SUMMARY

• Pediatric cancers in which fibroblast growth factor receptor (FGFR) mutations and fusions were most commonly observed were reported from an analysis of the Foundation Medicine genomic database (Foundation Insights^TM) as summarized in Table: Pediatric Cancers With FGFR Mutations and Fusions.¹
• RAGNAR (NCT04083976) is evaluating the efficacy, safety, and pharmacokinetics of BALVERSA in adult and pediatric patients (children ≥6 to <18 years) with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), FGFR mutations, gene fusions, or internal tandem duplications and documented disease progression. Patients must have received ≥1 prior line of systemic therapy in the advanced, unresectable, or metastatic setting; or be a child/adolescent with a newly-diagnosed solid tumor and no acceptable standard therapies. Investigator-assessed objective response rate (ORR) was 9.1% (95% confidence interval [CI], 0.2-41.3), disease control rate (DCR) was 72.7% (95% CI, 39.0-94.0), and median progression-free survival (PFS) was 29.47 months. All BALVERSA-treated patients had ≥1 treatment-emergent adverse event (TEAE). Adverse events unique to pediatric patients included growth disorders (36.4%).^1-4
• Lee et al (2023)⁵ presented results from the National Cancer Institute (NCI)-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial arm B (N=20). The NCI-COG Pediatric MATCH trial assigned patients aged 1-21 years with relapsed or refractory solid tumors, central nervous system (CNS) tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based off the tumors genetic alterations. Arm B (APEC1621B) evaluated BALVERSA in patients whose tumors had FGFR1/2/3/4 alterations. In the BALVERSA treatment arm, partial responses (PR) were observed in 2 patients (10%, 90% CI, 3.4%, 26.2%), and stable disease (SD) was observed in 6 patients with gliomas (median duration of SD 6.5 cycles). Six-month PFS was 45% (95% CI, 23.1%, 64.7%), and 6-month overall survival (OS) was 89.7% (95% CI, 64.8%, 97.3%). Treatment related adverse events (TRAEs) included those previously reported with FGFR inhibitors including hyperphosphatemia and nail changes or infections.
• Case reports have described the use of BALVERSA in pediatric patients diagnosed with recurrent or progressive FGFR-mutated CNS tumors, pilomyxoid astrocytoma with leptomeningeal dissemination, and low-grade astrocytoma of the optic pathway and hypothalamus.^6-8 
• For information on ongoing clinical trials investigating the use of BALVERSA in pediatric patients, please visit www.clinicaltrials.gov.

Clinical data

Witt et al (2024)⁴ reported efficacy and safety results from the pediatric cohort of the RAGNAR study (N=11).

Study Design

• Phase 2, open-label, single-arm, multicenter study
• The pediatric cohort is recruiting patients with advanced solid tumors and brain tumors (planned n=26), including 20 previously treated patients and 6 newly-diagnosed patients with no standard of care therapies available.
• Pediatric key eligibility criteria^1,4:
  • Age ≥6 to <18 years with measurable disease and histologic demonstration of unresectable, locally advanced, or metastatic solid tumor malignancy
  • FGFR mutations, gene fusions, or internal tandem duplications identified by local test reports or central molecular testing with next-generation sequencing or the Qiagen therascreen FGFR assay.
  • Have had ≥1 prior systemic therapy and have exhausted or are unable to tolerate standard of care therapies; or are newly diagnosed with no standard therapies.
  • Documented disease progression, defined as any progression that requires a change in treatment prior to full study screening.
• Patients received oral BALVERSA for 21 days in a continuous 21-day cycle until disease progression.
  • For patients aged 15 to <18 years, the starting dose was 8 mg once daily, which could be uptitrated to 9 mg once daily based on cycle 1 day 14 (C1 D14) serum phosphate concentrations.
  • For patients aged 12 to <15 years, the starting dose was 5 mg once daily, which could be uptitrated to 6/8 mg once daily based on C1 D14 and C2 D7 serum phosphate concentrations.
  • For patients aged 6 to <12 years, the starting dose was 3 mg once daily, which could be uptitrated to 4/5 mg once daily based on C1 D14 and C2 D7 serum phosphate concentrations.
• Primary endpoint: ORR per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) criteria
• Secondary endpoints: duration of response (DOR), DCR, clinical benefit rate, PFS, OS, and safety

