肿瘤

新诊断晚期卵巢癌的维持性免疫治疗肿瘤:同源重组精通(HRP)的疗效评估 IIb 期生命试验的病人

作者:会飞的大胖纸 来源:医学论坛网 日期:2021-06-30
导读

         背景:在 VITAL(NCT02346747)试验中,用 Vigil 维持治疗,Vigil 是一种自体肿瘤细胞疫苗,转染了编码 GMCSF 和 bishrna-furin 的 DNA 质粒,用于 TGFb 在晚期高级别卵巢癌患者中,一线铂类化疗后的表达控制可提高无复发生存率(RFS)(HR=0.69,90%CI)0.441.07,p=0.078),在 BRCAwt 患者中显著(HR=0.51,9

关键字:  肿瘤 

背景:在 VITAL(NCT02346747)试验中,用 Vigil 维持治疗,Vigil 是一种自体肿瘤细胞疫苗,转染了编码 GMCSF 和 bishrna-furin 的 DNA 质粒,用于 TGFb 在晚期高级别卵巢癌患者中,一线铂类化疗后的表达控制可提高无复发生存率(RFS)(HR=0.69,90%CI)0.44–1.07,p=0.078),在 BRCAwt 患者中显著(HR=0.51,90%CI 0.30-0.88,p=0.020)(Rocconi 等人,《柳叶刀肿瘤学》。2020). 在这里,我们报告了事后 HR 缺乏症(HRD)亚组分析和鉴定的另一个分子亚组敏感守夜治疗涉及字符串分析。

 

Background: In the VITAL (NCT02346747) trial, maintenance therapy with Vigil, an autologous tumor cell vaccine transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin for TGFβ expression control, following frontline platinum-based chemotherapy led to a recurrence-free survival (RFS) benefit in patients with advanced high-grade ovarian cancer (HR=0.69, 90% CI 0.44–1.07, p=0.078) and significantly in BRCA-wt patients (HR=0.51, 90% CI 0.30-0.88, p=0.020) ( Rocconi et al. Lancet Oncol. 2020). Here we report post-hoc HR deficiency (HRD) subgroup analysis and identification of an additional molecular subgroup sensitive to Vigil therapy involving STRING analysis.

 

方法:这项双盲、安慰剂对照、2b 期研究随机选择 92 例新诊断的Ⅲ/Ⅳ期卵巢癌患者进行临床研究对前线手术和化疗的反应(CR)。患者接受 1 x 10e7 细胞/ml 的守夜或安慰剂皮内每月一次,最多 12 剂或疾病进展。RFS 是盲法独立中心评价的主要终点。HRD 状态根据 myChoice-CDx 分析确定(熟练者 HRD 评分<42)。利用肿瘤利用 DNA 多态性数据,构建了蛋白质-蛋白质相互作用网络字符串数据库。利用该网络的拓扑距离和 hub 基因的识别等性质,预测了一个对守夜敏感的目标分子群体。

 

Methods: This double-blind, placebo-controlled, Phase 2b study randomized 92 patients with newly diagnosed stage III/IV ovarian cancer with a complete clinical response (CR) to frontline surgery and chemotherapy. Patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses or disease progression. RFS was the primary endpoint assessed by blinded independent central review. HRD status was determined according to the Myriad Genetics myChoice CDx assay (HRD score < 42 for proficient). Using tumor annotated DNA polymorphism data, a protein-protein interaction network was constructed using the STRING database. Properties of this network including topological distance and the identification of hub genes were used to predict a target molecular population sensitive to Vigil.

 

结果:在根据方案人群(PP,n=91),对 62 例 BRCA wt 患者进行 HRD 状态检测。45 例患者 HR 熟练(HRP),17 例 HR 缺乏(HRD)。无 HRP 患者在守夜组报告治疗相关的 3 级或以上不良事件。从与对照组相比,HRP 患者的随机中位数 RFS 在 Vigil(n=25)下得到改善安慰剂(n=20)(表 1)。同样,在守夜组中观察到总体生存(OS)益处与安慰剂相比(表 1)。改善 RFS 被证明适用于一部分患有糖尿病的患者字符串预测了分子轮廓。

 

 

Results: In the per-protocol population (PP, n=91), 62 BRCA-wt patients were tested for HRD status. Forty-five patients were HR proficient (HRP) and 17 patients were HR deficient (HRD). No HRP patients in the Vigil group reported treatment related Grade 3 or higher adverse events. From the time of study randomization median RFS was improved with Vigil (n=25) in HRP patients compared to placebo (n=20) (Table 1). Similarly, overall survival (OS) benefit was observed in the Vigil group compared to placebo (Table 1). Improved RFS was demonstrated for a subset of patients with STRING predicted molecular profile.

 

Endpoint

HRP (n=45)

Vigil (n=25)

Placebo (n=20)

Recurrence-Free   Survival (RFS)

  Median (mo.)

10.6

5.7

 95% CI (mo.)

5.9-NA

5.6-14.9

 HR (90%CI)

0.386   (0.199-0.750), p=0.007

 

Overall   Survival (OS)

 Median (mo.)

NR

26.9

 95% CI (mo.)

28.7-NA

17.1-NA

 HR (90%CI)

0.342 (0.141-0.832), p=0.019

 

 

结论:守夜免疫治疗是一线维持 III/IV 期卵巢癌耐受性良好,BRCA 和 wt 均显示出临床益处 HRP 分子图谱。结果表明,一个独特的分子网络,提高灵敏度疗法。

 

Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed clinical benefit in both BRCA-wt and HRP molecular profile patients. Results suggest a unique molecular network that enhances sensitivity to Vigil therapy.

 

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