(P 239) FGFR IS A RELEVANT MOLECULAR TARGET IN PEDIATRIC AND AYA SARCOMAS

Objective: Oncogenic FGFR alterations in the form of activating mutations, amplifications, and fusions are detected in a variety of solid tumors, including those in children. Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. Since there is a need to identify and characterize molecular targets including oncogenic FGFR alterations in pediatric sarcomas so that drug development can occur in accordance with the RACE (Research to Accelerate Cures and Equity) for Children Act, we determined the types and frequency of FGFR alterations (FGFR1-4) in pediatric sarcomas to inform future clinical trial design.

Methods: Sarcomas 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 sarcoma cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed.

Results: We identified 18 patients with sarcomas harboring an activating FGFR alteration (FGFR1 in 8; FGFR2 in 1; FGFR4 in 9). Median age at diagnosis was 7.5 years (range 9 months-26 years old). Diagnoses included 6 embryonal rhabdomyosarcomas (RMS), 3 alveolar RMS, 2 RMS (NOS), 2 Ewing sarcomas, 2 osteosarcomas, DICER-1 associated sarcoma, spindle cell sarcoma, and malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation. We identified 7 patients with a gain-of-function mutation, 9 patients with amplifications (copy number>=7), a patient with an FGFR1::EBF2 fusion, and a patient with an amplification and VUS. Tumors with an FGFR missense mutation were primarily those with oncogenic hotspot mutations in FGFR4 [N535K/D (n=2); V550L/E (n=4)]. Recurrent co-occurring oncogenic alterations included MYC/MYCN amplifications (CN>=7) and TP53 inactivating alterations. Of interest, the RAS pathway was activated through HRAS/NRAS/KRAS alterations, including a KRAS G12V/S variant, or NF1/2 inactivation in a subset of tumors. Activation of oncogenes (PIK3CA, MDM2/4), inactivation of tumor suppressors (ATRX), and cell cycle dysregulation (CDK4, CDKN2A/B, CCND1/3) were also observed. Additional alterations with diagnostic implications included three PAX3::FOXO1 fusions in alveolar RMS, EWSR1::FLI1 fusion in a Ewing sarcoma, and DICER1 truncating alteration in a DICER1-associated sarcoma.
A 9-month-old patient diagnosed with an FGFR1 fusion positive spindle cell sarcoma responded to erdafitinib after progression on lenvatinib. Cycle 1 of erdafitinib was complicated by hyperphosphatemia requiring a dose interruption, initiation of sevelamer, and a low phosphorus diet. After 12 weeks of erdafitinib (with two 7-day interruptions for hyperphosphatemia) the thigh mass was no longer tender to palpation, he started walking and imaging showed reduction in size.

Conclusion: In summary, activating FGFR alterations were found in 18 pediatric sarcomas sequenced through the Profile and GAIN/iCAT2 studies, 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 RACE for Children Act.