Results

Patient Characteristics

Efficacy

• Efficacy was evaluated at a data cutoff of December 4, 2023, with a median follow-up of 9.7 months.
• Investigator-assessed ORR was 9.1% (1/11; 95% CI, 0.2-41.3), DCR was 72.7% (8/11; 95%CI, 39.0-94.0), median DOR was 19.75 months, and median PFS was 29.47 months.
• In all 6 patients with low-grade glioma (LGG) and in 1 patient with high-grade glioma, durable SD was observed for ≥4 months.
• Tumor response or durable SD was observed in patients with FGFR mutations and fusions.
  • One 13-year-old patient with anaplastic pilocytic astrocytoma and FGFR1-TACC1 fusion reported a PR of 19.5 months after 6 cycles of BALVERSA from August 9, 2020 to February 17, 2021.
  • Durable SD lasting ≥4 months was reported in 3 patients with FGFR1 mutations, 2 patients with FGFR1 fusions, 1 patient with FGFR2 fusion, and 1 patient with FGFR1 duplication.
• In the OS analysis, 9 (81.8%) patients were censured and 2 (18.2%) patients died.

Safety

• All BALVERSA-treated patients had ≥1 TEAE (Table: Summary of TEAEs).
  • Grade ≥3 TEAEs were reported in 8 (72.7%) patients, of which 5 (45.5%) cases were considered treatment-related.
  • Serious TEAEs were reported in 8 (72.7%) patients, of which 4 (36.4%) cases were considered treatment-related (tibia fracture, dehydration, epiphysiolysis, and peripheral neuropathy).
  • Most TEAEs were managed with dose modification and symptomatic or conservative management.
• Adverse events unique to pediatric patients included growth disorders in 4 (36.4%) patients including limb fracture (n=4). Additionally, one patient reported grade 3 epiphysiolysis.
• No central serous retinopathy events were reported.
• No treatment-related deaths were reported.

Lee et al (2023)⁵ reported results from the NCI-COG Pediatric MATCH trial arm B (N=20).

Study Design^5,9

• Single arm study with patients receiving BALVERSA 4.7 mg/m²/dose (max dose: 8 mg) once daily for 28-day cycles. Treatment repeats every 28 days until disease progression or drug related dose limiting toxicity (max 26 cycles).
  • Dose and schedule aligned with adult recommended phase 2 dose (adjusted for body surface area)
• May receive up to 2 years of treatment on study.
• Patients undergo an x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography scan, radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study.
• Primary endpoint: ORR
• Secondary endpoint: PFS, tolerability, pharmacokinetics

Results

Patient Characteristics

Efficacy

• PRs were confirmed by central review in 2/20 patients (10%, 90% CI, 3.4%, 26.2%), both with LGGs or low-grade glioneuronal tumors (LGGNTs) and FGFR1 hotspot mutations (K687E and N577K).
• SD was observed in 6 additional patients with gliomas.
  • Median duration of SD was 6.5 cycles.
• Six-month PFS was 45% (95% CI, 23.1-64.7), and 6-month OS was 89.7% (95% CI, 64.8-97.3).

Safety

• TRAEs included those previously reported with FGFR inhibitors including hyperphosphatemia and nail changes or infections.
  • Grade 1 vision changes were reported.
  • Grade 3 spinal cord compression was reported.
  • Grade 4 intracranial hemorrhage was reported.

CASE REPORTS

Stepien et al (2024)⁶ described the use of BALVERSA in 3 pediatric patients diagnosed with recurrent or progressive FGFR-mutated CNS tumors through a compassionate use program in an Austrian hospital. Patient 1 was female and Patients 2 and 3 were male.

• Patient 1 and Patient 2 were diagnosed with high-risk posterior fossa A ependymoma at ages 5 and 9 years, respectively. Patient 1 and Patient 2 showed FGFR3 and FGFR1 overexpression and were initiated on BALVERSA at ages 10 and 12 years as a fourth- and sixth-line treatment for refractory tumors, respectively. Both patients did not respond to BALVERSA treatment.
  • In Patient 1, treatment was discontinued due to side effects (leg pain, dry skin, dysgeusia, brittle nails, diarrhea, abdominal pain) and lack of response after 4 months. Notable past medical history included renal phosphate loss requiring oral substitution, which could be discontinued after the initiation of BALVERSA treatment.
  • In Patient 2, treatment with BALVERSA was started at a late stage of the disease and was discontinued after 2 weeks based on deterioration of the patients’ clinical condition, excluding this patient from objective response evaluation.
    • A CT scan performed a few days later showed intratumoral bleeding, which was attributed to tumor progression and not to treatment with BALVERSA.
• Patient 3 was diagnosed at the age of 5 years with a pediatric LGG, not otherwise specified grade II-III according to the World Health Organization classification 2016, located in the mesencephalic region.
  • Previous treatment history and strategy included first-line treatment with irradiation and temozolomide and active surveillance. Based on tumor progression, metastases, and the presence of FGFR1-internal tandem duplication (ITD), treatment with BALVERSA was initiated (patient age, 13 years). After 3 months of therapy with BALVERSA, a reduction in tumor volume and contrast enhancement were observed. Following treatment initiation, the patient experienced pain in the lower extremities, diarrhea, and dystrophic nail changes, resulting in a pause in treatment (Days 11-23), followed by a dose reduction of BALVERSA from 5 mg/day to 4 mg/day, thus leading to better clinical tolerability.
  • Treatment with BALVERSA was subsequently discontinued after 6.5 months, based on a reported hormone-independent growth spurt in conjunction with massive dystrophic nail changes, with stabilization of tumor size reported as ongoing for 6 months after the discontinuation of BALVERSA.

