SUMMARY

• Gene fusions are identified as oncogenic drivers in glioblastoma multiforme (GBM) and other primary central nervous system (CNS) tumors, including the fibroblast growth factor receptor (FGFR) family.¹
• RAGNAR (NCT04083976) is an ongoing, phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA in adult and pediatric patients with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), fibroblast growth factor receptor (FGFR) mutations or fusions, and documented disease progression.² For complete study details, refer to https://clinicaltrials.gov/study/NCT04083976.
  • Preliminary results of molecular eligibility screening for the RAGNAR study included 19% (21/110) of patients with high-grade glioma (HGG; FGFR3 fusion [95%] with FGFR3-TACC3 fusion as the most frequent variant) and 2% (2/110) of patients with low-grade glioma (LGG; FGFR1 mutation [100%] with FGFR1-K656E mutation as the most frequent variant).³
  • Pant et al (2023)⁴ reported primary analysis results after a median follow-up of 17.9 months from a primary cohort of patients (n=217) with 16 different solid tumor types in the RAGNAR study. For 30 patients with HGG, the objective response rate (ORR) assessed by independent review committee (IRC) was 10%. For 7 patients with LGG, the ORR was 29%. BALVERSA-related grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 46% (100/217) of patients. The most common grade ≥3 TEAEs were stomatitis (12%), palmar-plantar erythrodysesthesia (6%), and hyperphosphatemia (5%). Safety was not evaluated separately for patients with gliomas.
  • Reardon et al (2023)⁵ presented results of a subgroup analysis among patients with HGG or LGG with prespecified FGFR mutations enrolled in the broad panel cohort of the RAGNAR study (N=37). For patients with HGG (n=30) vs LGG (n=7), the IRC-assessed ORR was 10.0% vs 28.6%. The safety profile was consistent with the known safety profile of BALVERSA.
  • Witt et al (2024)⁶ presented efficacy and safety results from the pediatric cohort of the RAGNAR study (N=11), which included patients with LGG (n=6) and HGG (n=3) with FGFR mutations. One patient with HGG achieved partial response (PR) lasting 19.75 months. Stable disease (SD) was observed for ≥4 months in all patients with LGG and 1 patient with HGG. Adverse events unique to pediatric patients included growth disorders in 4 (36.4%) patients, such as limb fracture and epiphysiolysis.
  • Lugowska et al (2024)⁷ presented results from an exploratory cohort of patients with FGFR mutations that were not predefined as potentially susceptible alterations (N=53). Of the 53 patients, 3 (6%) had HGG. Efficacy and safety were not evaluated separately for patients with CNS tumors.
• Gong et al (2024)⁸ reported the primary efficacy analysis results of the NCI-MATCH (EAY131; NCT02465060) Subprotocol K2 study (EAY131-K2), a phase 2, open-label, single-arm study that evaluated the efficacy and safety of BALVERSA in patients with treatment-refractory solid tumors harboring FGFR1-4 mutations or FGFR1-3 fusions (N=35), including patients with brain tumors (n=7). Four patients with brain tumors and FGFR-alterations reported SD as their best confirmed response to BALVERSA. Two patients with brain tumors had SD and showed a decrease in lesion size from baseline. Safety was not evaluated separately for patients with brain tumor.
• Lee et al (2023)⁹ presented results of the NCI-COG MATCH (NCT03155620) Arm B study (APEC1621B), a phase 2, open-label, single-arm study that evaluated the efficacy and safety of BALVERSA in pediatric patients with tumors harboring predefined FGFR1-4 mutations (N=20), including 17 patients with glioma or glioneuronal tumor (high-grade, n=6; low-grade, n=11). Of these 17 patients, 2 patients with LGG/low-grade glioneuronal tumors had PR and 6 patients with gliomas had SD for a median of 6.5 cycles. Safety was not evaluated separately for patients with gliomas.
• Results of a phase 1 study¹⁰ (N=187), a preliminary efficacy analysis¹¹ (N=23), and case report studies^12-15 in patients with FGFR-mutated CNS tumors receiving BALVERSA have been published.
• In a preclinical study, BALVERSA inhibited growth of glioma cells harboring FGFR3‐TACC3 fusions in vitro and in vivo. A preliminary report of preclinical activity included 2 patients with glioma harboring this genetic alteration exhibiting SD and a minor response, respectively, when treated with BALVERSA.¹⁶
• No data regarding CNS or blood-brain barrier (BBB) penetration of BALVERSA were identified in published literature.
• No data regarding the use of BALVERSA in patients with urothelial carcinoma (UC) and baseline CNS metastases were identified in published literature.

