晚期实体瘤患者中止免疫检查点抑制剂治疗的结局：系统综述与Meta分析

对于因非疾病进展（PD）原因中止免疫检查点抑制剂（ICIs）治疗的转移性肿瘤患者的临床结局研究较少。我们对所有报道因非PD原因中止ICIs的临床试验（随机或非随机）和观察性研究进行了Meta分析。检索了PubMed、Embase和Scopus数据库，截止至2023年12月，筛选出评估PD-(L)1和CTLA-4抑制剂在转移性实体瘤患者中的疗效的研究，且这些患者因非PD原因中止治疗。每项研究均提供了泳道图或Kaplan-Meier生存曲线，用以重建中止免疫治疗后无进展生存期（PFS）的患者数据。主要终点为中止治疗后整体和按肿瘤组织类型、治疗类型及中止原因划分的PFS。采用Combersure方法在随机效应模型下估算非参数化的生存曲线。共纳入36项研究（2180例患者）。合并中位PFS（mPFS）为24.7个月（95% CI，18.8-30.6），12、24和36个月的PFS率分别为69.8%（95% CI，63.1-77.3）、51.0%（95% CI，43.4-59.8）和34.0%（95% CI，27.0-42.9）。单变量分析显示，黑色素瘤患者的中位PFS显著长于非小细胞肺癌（NSCLC，13.5个月）和肾细胞癌（RCC，10.0个月；组间比较p值<0.001）；用抗PD-(L)1 + 抗CTLA-4治疗的患者中位PFS（44.6）也显著优于单一抗PD-(L)1（19.9个月；p<0.001）；在NSCLC中，因治疗毒性而中止的患者其PFS更短（4.8）相比于因其他原因中止的患者（19.6；p=0.003）。多变量分析证实了这些差异。非PD原因中止ICIs的患者的长期预后受临床病理特征影响显著：黑色素瘤患者和/或接受抗PD-(L)1 + 抗CTLA-4治疗者的PFS较长，肾细胞癌或因毒性而中止治疗的NSCLC患者PFS较短。意大利大学和科研部（PRIN 2022Y7HHNW）资助。

The outcome of patients with metastatic tumors who discontinued immune checkpoint inhibitors (ICIs) not for progressive disease (PD) has been poorly explored. We performed a meta-analysis of all studies reporting the clinical outcome of patients who discontinued ICIs for reasons other than PD.We searched PubMed, Embase and Scopus databases, from the inception of each database to December 2023, for clinical trials (randomized or not) and observational studies assessing PD-(L)1 and CTLA-4 inhibitors in patients with metastatic solid tumors who discontinued treatment for reasons other than PD. Each study had to provide swimmer plots or Kaplan-Meier survival curves enabling the reconstruction of individual patient-level data on progression-free survival (PFS) following the discontinuation of immunotherapy. The primary endpoint was PFS from the date of treatment discontinuation overall and according to tumor histotype, type of treatment and reason of discontinuation. The Combersure's method was used to estimate meta-analytical non-parametric summary survival curves assuming random effects at study level.Thirty-six studies (2180 patients) were included. The pooled median PFS (mPFS) was 24.7 months (95% CI, 18.8-30.6) and the PFS-rate at 12, 24, and 36 months was respectively 69.8% (95% CI, 63.1-77.3), 51.0% (95% CI, 43.4-59.8) and 34.0% (95% CI, 27.0-42.9). Univariable analysis showed that the mPFS was significantly longer for patients with melanoma (43.0 months), as compared with non-small cell lung cancer (NSCLC, 13.5 months) and renal cell carcinoma (RCC, 10.0 months; between-strata comparison test p-value < 0.001); for patients treated with anti-PD-(L)1 + anti-CTLA-4 as compared with anti-PD-(L)1 monotherapy (44.6 versus 19.9 months; p-value < 0.001), and in NSCLC when the reason of treatment discontinuation was elective as compared with toxicity onset (19.6 versus 4.8 months; p-value = 0.003). The multivariable analysis confirmed these differences.The long-term outcome of patients who stopped ICIs for reasons other than PD was substantially affected by clinicopathological features: PFS after treatment discontinuation was longer in patients with melanoma, and/or treated with anti-PD-(L)1 + anti-CTLA-4, and shorter in patients with RCC or in those patients with NSCLC who stopped treatment for toxicity onset.The Italian Ministry of University and Research (PRIN 2022Y7HHNW).