Erdafitinib Shows Promising Early Efficacy and Manageable Safety Profile in FGFR-TACC Fusion-Positive Glioma
核心洞察
Erdafitinib demonstrated a predictable safety profile with 8 mg daily identified as the recommended phase 2 dose in patients with recurrent IDH wild-type glioma (搜索) harboring FGFR-TACC (搜索) gene fusions.
Preliminary efficacy data from 5 patients showed encouraging responses including one complete response, two partial responses, and one stable disease case.
The study represents the first clinical trial focused specifically on examining erdafitinib activity in gliomas with F3T3 (搜索) fusions, targeting a genetic alteration present in 3-6% of adult IDH wild-type gliomas.
Erdafitinib (Balversa) demonstrated a predictable toxicity profile and showed early efficacy signals in patients with recurrent or progressive IDH wild-type glioma (搜索) harboring FGFR-TACC (搜索) (F3T3 (搜索)) gene fusions, according to findings from the safety run-in cohort of the phase 2 ETCTN 10559 trial presented at the 2025 Society for Neuro-Oncology Annual Meeting.
The safety run-in cohort completed therapy in October 2024, establishing 8 mg daily continuous dosing as the recommended phase 2 dose (RP2D) of erdafitinib. Only one patient experienced a dose-limiting toxicity (DLT), which was grade 3 central serous retinopathy—the sole grade 3 treatment-emergent adverse effect reported and the only adverse event leading to erdafitinib discontinuation.
Safety Profile Confirms Expected Tolerability
All patients experienced treatment-emergent adverse effects during the DLT period of cycle 1, but no events were grade 4 or higher. Grade 2 adverse effects included dyspepsia (n = 2), hyperphosphatemia (n = 1), and hyponatremia (n = 1). Grade 1 hyperphosphatemia was commonly observed (n = 4). Notably, no adverse events led to erdafitinib dose reductions or treatment interruptions. One patient experienced grade 3 cerebral edema that was deemed unrelated to treatment.
"The safety profile of erdafitinib within gliomas is within [the] expected known safety profile [of the agent] in other tumor types, and we were able to identify durable responses in this population," stated lead study author Macarena de la Fuente, MD, associate professor of neuro-oncology and chief of the Neuro-Oncology Division at the University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center (搜索).
Early Efficacy Signals Show Promise
Preliminary efficacy data were available for 5 patients, revealing best overall responses of complete response (n = 1), partial response (n = 2), stable disease (n = 1), and progressive disease (n = 1). The agent generated durable responses in this analysis, marking an important milestone for this patient population.
Case Study Highlights
Two detailed case studies from the safety run-in cohort illustrated the potential of erdafitinib in this setting. The first involved a 60-year-old woman with recurrent WHO grade 4 F3T3 (搜索) fusion-positive glioblastoma (搜索) who underwent biopsy, received radiotherapy plus temozolomide, followed by 6 cycles of adjuvant temozolomide. At 15 months from initial diagnosis, she presented with clinical and radiographic disease progression. After enrolling in ETCTN 10559 in April 2024, she completed over 19 cycles of therapy with treatment ongoing, achieving a partial response at cycle 1 and a complete response at cycle 13.
The second case study featured a 68-year-old man with IDH wild-type, F3T3 (搜索) fusion-positive, WHO grade 4 glioblastoma (搜索) that was MGMT promoter unmethylated. Following subtotal resection of a right parieto-temporal mass, he received 3 weeks of hypofractionated radiotherapy with concurrent temozolomide, followed by 4 cycles of adjuvant temozolomide. He enrolled in ETCTN 10559 in October 2024 and achieved a partial response at cycle 8.
Targeting a Critical Genetic Alteration
The investigation of erdafitinib was based on the prevalence and significance of F3T3 (搜索) gene fusions, which represent the most common gene fusions in adult glioma (搜索), present in approximately 3% to 6% of adult patients with IDH wild-type glioma. These fusions are truncal alterations that emerge during gliomagenesis and independently predict favorable outcomes in gliomas while being retained in recurrent glioblastoma (搜索). In vitro and in vivo studies have demonstrated that F3T3 fusions exhibit strong oncogenic activity and sensitivity to F3T3 inhibitors.
Erdafitinib, a potent oral pan-FGFR (搜索) tyrosine kinase inhibitor, received FDA approval in 2024 for salvage treatment of patients with locally advanced or metastatic urothelial carcinoma (搜索) harboring FGFR alterations whose disease has progressed during or after treatment with one or more prior lines of systemic therapy. While responses to erdafitinib in patients with glioma (搜索) have been reported in basket trials, ETCTN 10559 represents the first clinical trial focused solely on examining the agent's activity in gliomas harboring F3T3 (搜索) fusions.
Trial Design and Patient Characteristics
This multicenter, single-arm trial enrolled patients with recurrent or progressive F3T3 (搜索) fusion-positive glioma (搜索) using a two-cohort safety lead-in design. Cohort 1 (n = 6) evaluated erdafitinib at a continuous dose of 8 mg daily. If at least 2 DLT events were observed, patients would be enrolled in safety lead-in cohort 2 (n = 6) to receive erdafitinib at 6 mg daily. With 1 or no DLT events in either cohort, an additional 21 patients would be enrolled in the dose-expansion cohort.
Patients had a mean age of 63.3 years (standard deviation, 6.9) and a median age of 64 years (range, 52-72). The cohort included three male and three female patients, with most patients being White (n = 5) and not Hispanic or Latino (n = 4). All patients had grade 4 glioblastoma (搜索) and had received prior radiation and temozolomide. Most patients had a Karnofsky performance score of 90 (n = 5), and patients had received 1, 2, or 3 prior lines of therapy (n = 2 each).
Expansion Phase Underway
The dose-expansion cohort of this phase 2 trial began enrollment in February 2025, with 90% of the planned 21 patients enrolled and 12 clinical trial sites activated. This expansion phase will provide additional data on the efficacy and safety of erdafitinib in this genetically defined patient population, potentially establishing a new treatment option for patients with F3T3 (搜索) fusion-positive gliomas.