SUMMARY

• Treatment-related hyperphosphatemia is observed as a class effect of selective fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors.^1,2
• Under normal physiological conditions, fibroblast growth factor 23 (FGF23) binds to FGFR in the renal proximal tubule, inhibiting renal phosphate reabsorption.^3,4
  • 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.^3-5
  • Blocking of sodium-dependent phosphate cotransporter may also decrease sodium reabsorption, leading to hyponatremia.⁶
• 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 select FGFR alterations who had disease progression during or after 1 or 2 prior lines of therapy.⁷
  • In an analysis of results from cohort 1 (n=266), the safety profiles were consistent with the known safety profiles of BALVERSA and chemotherapy. In the safety population, hyponatremia was reported as a serious adverse event (SAE). Any-grade and grade ≥3 hyponatremia, respectively, were reported in 3 (2.2%) and 3 (2.2%) patients in the BALVERSA arm and 1 (0.9%) and 1 (0.9%) patients in the chemotherapy arm.⁸
• BLC2001 (NCT02365597) is an ongoing, phase 2, open-label, multicenter study of BALVERSA in patients with locally advanced and unresectable or metastatic UC and prespecified FGFR alterations (FGFR3 mutation or FGFR2/3 fusion).^1,9
  • In the final analysis (n=101), 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 grade 3-4 treatment-emergent adverse events (TEAEs) included hyponatremia (11%).⁹
• Follow dose modification guidelines for adverse reactions within product labeling.

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 select FGFR alterations.

THOR Study

THOR 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 UC and select FGFR alterations who had disease progression during or after 1 or 2 prior lines of therapy.⁷

In cohort 1, 266 patients were randomized 1:1 to receive an uptitration regimen of BALVERSA 8 mg once daily or chemotherapy (docetaxel 75 mg/m² intravenous [IV] every 3 weeks [Q3W] or vinflunine 320 mg/m² IV Q3W).⁷

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), 136 patients received BALVERSA 8 mg once daily. The safety profiles in both arms were consistent with the known safety profiles of BALVERSA and chemotherapy.⁷

• The incidence of hyponatremia is summarized in Table: THOR: Incidence of Hyponatremia.

BLC2001 Study

BLC2001 is an ongoing, phase 2, open-label, multicenter study evaluating the use of BALVERSA in patients with locally advanced and unresectable or metastatic UC who had prespecified FGFR alterations (FGFR3 mutation or FGFR2/3 fusion) and disease progression during or following ≥1 line of prior systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy, or were chemotherapy-naïve due to cisplatin ineligibility. Patients had tumor tissues with one of the following FGFR3 gene mutations: R248C, S249C, G370C, and Y373C, or one of the following FGFR fusions: FGFR3TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, and FGFR2-CASP7.¹

Final Analysis

In the final analysis, after a median of 24 months 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 once daily (2 patients enrolled after the clinical cutoff date for the primary analysis).⁹

• The safety profile of BALVERSA remained consistent with that of the primary analysis.
• No grade 4 adverse events (AEs) were considered related to BALVERSA, and no new treatment-related AEs were observed with the longer follow-up. Overall, grade 3-4 TEAEs were reported in 72 (71%) patients, with the most common being hyponatremia, occurring in 11 (11%) patients.

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 October 2024.