Tumor-agnostic and cross-indication actionable alterations in <i>IDH</i> -wildtype glioma: Precision oncology opportunities in an aggressive disease.

Abstract

e14060 Background: Gliomas have few approved targeted therapies. Given frequent blood-brain-barrier disruption in gliomas, molecular targets with FDA-approved therapies in other solid tumors represent relevant precision-oncology opportunity. Methods: A total of 235 glioma tumor tissue samples underwent targeted next-generation sequencing at Datar Cancer Genetics. Clinical actionability was assessed using ESCAT. Subgroup analyses were performed based on IDH status. Results: Of 235 samples, 6 were grade I (2.6%), 17 grade II (7.2%), 38 grade III (16.2%), and 159 grade IV (67.8%); grade was unavailable in 15 (6.4%). Overall, 43.8% (103/235) harbored ≥1 tumor-agnostic or cross-indication actionable alteration with an FDA-approved therapy in solid tumors. Tumor-agnostic biomarkers included TMB-H (11.6%; 16/138), dMMR (1.7%; 2/116), BRAF V600E (4.9%; 11/225), and NTRK fusions (0.6%; 1/178); HER2 amplifications and RET fusions were not detected. Canonical CNS alterations included IDH1/2 (24.0%; 54/225), TERT promoter (36.1%; 73/202), TP53 (42.4%; 95/224), H3F3A (3.8%; 7/185), ATRX (8.2%; 18/219), EGFR amplification (21.2%; 43/203), CDKN2A/2B loss (18.8%; 38/202), EGFRvIII (12.9%; 23/178), and EGFR mutations (10.7%; 24/225). Cross-indication alterations involved PI3K-AKT-mTOR ( PIK3CA 8.4% [19/225], PTEN 18.3% [41/224]) and FGFR (4.3%; 10/235); KIAA1549-BRAF and PTPRZ1-MET fusions were each detected in 1.1% (2/178). ESCAT Tier I alterations were present in 29% (69/235) and Tier II–III in 56% (132/235). Though incidence of tumor-agnostic biomarkers was similar in IDH -mutant and IDH -wildtype ( IDH -WT) gliomas (13.0% [7/54] vs 11.6% [21/181]), the cross-indication biomarkers were enriched in IDH -WT gliomas (40.9% [74/181] vs 20.4% [11/54]). In grade IV gliomas, cross-indication biomarkers were more frequent in IDH -WT than IDH -mutant tumors (45.3% [62/137] vs 18.2% [4/22]), with similar findings in combined grade III–IV gliomas (42.9% [66/154] vs 25.6% [11/43]). Conclusions: Despite poorer prognosis, IDH -WT gliomas are enriched for cross-indication actionable alterations, reflecting biological actionability without established clinical benefit, and supporting comprehensive molecular profiling to guide indication-expanded therapies, clinical trial enrolment, and prospective interventional basket trials. Tumor-agnostic and cross-indication actionable alterations in gliomas. Biomarker Overall % (n/N) IDH -WT (%) IDH -Mutant (%) Approved Indication PTEN mutations 18.3 (41/224) 21.8 7.4 Breast FGFR1/2/3 alterations 4.3 (10/235) 5.5 0.0 Multiple ERBB2 mutations 0.0 (0/179) 0.0 0.0 Multiple BRCA1/2 mutations 0.6 (1/156) 0.8 0.0 Multiple PIK3CA mutations 8.4 (19/225) 7.6 11.1 Breast TMB-H 11.6 (16/138) 8.9 23.1 Tumor-agnostic dMMR/MSI-H 1.7 (2/116) 2.0 0.0 Tumor-agnostic NTRK fusions 0.6 (1/178) 0.7 0.0 Tumor-agnostic