Drummond Katharine J, Spiteri Montana, Cain Sarah A, Jones Jordan, Shaya Sammy, Topp Monique, Lu Tianyao, Tobler Robert, Valkovic Adam L, Moore Zachery, Fatunla Oluwaseun E, Kriel Jurgen, Moffet Joel J D, McAlpine Heidi, Rosier Marius, Guan Hefei, Dimou James, Schadewaldt Verena, Roberts-Thomson Samuel, McArdle David, Lui Elaine, Voelker-Albert Moritz, di Sanzo Simone, Nijagal Brunda, Narayana Vinod K, Mitchell Camilla B, Vissers Joseph H A, Grimmond Sean, Rosenthal Mark A, Palmer Lucy M, Best Sarah A, Freytag Saskia, Whittle James R
Department of Neurosurgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia.
Nat Med. 2025 Aug 21. doi: 10.1038/s41591-025-03884-4.
Mutant isocitrate dehydrogenase (mIDH) inhibition significantly improves progression-free survival in patients with mIDH WHO grade 2 glioma; however, a large proportion of patients will progress, and mechanisms of adaptation to mIDH inhibition remain poorly understood. Perioperative studies with evaluation of paired pre- and post-treatment samples enable detailed understanding of drug response, facilitating biomarker development, but are rare in glioma owing to safety and cost concerns. Here we conducted a single-arm, open-label feasibility perioperative trial in patients with mIDH1 low-grade glioma, treatment naive to radiation and chemotherapy, with safusidenib (AB-218/DS-1001b), an orally available small-molecule inhibitor of mIDH1. As of 8 November 2024, 10 patients were enrolled and have completed the perioperative component, with a median follow-up of 14 months. Patients continue postoperative safusidenib with ongoing follow-up for safety and efficacy. The primary endpoint showed the feasibility and acceptability of conducting a two-stage perioperative trial. One patient experienced a serious surgery-related adverse event, and ten reported safusidenib-related adverse events; most were grade 1, and one experienced grade 3 elevation of transaminases. Tumor 2-hydroxyglutarate quantification revealed on-target activity, associated with alterations in differentiation programs and neural excitability, functionally validated in post hoc analysis by patch-clamp electrophysiology. Taken together, these results provide a detailed investigation of observations associated with mIDH inhibition in glioma. The study shows the safety and feasibility of this perioperative approach, which can be applied broadly in clinical trial design, serving as proof of concept for advancing drug development in glioma. ClinicalTrials.gov registration: NCT05577416 .
突变型异柠檬酸脱氢酶（mIDH）抑制可显著改善mIDH 2级胶质瘤患者的无进展生存期；然而，很大一部分患者仍会病情进展，对mIDH抑制的适应机制仍知之甚少。对配对的治疗前和治疗后样本进行围手术期评估的研究能够详细了解药物反应，促进生物标志物的开发，但由于安全性和成本问题，在胶质瘤研究中很少见。在此，我们对未接受过放疗和化疗的mIDH1低级别胶质瘤患者进行了一项单臂、开放标签的围手术期可行性试验，使用口服小分子mIDH1抑制剂safusidenib（AB-218/DS-1001b）。截至2024年11月8日，10名患者入组并完成了围手术期部分，中位随访时间为14个月。患者术后继续服用safusidenib，并持续随访以观察安全性和疗效。主要终点显示了进行两阶段围手术期试验的可行性和可接受性。一名患者经历了严重的手术相关不良事件，十名患者报告了与safusidenib相关的不良事件；大多数为1级，一名患者出现3级转氨酶升高。肿瘤2-羟基戊二酸定量显示了靶向活性，与分化程序和神经兴奋性的改变相关，在事后分析中通过膜片钳电生理学进行了功能验证。综上所述，这些结果对胶质瘤中与mIDH抑制相关的观察结果进行了详细研究。该研究表明了这种围手术期方法的安全性和可行性，可广泛应用于临床试验设计，为推进胶质瘤药物开发提供了概念验证。ClinicalTrials.gov注册号：NCT05577416 。
