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

Abstract

Abstract Background 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. Patients and Methods 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 unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6). Results 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 6 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 1 patient (8%), stable disease in 5 (42%), and progressive disease in 6 (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 the benefit of FGFR inhibition in FGFR3–TACC3 + HGGs. Conclusions 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.