贝伐单抗联合亚硝基脲类药物治疗复发高级别胶质瘤的单臂Ⅱ期临床研究

A single-arm phase Ⅱ clinical study of bevacizumab plus nitrosoureas treatment in patients with recurrent high-grade gliomas

背景与目的:复发高级别胶质瘤目前尚无标准治疗。该研究旨在评估贝伐单抗联合亚硝基脲类药物治疗复发高级别胶质瘤的疗效和安全性,并探索预测疗效的分子标志物。方法:本研究为一项单臂Ⅱ期临床试验(编号NCT02698280),入组复发高级别胶质瘤[世界卫生组织(World Health Organization,WHO)Ⅲ～Ⅳ级]患者。每6周为1个疗程,患者每3周接受1次贝伐单抗5 mg/kg静脉滴注,每6周静脉滴注亚硝基脲1次,每次90 mg/m^2。每6周根据神经肿瘤临床疗效评价(response assessment in neuro-oncology,RANO)标准评价疗效。主要疗效指标为无进展生存期(progression-free survival,PFS)、6个月无进展生存率(progression-free survival at 6 months,PFS-6)及影像学评价,次要疗效指标为总生存期(overall survival,OS),并观察不良反应。统计O^6-甲基鸟嘌呤DNA甲基转移酶(O^6-methylguanine-DNA methyltransferase,MGMT)启动子甲基化、异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)及端粒酶逆转录酶(telomerase reverse transcriptase,TERT)启动子等分子病理状态对疗效的指示作用。结果:共入组23例患者,最终可分析的患者有20例。中位随访时间为8.2个月(3.2～23.1个月),PFS-6达25%,中位PFS为3.7个月(95%CI:1.85～5.55)。根据RANO标准,6例患者部分缓解,9例患者疾病稳定,5例患者对治疗无反应,直接评价为疾病进展,客观缓解率(objective response rate,ORR)为30%。中位OS为9.2个月(95%CI:7.27～11.13)。不良反应大部分为常见不良反应事件评价标准(The Common Terminology Criteria for Adverse Events,CTCAE)1～2级,血小板下降、高血压及乏力多见。可分析组织的分子病理结果显示,TERTp野生型患者(n=11)的PFS较TERTp突变型(n=7)更长(6.0个月vs 1.9个月,P=0.02),MGMT启动子甲基化(n=10)较非甲基化患者的ORR(n=8)具有更好的趋势(30.0%vs 12.5%,P=0.18),TERTp野生型(n=11)较TERTp突变型(n=7)患者的ORR具有更好的趋势(36.3%vs 14.2%,P=0.32)。结论:贝伐单抗联合亚硝基脲类药物治疗复发高级别胶质瘤有效且安全;TERT启动子野生型提示更长的PFS。MGMT启动子甲基化和TERT启动子野生型的ORR趋于更好。

Background and purpose： There is no standard treatment for recurrent high-grade gliomas. This study aimed to evaluate the curative efficacy and safety of bevacizumab plus nitrosoureas regimen in patients with recurrent high-grade gliomas, and to explore the molecular biomarkers for efficacy prediction. Methods： This was a single-arm phase Ⅱ clinical trial（Number NCT02698280） enrolling patients with recurrent high-grade gliomas.Every 6 weeks was defined as one therapeutic cycle. Bevacizumab was administered intravenously at 5 mg/kg every 3 weeks; and nitrosoureas at 90 mg/m2 every 6 weeks. Radiological response was assessed every 6 weeks according to the Response Assessment in Neuro-Oncology（RANO） criteria. The primary endpoint was progression-free survival（PFS）, progression-free survival at 6 months（PFS-6） and radiological response. The secondary endpoint was overall survival（OS）. Adverse events were recorded. The indicative value of O6-methylguanine-DNA methyltransferase（MGMT） promoter, isocitrate dehydrogenase（IDH） and telomerase reverse transcriptase（TERT） promoter were analyzed. Results： Twenty-three patients were enrolled in this study, in which the results of 20 patients were available and analyzed. The median follow-up time was 8.2（range： 3.2 to 23.1） months. The PFS-6 was 25% and median PFS was 3.7 months（95%CI： 1.85-5.55）. According to RANO criteria, 6 patients reached partial response, 9 had stable disease, and 5 patients directly got progression disease without any response. Thus objective response rate（ORR） was30%. Median OS was 9.2 months（95%CI： 7.27-11.13）. Most of treatment-related adverse events were The Common Terminology Criteria for Adverse Events（CTCAE） grade one or two. Decrease of platelet, hypertension and fatigue were common. The molecular biomarker analysis of available tissues showed TERTp wild-type patients（n=11） had longer PFS than TERTp mutated patients（n=7）（6.0 months vs 1.9 months, P=0.02）. MGMTp methylated group（n=10）had better trend in response rate than MGMTp unmethylated group（n=8）（30% vs 12.5%, P=0.18）, and TERTp wildtype group（n=11） had better trend in response rate compared with TERTp mutation group（n=7）（36.3% vs 14.2%,P=0.32）. Conclusion： Bevacizumab plus nitrosoureas regimen could be considered effective and safe in treatment of recurrent high-grade gliomas. Wild-type TERT promoter can indicate longer PFS. MGMTp methylated group and TERTp wild-type group have better trend in response rate.