Geurts, Marjolein

Abstract Oncogenic BRAF alterations occur in a subset of diffuse gliomas across WHO grades and are increasingly identified through modern molecular diagnostics. In addition to standard glioma therapies, targeted treatments are available for patients with BRAF-altered glioma supported by variable evidence spanning randomized trials, single-arm studies, and real-world evidence. This joint consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO) synthesizes current knowledge on the diagnosis and management of BRAF-altered gliomas across age groups, tumor grades, and lines of therapy. Particular emphasis is placed on expert consensus in clinical scenarios where high-quality trial evidence remains limited. The review addresses rationale testing for BRAF alterations, selection, and monitoring of targeted therapies, management of treatment-related toxicities, approaches to resistance, and priorities for future research. It aims to provide practical, evidence-based guidance for clinicians while highlighting gaps to inform prospective studies.

Abstract Background PARP-1 has a well-established role in DNA repair. PARP-1 selective inhibitors are a new subclass of PARPi that offer potential for improved tolerability. NMS-03305293 (NMS-293) is an oral, brain-penetrant PARP-1 selective inhibitor with strong antitumor activity in BRCA mutated preclinical models. Furthermore, NMS-293 is synergistic with temozolomide (TMZ) in glioblastoma mouse models. Methods Two phase I/I-II dose-escalation/expansion studies assessed safety, tolerability, and preliminary antitumor activity of NMS-293. Both are actively recruiting. In PARPA-293-001 (NCT04182516), NMS-293 was administered orally, ranging from 20 mg (QD) to 160 mg (BID) for 21 or 28 days on 28-day cycle in adult patients with advanced/metastatic, relapsed/refractory solid tumors who have exhausted standard treatment options. In PARPA-293-002 (NCT04910022), NMS-293 was administered in a range of doses orally, QD or BID on days 1-7 plus TMZ 150mg/m2 QD on days 1-5 in repeated 28-day cycle in adult patients with recurrent diffuse gliomas. Tumor responses were measured by investigator-assessed RANO criteria. Results The unpooled safety database at the data-cut-off (02-AUG-23), includes 45 patients in PARPA-001 and 21 patients in PARPA-002. PARPA-001 showed an MTD of 100 mg BID for 28 days on a 28-day cycle, a dose with meaningful PK relative to preclinical activity. PARPA-002 dose finding is ongoing with no DLTs as of cutoff date. The most frequent (≥10%) any-grade treatment related adverse events (TRAEs) in PARPA-001 were reversible QTcF prolongation, nausea, asthenia, decreased appetite and vomiting, mainly mild/moderate. In PARPA-002, with discontinuous NMS-293 plus TMZ, no G≥3 TRAEs were reported. The most frequent (≥10%) any-grade TRAEs were: nausea, fatigue, vomiting, decreased appetite, and platelet count decreased, mainly G1 adverse events. Overall, no dose-dependent trends of myelosuppression have been observed. 14 recurrent glioma patients across dose levels in PARPA-002 were evaluable for tumor response. A patient with glioblastoma had confirmed partial response (PR) with duration 7.6+ weeks, remaining on treatment at cutoff date. A patient with grade 3 IDH-mutant astrocytoma had unconfirmed PR with ongoing tumor shrinkage at 16.1+ weeks. A patient with glioblastoma had complete radiological disappearance of enhancing non-target lesions, remaining on treatment at cutoff date. NMS-293 PK profiles showed an increase in exposure with the dose with approximately 5 to 13 hours half-life. Conclusion NMS-293, a PARP-1 selective, brain penetrant inhibitor was well tolerated in phase I clinical trials with no dose dependent trends of myelosuppression. Furthermore, NMS-293 showed encouraging clinical activity in combination with TMZ in difficult-to-treat recurrent glioma patients. Citation Format: Marjolein Geurts, Dorothee Gramatzki, Sara Merler, Matteo Duca, Fabio Girardi, Ugur T. Sener, Domenico Roberti, Grazia Saturno, Patrizia Crivori, Alessia Montagnoli, Lisa Mahnke, Siqing Fu, Paola Gaviani, Kurt A. Jaeckle, Jian Zhang, Yehui Shi, Valentina Guarneri, Michael Weller, Sani H. Kizilbash, Martin J. van den Bent, Michele Milella, Silvia Damian. Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A12.

Abstract The treatment of newly diagnosed oligodendroglioma has been revolutionized in the past decade by multiple studies demonstrating that the addition of chemotherapy to radiation therapy results in a significant survival benefit. While the most direct evidence comes from clinical trials that utilized PCV, a chemotherapy regimen consisting of procarbazine, CCNU (lomustine), and vincristine, there is circumstantial evidence suggesting that the oral agent temozolomide (TMZ), which is both better tolerated and logistically simpler than PCV, may also be effective. The lack of currently available direct comparative data for PCV vs TMZ results in a diversity of practice. In this article, Ruff and Buckner argue for PCV as part of the standard-of-care regimen for newly diagnosed anaplastic oligodendroglioma, while Geurts and van den Bent defend the use of TMZ.