Target therapy matched to genomic alterations in patients with recurrent IDH wildtype glioblastoma: A real-life cohort analysis from Veneto Institute of Oncology, Padua (Italy)

Next-generation sequencing (NGS) allows to identify patients (pts) that may respond to target therapies (TT). Only a few data are available regarding TT for recurrent glioblastoma (rGBM). We retrospectively analyzed a cohort of pts with rGBM treated with TT based on NGS profile obtained on formalin-fixed paraffin-embedded tissue samples. We identified 7 druggable alterations, classified according to ESCAT: BRAFV600E (IB), NTRK fusions (IC), FGFR1-3 alterations (IIB), ROS1 fusions, MET amplification/fusions, PIK3CA mutations and PTEN loss/mutations (IIIA). Between 03/20 and 03/23, 37 pts received TT. All pts received radiotherapy and temozolomide as first-line. Median line of TT was 3 (range 2-7). TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), vebreltinib (2 pts), capmatinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts). At data cut-off (05/23), 24 patients had died. In the entire cohort, median overall survival and progression-free survival (PFS) after starting TT was 8.19 and 2.11 months (mo), respectively. The dabrafenib/trametinib (D/T) subgroup had the longest median PFS (5.23 mo), a disease control rate (DCR) of 77%, an objective response rate of 22%, and a median duration of response of 22.5 mo. 7/9 pt had died and 2 are continuing D/T. The pt with ROS1-GOCP fusion maintained a complete response for 12 mo with entrectinib. A multifocal rGBM patient with PTPRZ1-MET fusion, identified by Caris MI-Transcriptome, had impressive PR after 8 weeks of vebreltinib in third-line during participation in APL-101-01 study (NCT03175224): duration of response is pending as TT is ongoing. Among the others, no complete/partial responses were detected. DCR was 67% in MET-inhibitors, 50% in larotrectinib and erdafitinib, 8% in ipatasertib+/-atezolizumab subgroups. No toxicities were reported with D/T. Among all pts, no grade 4 adverse events were observed and in any case, TT was interrupted for toxicity. Our results confirm the activity of D/T in BRAFV600E mutant rGBM. We had a dramatic response to a MET inhibitor. Deeper explorations are needed in targeting FGFR e ROS1.