Vorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): secondary and exploratory endpoints from a randomised, double-blind, placebo-controlled, phase 3 trial.

We report 6 months of additional double-blinddata, from second interim analysis (Sept 6, 2022) to unblinding (March 7, 2023), and the effect of vorasidenib on volumetric tumour growth rate, health-related quality of life (HRQOL), neurocognitive function, and seizure control.

我们报告了从第二次中期分析（2022年9月6日）到解盲（2023年3月7日）的额外6个月的双盲数据，以及vorasidenib对肿瘤体积生长率、健康相关生活质量（HRQOL）、神经认知功能和癫痫控制的影响。

Methods

INDIGO was a randomised, double-blind, placebo-controlled, phase 3 trial done in 92 hospitals in Canada, France, Germany, Israel, Italy, Japan, the Netherlands, Spain, Switzerland, the UK, and the USA.

INDIGO 是一项在加拿大、法国、德国、以色列、意大利、日本、荷兰、西班牙、瑞士、英国和美国的92家医院进行的随机、双盲、安慰剂对照的III期临床试验。

Patients aged 12 years or older with residual or recurrent grade 2 IDH1/2-mutant diffuse glioma, a Karnofsky performance-status score of 80 or higher, at least one previous surgery, and no other previous anticancer treatment were eligible.

年龄在12岁或以上的患者，患有残留或复发的2级IDH1/2突变弥漫性胶质瘤，Karnofsky表现状态评分为80或更高，至少接受过一次手术，且未接受过其他抗癌治疗，符合入选条件。

Patients were randomly assigned (1:1; stratified according to locally determined chromosome 1p/19q codeletion status and baseline tumour size) to oral vorasidenib (40 mg) or placebo once a day in continuous 28-day cycles until disease progression or unacceptable toxicity.

患者按1:1比例随机分配（根据局部确定的染色体1p/19q共缺失状态和基线肿瘤大小进行分层），每天一次口服40毫克的vorasidenib或安慰剂，连续28天为一个周期，直至疾病进展或出现不可接受的毒性。

Progression-free survivalper masked independent review committee was the primary endpoint, and time to next intervention was the key secondary endpoint.

通过蒙蔽独立审查委员会评估的无进展生存期是主要终点，下一次干预的时间是关键次要终点。

Prespecified secondary endpoints included tumour growth rate (6-monthly change in tumour volume) and HRQOL (Functional Assessment of Cancer Therapy-Brain [FACT-Br]).

预设的次要终点包括肿瘤生长速率（肿瘤体积每六个月的变化）和健康相关生活质量（癌症治疗功能评估-脑部[FACT-Br]）

Prespecified exploratory endpoints included neurocognitive function (cognitive performance instruments) and seizure activity (self-reported).

预设的探索性终点包括神经认知功能（认知表现工具）和癫痫活动（自我报告）

The full analysis set was used for all efficacy analyses and included all randomly assigned patients, and the safety analysis set was used for all safety analyses and included all patients who received one or more doses of vorasidenib or placebo.

所有疗效分析均使用完整分析集，包括所有随机分配的患者，所有安全性分析均使用安全性分析集，包括所有接受一次或多次vorasidenib或安慰剂治疗的患者。

The trial is registered with ClinicalTrials.gov, NCT04164901.

该试验已在ClinicalTrials.gov注册，注册号为NCT04164901。

Recruitment is complete and the trial is ongoing.

招募工作已完成，试验正在进行中。

Results

Between Jan 9, 2020, and Feb 22, 2022, 331 patients were enrolled and randomly assigned to vorasidenib (n=168) or placebo (n=163). 187 (56%) patients were male, 144 (44%) were female, and 257 (78%) were White.

在2020年1月9日至2022年2月22日期间，共有331名患者被纳入研究，并随机分配至vorasidenib组（n=168）或安慰剂组（n=163）。其中187名（56%）为男性，144名（44%）为女性，257名（78%）为白人。

Median follow-up was 20·1 months (IQR 15·9 to 23·8).

中位随访时间为20.1个月（四分位数间距15.9至23.8个月）。

With an additional 6 months of follow-up, median progression-free survival(not reached [95% CI 22·1 to not estimated] vs 11·4 months [95% CI 11·1 to 13·9]; hazard ratio[HR] 0·35 [95% CI 0·25 to 0·49]) and time to next intervention (not estimated [not estimated to not estimated] vs 20·1 months [17·5 to 27·1]; HR 0·25 [0·16 to 0·40]) remained substantially improved with vorasidenib versus placebo.

