Druggable molecular alterations in IDH1/2 wildtype glioblastoma and therapeutic implications in patients with recurrent disease: a real-life cohort analysis using extensive next-generation sequencing

BACKGROUND Glioblastoma (GBM) accounts for approximately 60% of all malignant gliomas and it has an aggressive behavior and dismal prognosis, with a median overall survival despite standard chemo-radiation of 15 months, a 2-year survival rate of around 27% and a 5-year survival rate of only 9.8%. Therapeutic options after the first recurrence are limited and their efficacy is poor, due to blood–brain barrier, intrinsic biological heterogeneity and immunosuppressive mechanisms of glioblastoma. Based on these premises, the need of new biomarkers to support new treatments appears urgent. The use of next-generation sequencing (NGS) tests is currently increasing in oncology, to identify alterations of cancer-related genes and, if possible, to establish a better personalized glioblastoma treatment. Unfortunately, in neuro-oncology NGS assays are less common than in other oncological fields and their clinical impact is not very clear, with some exceptions (BRAF V600E, NTRK fusions). Furthermore, a panel of genes dedicated to glioblastoma patients is not yet defined. However, recent studies have showed that, potentially, more than 20% of patients with glioblastoma could have a druggable molecular alteration and then benefit from a targeted therapy. MATERIAL AND METHODS A retrospective analysis of data obtained using FoundationOne®CDx in a large cohort of IDH1/2 wild-type GBM was performed. We aimed to 1) identify potentially druggable molecular alterations at diagnosis and/or recurrence based on ESCAT (ESMO Scale for Clinical Actionability of Molecular Targets) defined categories of targetability, 2) understand the clinical implications of NGS in terms of access to and activity of targeted therapies. RESULTS In 442 samples, an NGS profile was available in 98.2%. The median time from diagnosis to NGS profiling was 7.4 months (IQR: 3.4-13.2). Although 343 patients presented at least one actionable alteration, only 3.4% of them were classified as ESCAT IB–IC and 6.7% as ESCAT IIB. Only 41 patients (9.8%) received personalized treatment in clinical trials or as off-label – compassionate use from second-line (median line 3). Most patients did not receive targeted therapy due to clinical deterioration/death (49.6%). Patients treated with dabrafenib/trametinib (10 patients) had the highest disease control rate of 80% and an objective response rate of 20%, with a median progression-free survival (PFS) of 5.23 months. One recurrent GBM patient with ROS1-GOCP fusion maintained a complete response for 12 months on entrectinib. A multifocal GBM patient with a PTPRZ1-MET fusion achieved an impressive partial response with vebreltinib in the third-line, but duration of response was only 3.68 months. No complete/partial responses were seen with the other regimens. 4/10 (40%) patients on anti-BRAF/anti-MEK, 2/4 patients (50%) on erdafitinib, 1/2 (50%) patient on vebreltinib and 1/1 patient on capmatinib had a PFS ratio > 1.3. CONCLUSIONS This research demonstrated the feasibility of NGS in GBM samples. As the number of clinically relevant targets was limited and only a small group of GBM patients were treated with targeted therapy, NGS testing should be performed in the context of clinical trials. These results support the activity of anti-BRAF/anti-MEK, while for the other agents prospective study results are needed to draw solid conclusions.