Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial.
Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial.
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DOI：
10.1158/1078-0432.ccr-21-0611
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发表时间：
2021-08-15
期刊：
影响因子：
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通讯作者：
Wen PY
中科院分区：
文献类型：
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作者：
Mellinghoff IK;Penas-Prado M;Peters KB;Burris HA 3rd;Maher EA;Janku F;Cote GM;de la Fuente MI;Clarke JL;Ellingson BM;Chun S;Young RJ;Liu H;Choe S;Lu M;Le K;Hassan I;Steelman L;Pandya SS;Cloughesy TF;Wen PY
低级别胶质瘤(LGG)是一种恶性脑肿瘤。目前的治疗方法与短期和长期毒性有关。进展为更高级别的肿瘤与MRI上的对比度增强有关。大多数LGG在编码异柠檬酸脱氢酶1或2(IDH1/IDH2)的基因上存在突变。Vorasidenib(AG-881)是一种一流的脑穿透性药物，是突变的IDH1和突变的IDH2酶的双重抑制剂。我们对93例突变的IDH1/2(mIDH1/2)实体肿瘤患者进行了一项多中心、开放标签、I期、剂量递增研究，其中包括52名在标准治疗后复发或进展的胶质瘤患者。Vorasidenib口服，每天一次，28天为一个周期，直到病情进展或出现不可接受的毒性。注册已完成；此试验已在ClinicalTrials.gov注册，地址为NCT02481154。Vorasidenib在胶质瘤队列中显示出良好的安全性。转氨酶升高的剂量限制性毒性在剂量≥100mg时发生，并且是可逆的。在神经肿瘤学标准中，对于无强化的胶质瘤患者，每个反应评估的方案定义的客观应答率为18%(1个部分反应，3个轻微反应)。无强化组的中位无进展生存期为36.8个月[95%可信区间(CI)11.2~40.8]，强化组的中位无进展生存期为3.6个月(95%CI，1.8~6.5)。对无强化的胶质瘤患者的肿瘤体积的探索性评估显示，在许多患者中，肿瘤持续缩小。Vorasidenib耐受性良好，在复发或进展性无强化的MIDH LGG患者中显示出初步的抗肿瘤活性。
Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2–40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8–6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.