Debio1347, an Oral FGFR Inhibitor: Results From a Single-Center Study in Pediatric Patients With Recurrent or Refractory FGFR-Altered Gliomas

Gilheeney, Stephen W.; Bale, Tejus; Haque, Sofia; Dinkin, Marc; Vitolano, Stephanie; Rosenblum, Marc K.; Ibanez, Katarzyna; Prince, Daniel E.; Spatz, Krisoula; Dunkel, Ira J.; Karajannis, Matthias A.

doi:10.1200/po.20.00444

Cited by 23 publications

(28 citation statements)

References 22 publications

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“…Although two pediatric patients with gliomas have been previously reported in a case series of five patients to show a partial response to the FGFR inhibitor, Debio1347, these patients harbored well-characterized alterations including an oncogenic FGFR1 :: TACC1 fusion. 29 Our study is, to our knowledge, the first to report a pediatric patient with a predicted oncogenic novel FGFR1 fusion to benefit from targeted therapy. All of these pediatric patients were treated under single patient protocols or with off-label use, highlighting the need for clinical trials investigating FGFR inhibitors allowing for a more uniform evaluation of these compounds in pediatric malignancies.…”

Section: Discussionmentioning

confidence: 80%

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Vega

Comeau

Sallan

et al. 2022

JCO Precision Oncology

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PURPOSE Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations ( FGFR1-4) in pediatric cancers to inform future clinical trial design. METHODS Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed. RESULTS We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions ( FGFR3:: TACC3 [n = 3], FGFR1:: TACC1 [n = 1], FGFR1:: EBF2 [n = 1], FGFR1:: CLIP2 [n = 1], and FGFR2:: CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. CONCLUSION In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.

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Section: Discussionmentioning

confidence: 80%

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Vega

Comeau

Sallan

et al. 2022

JCO Precision Oncology

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“…We previously reported one patient who developed slipped capital femoral epiphyses (SCFE) on treatment with a selective FGFR1‐3 TKI, 2 but deemed this adverse event unrelated to study drug. With longer follow‐up in an expanded cohort of patients treated with different selective FGFR TKIs ( n = 7), we observed that all patients experienced a significant increase in linear growth velocity and two additional patients developed SCFE following 40 and 5 months, respectively, on treatment (see Figure 1).…”

Section: Figurementioning

confidence: 99%

“…With longer follow‐up in an expanded cohort of patients treated with different selective FGFR TKIs ( n = 7), we observed that all patients experienced a significant increase in linear growth velocity and two additional patients developed SCFE following 40 and 5 months, respectively, on treatment (see Figure 1). 2 Disease details and bony complications for all seven patients are provided in Table 1.…”

Section: Figurementioning

confidence: 99%

“…We previously reported one patient who developed slipped capital femoral epiphyses (SCFE) on treatment with a selective FGFR1-3 TKI, 2 but deemed this adverse event unrelated to study drug. With longer follow-up in an expanded cohort of patients treated with different Abbreviations: FGFR, fibroblast growth factor receptor; SCFE, slipped capital femoral epiphyses; TKI, tyrosine kinase inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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Slipped capital femoral epiphyses: A major on‐target adverse event associated with FGFR tyrosine kinase inhibitors in pediatric patients

Fischer

Antal

Spatz

et al. 2023

Pediatric Blood & Cancer

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Fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) are increasingly being used off label in pediatrics. Long-term safety data are limited, and serious toxicities unique to pediatrics may emerge. In a retrospective analysis of patients less than 18 years of age with recurrent/refractory FGFR altered gliomas treated with FGFR TKIs at MSKCC (n = 7), we observed slipped capital femoral epiphyses in three of seven patients along with increased linear growth velocity. Clinicians should closely

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“…First promising results on treatment with FGFR inhibition in young glioma patients have been published within the RAGNAR study 3 and on Debio1347. 4 Moreover, activation of FGFR signalling has been demonstrated in other high-risk paediatric brain tumour entities, such as ependymoma (EPN). 5,6 Erdafitinib (Balversa; erdafitinib [JNJ-42756493] was discovered in collaboration with Astex Pharmaceuticals) is a selective FGFR1-4 tyrosine kinase inhibitor that has been approved by the United States Food and Drug Administration (FDA) for the treatment of urothelial cancer harbouring FGFR2 or FGFR3 alterations.…”

Section: Introductionmentioning

confidence: 99%

Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients

Stepien,

Mayr,

Schmook

et al. 2024

Pediatric Blood & Cancer

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Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1–4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low‐grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1‐ITD‐harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation.

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Debio1347, an Oral FGFR Inhibitor: Results From a Single-Center Study in Pediatric Patients With Recurrent or Refractory FGFR-Altered Gliomas

Cited by 23 publications

References 22 publications

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Slipped capital femoral epiphyses: A major on‐target adverse event associated with FGFR tyrosine kinase inhibitors in pediatric patients

Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients

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