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ASCO 2020:后起之秀:靶向PD-L1的前体治疗药物CX-072

2020-06-09 任冉 健康界

免疫性炎症药物治疗的毒副反应依然是免疫治疗的痛点和难点。

今年ASCO上一个代号为CX-072的新型PD-L1抗体数据公布,从研究结果来看其安全性可谓优秀,比较贴心的是靶向PD-L1的前体治疗药物CX-072的“说明书”也一并出现在了ASCO壁报中,那我们就一起好好了解这个后起之秀。

在I / II期试验中,靶向PD-L1的前体治疗药物CX-072的肿瘤内定位、激活和免疫调节作用的证据。

背景:

PROBODY疗法(Pb Tx)是一种屏蔽抗体,通过肿瘤相关的蛋白酶在肿瘤微环境中选择性激活,并在正常组织中大部分保持无活性。CX-072是针对PD-L1的Pb-Tx,旨在降低正常组织中免疫相关不良事件的可能性,同时保持抗肿瘤活性。CX-072正在PROCLAIM-CX-072(NCT03013491)中进行研究,这是一项人类首次进入I / II期试验。CX-072以单药或与依匹莫单抗联用给予转移性或复发性实体瘤或淋巴瘤患者,这些患者尚无基于PD-1 / -L1的批准治疗。我们提供了基于组织的生物标志物研究的最新结果,该研究旨在评估CX-072在患者肿瘤中的激活,定位和作用机制。

方法:

在筛选阶段以及第一次或第三次剂量0.3~30 mg / kg CX-072的3~5天后收集肿瘤活检物。通过组织酶谱法测定肿瘤相关的蛋白酶活性。使用毛细管免疫电泳测量肿瘤内CX-072的激活,并通过超灵敏ELISA测量PD-L1的水平。使用免疫组织化学分析肿瘤内CD8表达。通过LC-MS / MS测量血浆中完整的总CX-072。

结果:

30例可评估的用药前活检中有26例(87%)具有可检测水平的相关蛋白酶活性。CX-072的瘤内激活可在8例活检中的3例(38%)中(以3 mg/kg剂量治疗)和12例(100%)活检中(以10mg/kg剂量治疗)进行量化。相反,CX-072在循环中仍然保持完整形式。剂量为10 mg / kg的患者中激活的肿瘤内CX-072与总肿瘤内PD-L1的摩尔比在〜14x到> 100x的范围内,并且这些患者的计算的肿瘤受体占有率≥99%,与定量系统药理学一致模型预测。CD8 +的增加 在18例CX-072单药治疗患者中,有11例(61%)的肿瘤中观察到CD8+T细胞和细胞毒性T细胞标志物升高,这与抑制PD-L1通路相一致。

结论:

这些结果表明,Pb Tx CX-072在患者中的表现与设计相符。

PROCLAIM-CX-072:分析接受PD-L1抗体前体治疗药物CX-072作为单一药物或与ipilimumab组合长期治疗的晚期实体瘤患者。

背景:

免疫检查点抑制剂(ICIs)的单一疗法已在许多癌症中证明有效。与单药治疗相比,ICIs PD-L1 + CTLA-4的联合使用可提高疗效,但毒性更强;因此,尽管已显示出药效的剂量反应效应,但仍经常需要调整CTLA-4剂量。

CX-072是一种研究性PD-L1抗体治疗药物,可在肿瘤微环境(TME)中优先激活;局部激活可能会降低免疫相关的AE(irAE)。PROCLAIM-CX-072-001确定了10 mg / kg Q2W(Mono10)作为推荐的单一疗法剂量。在这里,我们提供了Mono10以及CX-072与IPI(Combo)结合的剂量递增的数据,重点是长期(≥6mo)治疗。

方法:

Mono10在多种肿瘤类型中进行了评估。Q3W评估的组合剂量为CX-072 0.3~10 mg / kg和IPI 3~10 mg / kg。比较截至2019年11月30日治疗持续时间≥6 mo(≥6M-TD)的患者与治疗时间<6 mo(<6M-TD)的患者。

结果:

疾病控制率(DCR=CR+PR+SD)Mono10为41%(n=47/114;10 PRs)和Combo为37%(n=10/27;1CR+4 PRs(3mg/kg IPI时为1CR和3PRs[IPI3])。

 

PROCLAIM-CX-072研究结果

没有与治疗有关的不良事件(TRAE)导致死亡。在所有组中最常见的停药(dc)原因是疾病进展。

结论

CX-072单一疗法显示出持久的反应,与TME中PROBODY疗法的激活相一致。安全性概况支持CX-072作为单一疗法以及与IPI3结合时的耐受性。CX-072 + IPI3在具有多种肿瘤的高度预处理患者中显示出活性。与历史数据相比,CX-072和IPI3组合的安全性更高(等级≥3的比例为55%,导致36%的dc)。

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    2020-10-31 quxin068
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    2020-06-11 smartjoy
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