CLINICAL DATA

Phase 2 - RAGNAR Subgroup Analysis in Patients With Glioma

Reardon et al (2023)⁵ presented results of a subgroup analysis in patients with HGG (n=30) or LGG (n=7) with prespecified FGFR mutations enrolled in the broad panel cohort of the RAGNAR study (NCT04083976; N=37).

Study Design/Methods

• This subgroup analysis of the ongoing phase 2, open-label, single-arm, global, multicenter RAGNAR study evaluated the efficacy and safety of BALVERSA in patients with HGG or LGG with prespecified FGFR1-4 mutations or fusions.
• Eligible patients had HGG/LGG with prespecified FGFR1-4 mutations/fusions, documented disease progression, had received ≥1 prior line of systemic therapy, and had exhausted standard therapy options.
• Patients received BALVERSA PO once daily on a 21-day cycle until disease progression or intolerable toxicity.⁴
  • Adults and adolescent patients (aged ≥15 to <18 years) were initiated with BALVERSA 8 mg with possible uptitration to 9 mg based on cycle 1 day 14 serum phosphate levels.
  • Adolescent patients (aged ≥12 to <15 years) were initiated with BALVERSA 5 mg with possible uptitration to 6 mg or further to 8 mg based on cycle 1 day 14 and cycle 2 day 7 serum phosphate levels.
• Efficacy for patients with primary brain tumors was assessed using Response Assessment in Neuro-Oncology (RANO).^4,5
  • Primary endpoint: IRC-assessed ORR.
  • Secondary endpoints: Investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and adverse events (AEs).

Results

Patient Characteristics

• Demographics and baseline characteristics of BALVERSA-treated patients with HGG or LGG are presented in Table: RAGNAR HGG/LGG Subgroup Analysis: Demographics and Baseline Characteristics.

Efficacy

• Efficacy outcomes for patients with HGG or LGG are summarized in Table: RAGNAR HGG/LGG Subgroup Analysis: Efficacy.

• Of the 30 patients with HGG, 29 patients had FGFR fusions. One patient with an FGFR2 mutation was a nonresponder. The most frequently co-altered genes were TERT (53.3%), CDKN2A (30%), and PTEN (30%).
• Of the 7 patients with LGG, 4 patients had FGFR1-K656E mutations (57%) and the remaining 3 patients had FGFR1-3 fusions (43%). The 4 patients with FGFR-K656E mutations had an ORR of 25%. The remaining 3 patients with FGFR1-3 fusions had an ORR of 33.3%. Among the patients with LGG, the following co-altered genes were observed: BRAF, CDKN2A, CDKN2B, KRAS, NF1, and PIK3CA (14.3% for each gene).

Safety

• Grade ≥3 treatment-related adverse events (TRAEs) were reported in 51.4% of patients. Overall safety outcomes from the RAGNAR subgroup analysis are summarized in Table: RAGNAR HGG/LGG Subgroup Analysis: Safety.
• Serious TRAEs were reported in 16.2% of patients.
• TRAEs leading to dose reductions were reported in 51.4% of patients, dose interruptions in 54.1%, and discontinuations in 16.2%.
• Central serous retinopathy events were reported in 6.7% (2/37) of patients.
• No deaths due to TRAEs were reported.
• The safety profile was consistent with the known safety profile of BALVERSA in patients with metastatic UC and in the overall RAGNAR primary analysis population.^4,17

Phase 2 Study - NCI-MATCH Subprotocol K2 Study

Gong et al (2024)⁸ reported the primary efficacy analysis results of the NCI-MATCH (EAY131; NCT02465060) Subprotocol K2 study (EAY131-K2; N=35).

Study Design/Methods

• This phase 2, open-label, single-arm study evaluated the efficacy and safety of BALVERSA PO QD in adult patients with treatment-refractory solid tumors harboring FGFR1-4 mutations or FGFR1-3 fusions.
• Eligible patients had any solid tumor except transitional cell carcinoma of the bladder and/or urothelial tract, lymphoma, or myeloma (progressing on standard treatment or for whom no standard treatment was available); predefined FGFR1-4 mutations or FGFR1-3 fusions, as determined by tumor profiling; and were FGFR inhibitor treatment-naïve.
  • Patients were initiated with BALVERSA 8 mg with possible uptitration to 9 mg based on cycle 1 day 15 serum phosphate levels and in the absence of significant toxicity.
• Efficacy was assessed using RECIST version 1.1 every 2 cycles (for the first 26 cycles) and then every 3 cycles thereafter (until disease progression).
  • Primary endpoint: ORR.
  • Key secondary endpoints: PFS, OS, and safety.

