Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States; Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.
Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.
Cancer Treat Rev. 2022 Feb;103:102334. doi: 10.1016/j.ctrv.2021.102334. Epub 2021 Dec 28.
Isocitrate dehydrogenase 1 (IDH1) has been investigated as a promising therapeutic target in select cancers with a mutated version of the enzyme (mtIDH1). With only one phase III trial published to date and two indications approved for routine clinical use by the FDA, we reviewed the entire clinical trial portfolio to broadly understand mtIDH1 inhibitor activity in patients. We queried PubMed.gov and ClinicalTrials.gov to identify published and ongoing clinical trials related to IDH1 and cancer. Progression-free survival (PFS), overall survival (OS), 2-hydroxyglutarate levels, and adverse events were summarized. To date, ten clinical trials investigating mtIDH1 inhibitors among patients with diverse malignancies (cholangiocarcinoma, acute myeloid leukemia, chondrosarcoma, glioma) have been published. Almost every trial (80%) has investigated ivosidenib. In multiple phase I trials, ivosidenib treatment resulted in promising radiographic and biochemical responses with improved survival outcomes (relative to historic data) among patients with both solid and hematologic mtIDH1 malignancies. Among patients enrolled in a phase III trial with advanced cholangiocarcinoma, ivosidenib resulted in a PFS rate of 32% at 6 months, as compared to 0% with placebo. There was a 5.2 month increase in OS with ivosidenib relative to placebo, after considering crossover. The treatment-specific grade ≥3 adverse event rate of ivosidenib was 2%-26% among all patients, and was just 3.6% among 284 patients who had a solid tumor across four trials. Although <1% of malignancies harbor IDH1 mutations, small molecule mtIDH1 inhibitors, namely ivosidenib, appear to be biologically active and well tolerated in patients with solid and hematologic mtIDH1 malignancies.
异柠檬酸脱氢酶 1（IDH1）已被研究为具有突变酶（mtIDH1）的选定癌症的有前途的治疗靶标。迄今为止，只有一项 III 期试验发表，并且 FDA 批准了两种用于常规临床使用的适应症，因此我们审查了整个临床试验组合，以广泛了解 mtIDH1 抑制剂在患者中的活性。我们在 PubMed.gov 和 ClinicalTrials.gov 上查询了与 IDH1 和癌症相关的已发表和正在进行的临床试验。总结了无进展生存期（PFS）、总生存期（OS）、2-羟基戊二酸水平和不良事件。迄今为止，已经发表了十项针对具有不同恶性肿瘤（胆管癌、急性髓系白血病、软骨肉瘤、神经胶质瘤）的患者进行 mtIDH1 抑制剂研究的临床试验。几乎每一项试验（80%）都研究了ivosidenib。在多项 I 期试验中，ivosidenib 治疗导致了有希望的影像学和生化反应，并改善了患有固体和血液 mtIDH1 恶性肿瘤的患者的生存结果（与历史数据相比）。在一项针对晚期胆管癌的 III 期试验中，ivosidenib 治疗的患者在 6 个月时 PFS 率为 32%，而安慰剂组为 0%。与安慰剂相比，ivosidenib 使 OS 延长了 5.2 个月，考虑到交叉。所有患者的ivosidenib 的治疗特异性 3 级及以上不良事件发生率为 2%-26%，而在四项试验中 284 名患有实体瘤的患者中仅为 3.6%。尽管只有不到 1%的恶性肿瘤携带 IDH1 突变，但小分子 mtIDH1 抑制剂，即ivosidenib，在患有固体和血液 mtIDH1 恶性肿瘤的患者中似乎具有生物活性和良好的耐受性。