在额外的6个月随访后，与安慰剂相比，vorasidenib组的中位无进展生存期（未达到[95%置信区间22.1至未估计]对比11.4个月[95%置信区间11.1至13.9]；风险比[HR] 0.35 [95%置信区间0.25至0.49]）以及下一次干预的时间（未估计[未估计至未估计]对比20.1个月[17.5至27.1]；HR 0.25 [0.16至0.40]）显著改善。

Tumour growth rate was -1·3% (95% CI -3·2 to 0·7) with vorasidenib and 14·4% (95% CI 12·0 to 16·8) with placebo (difference 15·9% [95% CI 12·6 to 19·3]).

肿瘤生长率在接受vorasidenib治疗组为-1.3%（95%置信区间-3.2至0.7），而在接受安慰剂组为14.4%（95%置信区间12.0至16.8）（差异15.9% [95%置信区间12.6至19.3]）。

Mean FACT-Br total scores were similar between the vorasidenib and placebo groups (158·2 [SD 26·4] and 158·8 [23·3]) at baseline and remained high (154·2 [29·8] and 153·2 [29·4]) by the end of treatment.

在基线时，接受vorasidenib治疗组和接受安慰剂组的平均FACT-Br总分相似（分别为158.2 [标准差26.4]和158.8 [标准差23.3]），治疗结束时，两组的分数仍然较高（分别为154.2 [标准差29.8]和153.2 [标准差29.4]）。

There was no difference between vorasidenib or placebo in neurocognitive functions of verbal learning, executive function, attention, working memory, and psychomotor function from baseline through to end of treatment.

从基线到治疗结束，vorasidenib组与安慰剂组在言语学习、执行功能、注意力、工作记忆和心理运动功能的神经认知功能上没有差异。

The vorasidenib group had lower rates of seizures than the placebo group (18·2 seizures per person-year [95% CI 8·4 to 39·5] vs 51·2 seizures per person-year [22·9 to 114·8]).

Vorasidenib组的癫痫发作率低于安慰剂组（每年人18.2次发作[95% CI 8.4至39.5]对比51.2次发作[22.9至114.8]）。

The most common grade 3 or worse treatment-emergent adverse events (TEAEs) in the vorasidenib and placebo groups, respectively, were increased alanine aminotransferase (17 [10%] and two [1%]), increased aspartate aminotransferase (eight [5%] and none), seizures (seven [4%] and five [3%]), and increased γ-glutamyltransferase (five [3%] and two [1%]).

在接受 vorasidenib 和安慰剂的患者中，最常见的3级或更严重的治疗后不良事件（TEAEs）分别是丙氨酸氨基转移酶升高（17 [10%] 和 2 [1%]）、天冬氨酸氨基转移酶升高（8 [5%] 和无）、癫痫发作（7 [4%] 和 5 [3%]）以及γ-谷氨酰转移酶升高（5 [3%] 和 2 [1%]）。

Serious TEAEs occurred in 20 (12%) patients in the vorasidenib group and ten (6%) in the placebo group; the most common were seizures.

在接受 vorasidenib 的患者中有20名（12%）出现严重TEAEs，在接受安慰剂的患者中有10名（6%）出现；最常见的严重TEAEs是癫痫发作。

There were no treatment-related deaths.

未观察到与治疗相关的死亡事件。

interpretation

Vorasidenib reduced tumour growth rate and improved seizure control compared with placebo, with no observed negative effects on HRQOL or neurocognition.

与安慰剂相比，Vorasidenib降低了肿瘤生长速度并改善了癫痫控制，且未观察到对健康相关生活质量或神经认知有负面影响。

Additional follow-up supported the robustness of progression-free survivaland time to next intervention in patients with grade 2 IDH1/2-mutant diffuse glioma.

额外的随访支持了2级IDH1/2突变弥漫性胶质瘤患者无进展生存期和下一次干预时间的稳健性。

These findings support the use of vorasidenib in patients with grade 2 IDH1/2-mutant gliomas who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy.

这些发现支持在仅接受过手术干预且不需要立即进行放疗或化疗的2级IDH1/2突变胶质瘤患者中使用vorasidenib。

funding

Servier.

赛诺菲。