新发转移性鼻咽癌化疗免疫治疗后同步与序贯PD-1阻断联合局部区域放疗的比较：一项里程碑分析。

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中文摘要

背景： 化疗免疫治疗后行巩固性局部区域放疗已越来越多地用于经选择的新发转移性鼻咽癌（dmNPC）患者。然而，在局部区域放疗（LRRT）期间是否应继续同步进行PD-1阻断仍不确定。
方法： 我们回顾性分析了238例接受铂类化疗联合抗PD-1治疗后行根治性局部区域放疗的新发转移性鼻咽癌患者。进行了12个月里程碑分析以减少永生时间偏倚，并使用逆概率治疗加权来平衡基线和治疗相关特征。采用递归分割分析进行风险分层，纳入疾病负荷、治疗前乳酸脱氢酶、化疗免疫治疗后EB病毒DNA清除情况以及影像学反应。评估放疗后的纵向绝对淋巴细胞计数。
结果： 在238例患者中，185例在局部区域放疗期间接受了同步PD-1阻断，53例未接受。经加权和里程碑调整后，同步PD-1阻断与较差的无进展生存期（PFS）相关（加权风险比，3.189；95% CI，1.352-7.524；P=0.008）。同步组的无远处转移生存期也较差，而两组间的无局部区域复发生存期相似。在观察到的四种治疗模式中，三明治策略，即化疗免疫治疗后行LRRT而不进行同步PD-1阻断并随后进行维持免疫治疗，显示出最有利的结局。在仅限于全程和三明治策略的里程碑调整比较中，三明治策略仍与更优的PFS相关（风险比，0.254；95% CI，0.078-0.821；P=0.022）。探索性亚组分析提示，在高风险患者中同步PD-1阻断的结局模式较差，尽管各亚组样本量有限。放疗后3个月持续性淋巴细胞减少与不良结局相关，尤其是在接受同步PD-1阻断的患者中。
结论： 总之，在接受一线化疗免疫治疗后行根治性LRRT的dmNPC患者中，LRRT期间同步PD-1阻断与生存结局改善无关，并且在IPTW调整的里程碑分析中与较差的PFS和DMFS相关。探索性分析提示根据基线风险和放疗后免疫恢复可能存在异质性，但这些发现受限于较小的亚组样本量。有必要开展前瞻性研究以确定PD-1阻断与LRRT的最佳序贯方式。

英文摘要

BACKGROUND: Chemoimmunotherapy followed by consolidative locoregional radiotherapy has increasingly been used for selected patients with de novo metastatic nasopharyngeal carcinoma (dmNPC). However, whether PD-1 blockade should be continued concurrently during locoregional radiotherapy (LRRT) remains uncertain.
METHODS: We retrospectively analyzed 238 patients with de novo metastatic nasopharyngeal carcinoma who received platinum-based chemotherapy plus anti-PD-1 therapy followed by definitive locoregional radiotherapy. A 12-month landmark analysis was performed to reduce immortal time bias, and inverse probability of treatment weighting was used to balance baseline and treatment-related characteristics. Recursive partitioning analysis incorporating disease burden, pretreatment lactate dehydrogenase, post-chemoimmunotherapy Epstein-Barr virus DNA clearance, and radiological response was used for risk stratification. Longitudinal absolute lymphocyte counts were evaluated after radiotherapy.
RESULTS: Among 238 patients, 185 received concurrent PD-1 blockade during locoregional radiotherapy and 53 did not. After weighting and landmark adjustment, concurrent PD-1 blockade was associated with inferior progression-free survival (PFS) (weighted hazard ratio, 3.189; 95% CI, 1.352-7.524; P=0.008). Distant metastasis-free survival was also inferior in the concurrent group, whereas locoregional recurrence-free survival was similar between groups. Among the four observed treatment patterns, the sandwich strategy, defined as chemoimmunotherapy followed by LRRT without concurrent PD-1 blockade and with subsequent maintenance immunotherapy, showed the most favorable outcomes. In the landmark-adjusted comparison restricted to the full-course and sandwich strategies, the sandwich strategy remained associated with superior PFS (hazard ratio, 0.254; 95% CI, 0.078-0.821; P=0.022). Exploratory subgroup analyses suggested a less favorable outcome pattern with concurrent PD-1 blockade among high-risk patients, although individual subgroup sizes were limited. Persistent lymphopenia at 3 months after radiotherapy was associated with poor outcomes, particularly among patients receiving concurrent PD-1 blockade.
CONCLUSION: In conclusion, among patients with dmNPC treated with first-line chemoimmunotherapy followed by definitive LRRT, concurrent PD-1 blockade during LRRT was not associated with improved survival outcomes and was linked to inferior PFS and DMFS in an IPTW-adjusted landmark analysis. Exploratory analyses suggested potential heterogeneity according to baseline risk and post-radiotherapy immune recovery, but these findings were limited by small subgroup sizes. Prospective studies are warranted to define the optimal sequencing of PD-1 blockade and LRRT.