Results

Efficacy

• Of the 35 enrolled patients, 25 were considered evaluable for the primary efficacy analysis, including patients with brain tumors (n=7).
  • At the cutoff date of June 02, 2022, the ORR was 16% (4/25; 90% CI, 5.7-33.0).
  • Overall, 28% (7/25) of patients each had SD and progressive disease as the best confirmed response; 7 patients were unevaluable for response.
  • Of the 7 patients who reported SD as their best confirmed response to BALVERSA, 4 patients had FGFR-alterations and brain tumors.
• Of the 15 efficacy-evaluable patients assessed for change in lesion size, 2 patients with brain tumors had SD and showed a decrease in lesion size from baseline.
• The median OS was 11 months and the median PFS was 3.6 months.
  • Among patients with a PR or PFS >168 days who were not included in the primary analysis, 2 patients had glioblastoma and 1 patient had a dysembryoplastic neuroepithelial brain tumor.
    • One patient with glioblastoma (FGFR3 fusion) had a nonevaluable best response and PFS of 7.6 months.
    • The other patient with glioblastoma (FGFR3 fusion) had SD as the best response and PFS of 6.1 months.
    • The patient with dysembryoplastic neuroepithelial brain tumor (FGFR1 fusion) had SD as the best response and PFS of 33.1 months.

Safety

• Safety was not evaluated separately for patients with brain tumor.
• Of the 35 patients who received BALVERSA, 34 were assessed for safety.
  • The most common grade 1-2 TRAEs were dry mouth (18/34; 52.9%), diarrhea (17/34; 50.0%), fatigue (16/34; 47.1%), and anemia (11/34; 32.4%).
  • The most frequent grade 3 TRAEs were mucositis (5/34; 14.7%), followed by fatigue, anemia, nausea, paronychia, and palmar-plantar erythrodysesthesia syndrome (1/34; 2.9% each).
  • No grade 4-5 TRAEs were reported.
• AEs leading to discontinuation were reported in 16% (4/25) of patients. One discontinuation due to death was attributed to grade 5 disease progression deemed unrelated to BALVERSA treatment.
• Dose reductions were reported at 14 instances across 97 treatment cycles (14%).

Phase 2 Study - NCI-COG MATCH Arm B Study

Lee et al (2023)⁹ presented results of the NCI-COG MATCH (NCT03155620) Arm B study (APEC1621B; N=20).

Study Design/Methods

• This phase 2, open-label, single-arm study evaluated the efficacy and safety of BALVERSA in pediatric patients with solid tumors, lymphomas, and histiocytosis predefined FGFR1-4 mutations.¹⁸
• Eligible patients were aged <21 years and had solid tumors, lymphomas, or histocytes with predefined FGFR mutations.
  • Patients were initiated with BALVERSA 4.7 mg/m² PO QD (maximum dose: 8 mg) for 28-day cycles for up to 26 cycles, until disease progression or toxicity.
• Efficacy was assessed every 2-3 cycles.
  • Primary endpoint: ORR.
  • Key secondary endpoint: PFS.

Results

Efficacy

• Of the 20 enrolled patients evaluated for efficacy, 17 had glioma or glioneuronal tumor (high-grade, n=6; low-grade, n=11).
• PR and SD responses were reported among patients with LGG/low-grade glioneuronal or HGG/high-grade glioneuronal tumor harboring FGFR1 mutations.
  • PR was reported in 10% of patients (2/20; 90% CI, 3.4-26.2) with LGG/low-grade glioneuronal tumors.
  • SD for a median of 6.5 cycles was reported in 6 patients with gliomas.
• The 6-month PFS and OS were 45% (95% CI, 23.1-64.7) and 89.7% (95% CI, 64.8-97.3), respectively.

Safety

• Safety was not evaluated separately for patients with gliomas.
• TRAEs associated with FGFR inhibition included hyperphosphatemia and nail changes or infections.
• Other TRAEs included grade 1 vision changes; 1 case of grade 3 spinal cord compression and 1 case of grade 4 intracranial hemorrhage were reported.

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 16 June 2025.