JCO:氟嘧啶、伊立替康和贝伐珠单抗序贯治疗vs初始三药联合用于转移性结直肠癌孰优孰劣?

2019-02-09 Linda 肿瘤资讯

在转移性结直肠癌患者的初始治疗中,氟嘧啶、伊立替康和贝伐珠单抗,这三种药物应该序贯增药,还是初始就三药联合?哪个才是最优治疗策略?Journal of Oncology发表的一项研究显示,序贯增药相比于初始三药联合,非劣效性未得到证实。

在转移性直肠癌患者的初始治疗中,氟嘧啶、伊立替康和贝伐珠单抗,这三种药物应该序贯增药,还是初始就三药联合?哪个才是最优治疗策略?Journal of Oncology发表的一项研究显示,序贯增药相比于初始三药联合,非劣效性未得到证实。

研究背景

在贝伐珠单抗问世之前,有研究曾评价过氟嘧啶、奥沙利铂和伊立替康这三种药物以序贯增药疗法治疗转移性直肠癌,结果发现与初始三药联合方案相比患者总生存并不差。血管内皮生长因子抗体贝伐珠单抗问世之后,多项研究证实其与化疗联合用于转移性结直肠癌能延长无进展生存期(PFS)和总生存期(OS),提示该药或许也可以作为序贯增药疗法的组成部分。非劣效性对照研究XELAVIRI,试图探索在未经治疗的转移性结直肠癌患者中,哪种方案才是一线最佳治疗策略。

研究方法

主要入组标准为:年龄≥18岁,ECOG 0~1分,IV期,组织学确诊为结直肠癌,器官功能良好,肿瘤不可切除或患者不愿手术,≥1个可测量病灶。分层因素包括:白细胞(8,000/μL vs 8,000/μL),碱性磷酸酶 (<300 U/L vs ≥300 U/L) ,先前有无辅助治疗。

主要疗效终点为至治疗策略失败时间(TFS),定义为从随机分组到含伊立替康方案治疗失败的时间。取90% CI,单侧α水平设为0.05,非劣效性界值设为0.8。如果序贯疗法相比于初始三药疗法的TFS的非劣效性得到证明,则通过比较TFS期间有症状的毒性反应来确定哪个治疗策略更优。次要终点为各分子型亚组的疗效指标,以及安全性和耐受性。

共421例患者入组,随机分配至A组(212例)或B组(209例)。中位年龄分别为71岁和69岁。最初的研究方案为以卡培他滨为主的CAPIRI方案(卡培他滨+伊立替康),后来因越来越多的证据显示贝伐珠单抗联合CAPIRI与联合FOLFIRI(氟尿嘧啶+伊立替康)的疗效相当,后来方案修改为以静脉滴注氟尿嘧啶和卡培他滨为主皆可。患者一旦选定卡培他滨或FU,在整个研究治疗过程中便不再换药。

A组治疗方案:先给予FP(卡培他滨或氟尿嘧啶)+贝伐珠单抗,第一次进展后,以CAPIRI+贝伐珠单抗或FOLFIRI+贝伐珠单抗方案继续治疗。B组治疗方案:初始即给予CAPIRI+贝伐珠单抗或FOLFIRI+贝伐珠单抗治疗。

治疗至疾病进展、出现不可接受的毒性反应、完全缓解或医生/患者决定研究治疗终止或改变。治疗流程见下图。



治疗分配流程图。CR,完全缓解;NoT,未给予增药治疗;NT,新治疗(非研究治疗);PD,疾病进展;PFS,无进展生存期;PR,部分缓解;SD,疾病稳定;TFS,至治疗策略失败时间

研究结果

疗效

A组和B组的中位随访时间分别为36个月和33个月,中位治疗持续时间分别为7.4个月和6.7个月。A组212例患者中,有80例(37.7%)进入增药阶段,其余未进入增药阶段的132例患者中,有68.3%是因为未发生进展。A组在整个研究治疗过程中,有63.2%在某个时间点接受了伊立替康治疗。B组100%的患者接受了伊立替康治疗。

总人群的中位TPS在A组和B组分别为9.6个月和9.9个月,HR为0.86,90% CI为0.73~1.02,超出了预设的非劣效性界值0.8,结果未能证明序贯增药疗法相对于初始联合疗法的TFS具有非劣效性。

亚组分析显示,初始联合治疗的益处见于RAS/BRAF野生型患者(HR,0.61;90% CI,0.46~0.82;P=0.05),但未见于RAS突变者(HR,1.09;90% CI,0.81~1.46;P=0.58)。采用Cox比例风险回归模型分析显示,RAS突变状态与研究组间有交互作用(P=0.03)。

两组间中位OS无显著差异(HR,0.84;95% CI,0.66~1.06;P=0.14)。疗效结果见下表。

表. 总人群和各分子亚型组的疗效结果



毒性反应和安全性

计算两组的毒性反应评分,即每个治疗周期有症状的(2~5级)不良事件的数学平均数,结果显示A组的毒性评分优于B组(A组数学平均分0.6,标准差0.7;B组数学平均分0.7,标准差0.7)。与研究相关或不相关的≥3级不良事件在A组为80.7%,B组为77.1%。

研究结论

该项XELAVIRI研究中,序贯增药疗法相比于初始联合疗法的TFS HR为0.73~1.02,超出了预设的非劣效性界值0.8,序贯增药治疗的非劣效性未得到证实。在RAS/BRAF野生型患者中,初始联合治疗明显更优,HR为0.61(90% CI,0.46~0.82;P=0.05),这似乎也解释了在总人群中序贯增药疗法未被证明非劣效性的原因;而在RAS突变患者中,序贯增药治疗似乎与初始联合治疗的疗效相当,RAS状态对于治疗策略的指导可能是一个重要因素。不良事件发生率两组间似乎无本质差别,但若仅考虑有症状的(≥2级)的不良事件的毒性反应评分,则以序贯治疗组更优。

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    2019-03-04 lidong40
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