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)-Childrens 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.
• 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 daily (QD), which could be uptitrated to 9 mg QD based on cycle 1 day 14 (C1 D14) serum phosphate concentrations.
  • For patients aged 12 to <15 years, the starting dose was 5 mg QD, which could be uptitrated to 6/8 mg QD based on C1 D14 and C2 D7 serum phosphate concentrations.
  • For patients aged 6 to <12 years, the starting dose was 3 mg QD, which could be uptitrated to 4/5 mg QD 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 (CBR), 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 LGG and in 1 patient with HGG, 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^5,6

• Single arm study with patients receiving BALVERSA 4.7 mg/m²/dose (max dose: 8 mg) 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 (PET) 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 low-grade gliomas or low-grade glioneuronal tumors (LGG, LGGNT) and FGFR1 hotspot mutations (K687E and N577K).
• SD was observed in 6 additional patients with gliomas.
  • Median duration of stable disease 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.

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 27 May 2024.