The Impact of Molecular Subtype on Efficacy of Chemotherapy and Checkpoint Inhibition in Advanced Gastric Cancer
The Impact of Molecular Subtype on Efficacy of Chemotherapy and Checkpoint Inhibition in Advanced Gastric Cancer
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DOI：
10.1158/1078-0432.ccr-20-0075
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发表时间：
2020-07-15
影响因子：
11.5
通讯作者：
Shitara, Kohei
中科院分区：
文献类型：
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作者：
Kubota, Yohei;Kawazoe, Akihito;Shitara, Kohei
目的：我们评估了进展期胃癌（AGC）分子亚型与标准化疗或免疫检查点抑制剂疗效之间的相关性。实验设计：分析了2015年10月至2018年7月接受全身化疗且具有可用分子特征的AGC患者。我们调查了标准优先的有效性-（氟嘧啶+铂+/-曲妥珠单抗）和二线（紫杉烷类+/-雷莫芦单抗）化疗和后续抗PD-1治疗的四种分子亚型患者：MMR-D结果：共分析410例患者，MMR-D为5.9%，EBV+为4.1%，HER 2+为13.7%，均阴性为76.3%。在285例接受标准一线化疗的患者中，MMR-D、EBV+、HER 2+和全阴性亚型的中位无进展生存期（PFS）时间分别为4.2、6.0、7.5和7.6个月，客观缓解率（ORR）分别为31%、62%、60%和49%。多变量分析显示MMR-D患者的PFS短于全阴性患者[HR，1.97; 95% CI，1.09-3.53; P = 0.022]。在二线治疗中，疗效无显著差异。在110例接受抗PD-1治疗的患者中，中位PFS时间分别为13.0、3.7、1.6和1.9个月，ORR分别为58%、33%、7%和13%。12例MMR-D患者接受了后续抗PD-1治疗，与10例（83%）接受早期化疗的患者相比，PFS延长。结论：MMR-D可能导致AGC一线化疗的PFS缩短。在大多数MMR-D患者中，后续抗PD-1治疗比既往化疗获得更高的ORR和更长的PFS，支持更早使用免疫检查点抑制剂。
Purpose: We evaluated the association between molecular sub-types of advanced gastric cancer (AGC) and the efficacy of standard chemotherapy or immune checkpoint inhibitors.Experimental Design: Patients with AGC who received systemic chemotherapy from October 2015 to July 2018 with available molecular features were analyzed. We investigated the efficacy of standard first- (fluoropyrimidine + platinum +/- trastuzumab) and second-line (taxanes +/- ramucirumab) chemotherapy, and subsequent anti-PD-1 therapy in patients with four molecular subtypes: MMR-D (mismatch repair deficient), EBV+, HER2+, and all negative.Results: 410 patients were analyzed: MMR-D 5.9%, EBV+ 4.1%, HER2+ 13.7%, and all negative 76.3%. In 285 patients who received standard first-line chemotherapy, the median progression-free survival (PFS) times were 4.2, 6.0, 7.5, and 7.6 months and the objective response rates (ORR) were 31%, 62%, 60%, and 49% in MMR-D, EBV+, HER2+, and all-negative subtypes, respectively. Multivariate analysis showed shorter PFS in MMR-D versus all-negative patients [HR, 1.97; 95% CIs, 1.09-3.53; P = 0.022]. In second-line setting, there were no significant differences in efficacy. In 110 patients who received anti-PD-1 therapy, median PFS times were 13.0, 3.7, 1.6, and 1.9 months and the ORRs were 58%, 33%, 7%, and 13%, respectively. Twelve patients with MMR-D received subsequent anti-PD-1 therapy and showed longer PFS compared with that in 10 (83%) patients who received earlier-line chemotherapy.Conclusions: MMR-D might result in shorter PFS with first-line chemotherapy for AGC. Subsequent anti-PD-1 therapy achieved higher ORR and longer PFS than prior chemotherapy in most patients with MMR-D, supporting the earlier use of immune checkpoint inhibitors.