The INDIGO trial: Precision medicine finally comes to glioma.
The INDIGO trial: Precision medicine finally comes to glioma.
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INDIGO 试验：精准医学终于来到了神经胶质瘤。
DOI：
10.1093/neuonc/noad162
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发表时间：
2023
期刊：
影响因子：
15.9
通讯作者：
Kaelin,WilliamG
中科院分区：
文献类型：
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作者：
Shi,DianaD;Kaelin,WilliamG
一个紧迫的问题是，(R)-2HG 在 IDH 突变实体瘤中的作用是否可以像在白血病中一样可逆。抑制 (R)-2HG 导致许多 9、10 但不是全部 2 IDH1 突变神经胶质瘤临床前模型的细胞增殖和细胞活力发生微小变化。然而，需要注意的是，这些数据基于人工转化的星形胶质细胞或患者来源的细胞系或来自高级别（而不是低级别）患者的异种移植物。另一方面，IDH 突变神经胶质瘤中突变 IDH 等位基因的丢失虽然很少，但早期的 1 期研究显示，脑渗透性双重 mIDH1/2 抑制剂 vorasidenib 在复发性或进行性 IDH 突变神经胶质瘤中的活性有限，在病变增强的患者中没有观察到客观反应。 11 总的来说，这些观察结果引发了人们的担忧，即 (R)-2HG 以“肇事逃逸”的方式发挥作用，至少在神经胶质瘤进展的后期阶段是如此。目前尚不清楚阻断 (R)-2HG 在这种疾病的早期是否有用。INDIGO 试验的结果提供了关于低级别神经胶质瘤对 (R)-2HG 的持续需求的重要见解。这项 3 期试验将 331 名切除后残留或复发 2 级 IDH 突变神经胶质瘤的患者随机分配至安慰剂或 vorasidenib 组。沃拉西尼治疗延长了无进展生存期 (PFS)（11.1 个月 vs 27.7 个月）和下次干预时间（17.8 个月 vs 未达到），但总体生存数据尚未报告。这些数据代表了 IDH 突变神经胶质瘤患者治疗的显着进步，十多年来，这种疾病的标准治疗几乎没有变化。 vorasidenib 改善 PFS 的事实表明，在低级别 IDH 突变神经胶质瘤患者中，mIDH 的至少一些致癌作用是可逆的。这些数据也反映了 IDH1 突变型胆管癌患者的临床结果。 2 INDIGO 试验的结果强调需要从机制上了解 mIDH1 如何驱动神经胶质瘤生长。目前尚不清楚 vorasidenib 可以逆转 mIDH 的哪些下游效应，以及哪些下游效应与治疗反应有关。这些知识可能会产生预测性生物标志物，以更好地选择受益于 mIDH 抑制剂的患者。如上所述，mIDH 抑制剂治疗在晚期神经胶质瘤中的效果明显较差。 11 目前尚不清楚随着时间的推移会发生哪些生物学变化，从而赋予对 mIDH 抑制剂的耐药性。对于患有 mIDH 抑制剂无反应的患者，替代治疗策略（例如合成致死方法）可能有希望。 10、12
A pressing question has been whether the effects of (R)-2HG are reversible in IDH-mutant solid tumors as they are in leukemia. Inhibiting (R)-2HG has led to minimal changes in cell proliferation and cell viability in many, 9, 10 but not all, 2 preclinical models of IDH1-mutant glioma. A caveat, however, is that these data were based on artificially transformed astrocytes or patient-derived cell lines or xenografts derived from high-grade (rather than lower-grade) patients. On the other hand, loss of the mutant IDH allele has been described, albeit rarely, in IDH-mutant gliomas, and an earlier phase 1 study of the brain-penetrant dual mIDH1/2 inhibitor vorasidenib in recurrent or progressive IDH-mutant gliomas showed limited activity, with no objective responses observed in patients with enhancing lesions. 11 Collectively, these observations led to concerns that (R)-2HG acts in a “hit-and-run” fashion, at least in the later stages of glioma progression. It remained unclear whether blocking (R)-2HG would be useful earlier in the course of this disease.The results of the INDIGO trial provide important insights regarding the ongoing requirement of low-grade gliomas for (R)-2HG. This phase 3 trial randomized 331 patients with residual or recurrent grade 2 IDH-mutant gliomas after resection to placebo or vorasidenib. Vorasidenib treatment prolonged progression-free survival (PFS)(11.1 months vs 27.7 months) and time to next intervention (17.8 months vs not reached), with overall survival data not yet reported. These data represent a significant advancement in the treatment of IDH-mutant glioma patients, a disease for which there has been little change in standard-of-care treatment for well over a decade. The fact that vorasidenib improved PFS suggests that in low-grade IDH-mutant glioma patients, at least some of the oncogenic effects of mIDH are reversible. These data also mirror clinical results in IDH1-mutant cholangiocarcinoma patients. 2 The results of the INDIGO trial emphasize the need to understand, mechanistically, how mIDH1 drives glioma growth. It is not yet known which downstream effects of mIDH are reversed by vorasidenib, and which are linked to treatment response. Such knowledge may yield predictive biomarkers to better select patients who will benefit from mIDH inhibitors. As noted above, mIDH inhibitor treatment appears significantly less effective in later-stage gliomas. 11 It is not known what biologic changes occur over time that confer resistance to mIDH inhibitors. For patients with disease unresponsive to mIDH inhibitors, alternative treatment strategies such as synthetic lethal approaches may hold promise. 10, 12