALVERSA 8 mg daily or chemotherapy (docetaxel 75 mg/m² intravenous [IV] every 3 weeks [Q3W] or vinflunine 320 mg/m² IV Q3W). Of all patients, 136 received BALVERSA 8 mg daily and 130 received chemotherapy (82 assigned to docetaxel and 48 assigned to vinflunine).^5,6

Cohort 1 Analysis

In cohort 1, after a median of 15.9 months follow-up for efficacy and median duration of BALVERSA exposure of 4.8 months (range, 0.2-38.2). The safety profiles in both arms were consistent with the known safety profiles of BALVERSA and chemotherapy.⁵

• Among 135 patients receiving BALVERSA who were evaluated for safety, the most frequent grade 3-4 TRAEs included hyperphosphatemia, which was reported in 7 (5.2%) patients.
• The incidence of treatment-related hyperphosphatemia in the safety population is summarized in the Table: THOR Cohort 1 Safety Population: Incidence of Hyperphosphatemia.

BLC2001 Study

BLC2001 is a multicenter, open-label phase 2 study evaluating the use of BALVERSA in 99 patients with locally advanced and unresectable or metastatic UC who had prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 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-CASP7.¹²

Final Analysis

In the final analysis, after a median of 24 months of follow-up for efficacy (interquartile range [IQR], 22.7-26.6) and median treatment duration of 5.4 months (IQR, 2.8-9), 101 patients were treated with an uptitration regimen of BALVERSA 8 mg daily (2 patients enrolled after the clinical cutoff date for the primary analysis). Overall, 60 patients received BALVERSA 8 mg daily and 41 were uptitrated to BALVERSA 9 mg daily.⁷

• The safety profile of BALVERSA remained consistent with that in the primary analysis.⁷
• No grade 4 adverse events (AEs) were considered related to BALVERSA, and no new TRAEs were observed with the longer follow-up.⁷
• No incidences of grade 4 or 5 treatment-related or treatment-emergent hyperphosphatemia were reported.^7,16
• The incidence of treatment-related hyperphosphatemia is summarized in the Table: BLC2001: Treatment-Related Hyperphosphatemia in the Final Analysis.
• Treatment-related hyperphosphatemia leading to treatment discontinuation was reported in 1 (1%) patient.¹⁶

• Grade 1-2 and grade 3 treatment-emergent hyperphosphatemia was reported in 77 (76%) and 2 (2%) patients, respectively.⁷
• The incidence of treatment-emergent hyperphosphatemia is summarized in the Table: BLC2001: Treatment-Emergent Hyperphosphatemia.
• Incidence of treatment-emergent hyperphosphatemia was higher among patients who received BALVERSA 8 mg daily (n=52 [87%]) compared with patients who were uptitrated to BALVERSA 9 mg daily (n=27 [66%]).⁷

management of elevated phosphate levels in the THOR study

Table: Management of Elevated Phosphate Levels in the THOR Study summarizes interventions that investigators in the THOR study were instructed to perform for the management of elevated phosphate levels.⁵ These interventions from the THOR study may not reflect current practice. Interventions should be based on patient presentation and the clinical judgment of the treating physician. Refer to the product labeling for monitoring and dose modifications for elevated phosphate levels.

management of elevated phosphate levels in the blc2001 study

Table: Management of Elevated Phosphate Levels in the BLC2001 Study summarizes interventions investigators in the BLC2001 study were instructed to perform for the management of elevated phosphate levels.¹² These interventions from the BLC2001 study may not reflect current practice. Interventions should be based on patient presentation and the clinical judgment of the treating physician. Refer to the product labeling for monitoring and dose modifications for elevated phosphate levels.

Management of Hyperphosphatemia During BLC2001 Study

• In the interim analysis of the BLC2001 study, hyperphosphatemia was managed by dose interruption (n=23), dose reduction (n=9), and treatment with phosphate binders which included sevelamer (n=26), sevelamer carbonate (n=5), and lanthanum carbonate, calcium carbonate, and calcium acetate (n=1 each). One patient discontinued BALVERSA due to hyperphosphatemia.¹⁷
• Phosphate binders were used prophylactically for 5 patients and for 29 patients following phosphate assessment during the study.¹⁷
• Median total duration of phosphate binder treatment was 81 days.¹⁷
• Use of the following drugs that increase serum phosphate levels were prohibited unless there were no alternatives: potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives.¹²

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 23 August 2024.