TARGET: a phase I/II open-label multicentre study to assess safety and efficacy of fexagratinib in patients with relapsed/refractory FGFR fusion positive glioma

Oncogenic FGFR-TACC fusions are present in 3-5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1-3 inhibitor with preclinical activity in FGFR-TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR-TACC+ HGGs. TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR-TACC+ HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or inacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6). Twelve patients with recurrent IDH wildtype FGFR-TACC+ HGGs (all FGFR3-TACC3+) were included in the efficacy cohort (male/female ratio=1.4, median age=61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5-57%), with a median PFS of 1.4 months. All patients without progression at six months (n=3) were treated at first recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was RANO partial response in one patient (8%), stable disease in five (42%), and progressive disease in six (50%). Median survival was 17.5 months from inclusion. Grade 3 toxicities included lymphopenia, hyperglycaemia, stomatitis, nail changes, and alanine aminotransferase increase (n=1 each). No grade 4-5 toxicities were seen. A 32-gene signature was associated with benefit from FGFR inhibition in FGFR3-TACC3+ HGGs. Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3+ HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required.