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

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. Some high-grade gliomas have a specific genetic change where 2 genes, FGFR and TACC, join together. This change is thought to make tumors grow. There are drugs that can block FGFR, but it's not clear if they work for these types of brain tumors. The TARGET clinical trial tested one of these drugs on 12 patients with this specific kind of brain tumor after their tumor grew back following standard treatments like chemotherapy and radiation. Overall, most patients were able to handle the treatment without significant side effects. But after 6 months of treatment, 9 patients' tumors started growing again, while 3 patients' tumors did not grow. One patient's tumor actually got smaller after treatment. The treatment did not help patients with more advanced tumors.