Targeted therapies plus radiotherapy for diffuse intrinsic pontine glioma: the randomized phase 2 BIOMEDE trial.

BIOMEDE was a randomized phase 2 trial comparing the efficacy in terms of overall survival(OS) (primary endpoint) of epidermal growth factor receptor (EGFR) inhibitor erlotinib, mTOR inhibitor everolimus and multitargeted tyrosine kinase inhibitor dasatinib in combination with radiotherapy in patients with a biopsy-proven DIPG.

BIOMEDE是一项随机II期试验，比较了表皮生长因子受体（EGFR）抑制剂厄洛替尼、mTOR抑制剂依维莫司和多靶点酪氨酸激酶抑制剂达沙替尼联合放疗在活组织检查证实的DIPG患者中的总生存（OS）（主要终点）疗效。

Tumors were assessed centrally for immunohistochemical biomarkers (EGFR overexpression or PTEN loss) together with whole-exome and RNA sequencing.

肿瘤通过中心实验室进行免疫组化生物标志物（EGFR过表达或PTEN缺失）评估，同时进行全外显子组和RNA测序。

A cohort of 66 children with the same inclusion criteria and treated previously with temozolomide-based regimen was used to compare outcome.

使用之前接受过替莫唑胺为基础方案治疗的、具有相同纳入标准的66名儿童患者队列，以比较结果。

Treatment allocation was performed by randomization in 233 patients, designed so that a drug could not be allocated if the corresponding biomarker was absent: 36 received erlotinib, 102 received dasatinib and 95 received everolimus.

在233名患者中进行了随机分组，确保如果相应的生物标志物缺失，则不会分配药物：36人接受了厄洛替尼治疗，102人接受了达沙替尼治疗，95人接受了依维莫司治疗。

The trial was ended for futility of the primary endpoint following the recommendations of the independent data monitoring committee: OS from biopsy was not different from the control cohort (median OS = 10.8 months (95% confidence interval(CI): 9.5-13.0)) in any of the three arms (median OS = 9.7 months (95% CI: 7.8-14.6) for erlotinib; 9.9 months (95% CI: 8.8-11.2) for dasatinib; and 11.9 months (95% CI: 10.7-14.2) for everolimus).

根据独立数据监测委员会的建议，由于主要终点的无效性，试验被终止：从活检开始的总生存期与对照队列没有差异（中位总生存期=10.8个月（95%置信区间（CI）：9.5-13.0）），在三个治疗组中均无差异（厄洛替尼的中位总生存期=9.7个月（95% CI：7.8-14.6）；达沙替尼的中位总生存期=9.9个月（95% CI：8.8-11.2）；依维莫司的中位总生存期=11.9个月（95% CI：10.7-14.2）。

Everolimus showed significantly less ocular, renal, skin and gastrointestinal side effects and treatment discontinuation for toxicity (secondary endpoint).

Everolimus 显示出显著较少的眼部、肾脏、皮肤和胃肠道副作用以及因毒性导致的治疗中断（次要终点）。

TP53 mutations, frequently linked to multiple structural chromosomal aberrations, were the strongest predictor for poor survival in multivariate analysis (hazard ratio= 2.8 (95% CI: 1.9-4.2), P < 0.0001).

TP53 突变，常与多种结构染色体异常相关，是多变量分析中预后不良的最强预测因素（风险比=2.8（95% 置信区间：1.9-4.2），P < 0.0001）。

Both mutations in and activation of the mTOR pathway were associated with a better response to everolimus.

mTOR通路的突变和激活均与对依维莫司更好的反应相关。

Four long-term survivors treated with an mTOR inhibitor were alive free of treatment over 6 years from diagnosis.

接受mTOR抑制剂治疗的四名长期幸存者在诊断后超过6年的时间里无需治疗仍然存活。

With comprehensive tumor profiling, BIOMEDE validated prognostic biomarkers as well as informative theranostic biomarkers for future trials.

通过全面的肿瘤分析，BIOMEDE 验证了预后生物标志物以及对未来试验具有指导意义的治疗诊断生物标志物。

ClinicalTrials.gov: NCT02233049 .

ClinicalTrials.gov: NCT02233049 .