Majlessipour et al (2024)⁷ described the use of BALVERSA in a male pediatric patient, diagnosed at 9 years of age with pilomyxoid astrocytoma with leptomeningeal dissemination.

• The patient underwent chemotherapy with partial response at initial diagnosis and time of first progression.
• At the time of second progression and at age 14, he had an open biopsy for next-generation gene sequencing which identified an FGFR1 activating variant, confirming diagnosis of a rosette-forming glioneuronal tumor.
• The patient was enrolled in the NCI-COG Pediatric MATCH trial and was initiated on BALVERSA treatment at the age of 15 years and 4 months at a dose of 7 mg/day.
• Despite significant tumor response (~80% reduction in volume), treatment with BALVERSA was discontinued after 9 months due to severe adverse effects, including accelerated linear growth (14.3 cm or annualized rate: 19.06 cm/year; normal: 10 cm/year for 15-year-old male), kyphoscoliosis, and spinal cord compression with cervical myelopathy.
• X-ray and MRI imaging confirmed skeletal deformities of the cervical, thoracic and lumbar spine after 9 months of BALVERSA treatment (cervical lordosis and thoracic scoliosis). The patient also developed hip flexor contractures not visualized on imaging, which resulted in an underestimation of height measurements.
• Following the discontinuation of BALVERSA, dual-energy X-ray absorptiometry (DEXA) scan confirmed osteoporosis (mean bone density for the lumbar spine, 0.6322 gm/cm²; 3.8 standard deviations below the mean value of the age-matched population). Since a baseline DEXA scan was not performed prior to BALVESRA therapy, it remains unclear if the osteoporosis was due to BALVERSA therapy or not.
  • At the discontinuation of BALVERSA treatment and patient age of 16.2 years, bone age was determined to be 14 years. More than 15 months after the discontinuation of BALVERSA treatment, bone age remained 2 years behind the patient age.

Brizini et al (2024)⁸ described the use of BALVERSA in a 13-year-old male pediatric patient diagnosed with a low-grade astrocytoma (WHO, Grade 1) of the optic pathway and hypothalamus, harboring an FGFR1 tyrosine kinase domain ITD.

• The patient developed hypothalamic obesity due to the location of the tumor and the perilesional edema involving the hypothalamus at presentation, clinically manifested by an insatiable appetite and accelerated rate of weight gain (82.1 kg; >97^th percentile for age and sex).
• After a 4-month delay from the initial diagnosis, the patient was initiated on BALVERSA therapy at 4.7 mg/m²/day.
• After 4 weeks of BALVERSA therapy, the patient developed nail side effects (discoloration and brittleness) and hyperphosphatemia requiring chelation. BALVERSA was discontinued for a week and restarted as per protocol.
• At approximately 7 weeks of BALVERSA therapy, the patient experienced intermittent pain in his right leg, which resulted in complete cessation of ambulation.
• At approximately 12 weeks of treatment, the persistent knee pain was suspected to be due to a slipped capital femoral epiphysis of the right hip.
• BALVERSA was discontinued, and the patient underwent surgery with in situ pinning of the right hip and prophylactic pinning of the left hip.
• Brain MRI at the time of treatment discontinuation showed a 30% reduction in tumor size, which remained stable at two subsequent follow-up MRIs.

Additional information

Witt et al (2022)¹ described pediatric cancers in which FGFR mutations and fusions were most commonly observed from an analysis of the Foundation Medicine genomic database (Foundation Insights^TM).

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 09 May 2025.