Long-term overall survival with dual CTLA-4 and PD-L1 or PD-1 blockade and biomarker-based subgroup analyses in patients with advanced non-small-cell lung cancer: a systematic review and reconstructed individual patient data meta-analysis.

However, it remains unclear which patients benefit from the addition of CTLA-4 inhibitors.

然而，目前尚不清楚哪些患者能从添加CTLA-4抑制剂中获益。

We aimed to evaluate whether dual checkpoint blockade with CTLA-4 and PD-L1 or PD-1 inhibitors provides similar efficacy to PD-L1 or PD-1 inhibitor monotherapy, or whether these strategies produce distinct outcomes across NSCLC subpopulations.

我们旨在评估双重检查点阻断，即同时使用CTLA-4和PD-L1或PD-1抑制剂，是否与仅使用PD-L1或PD-1抑制剂单药治疗具有相似的疗效，或者这些策略是否在非小细胞肺癌（NSCLC）亚群中产生不同的结果。

Methods

We conducted a search of PubMed, MEDLINE, and Embase for randomised phase 3 trials published from database inception to Nov 21, 2024, that investigated PD-L1 or PD-1 inhibitors, with or without CTLA-4 inhibitors, in patients with advanced NSCLC.

我们对PubMed、MEDLINE和Embase进行了检索，研究了从数据库开始到2024年11月21日发表的随机III期试验，这些试验研究了在晚期非小细胞肺癌患者中使用PD-L1或PD-1抑制剂，无论是否联合使用CTLA-4抑制剂。

We focused on studies reporting Kaplan-Meier survival data at 5 years or biomarker analyses based on PD-L1, KRAS, and STK11 mutational status.

我们关注报告了5年Kaplan-Meier生存数据或基于PD-L1、KRAS和STK11突变状态的生物标志物分析的研究。

Individual patient data were extracted from Kaplan-Meier curves with WebPlotDigitizer version 5 and reconstructed with the IPDfromKM method.

使用WebPlotDigitizer版本5从Kaplan-Meier曲线中提取了个别患者数据，并使用IPDfromKM方法进行重建。

The primary endpoint of the study was 5-year overall survivalin the overall population and in subpopulations based on PD-L1 tumour proportion score (TPS), tumour histology, and mutational status (mutant vs wild-type) of KRAS and STK11.

该研究的主要终点是整体人群以及基于PD-L1肿瘤比例评分（TPS）、肿瘤组织学、KRAS和STK11的突变状态（突变型与野生型）的亚组人群的5年总生存期。

This study was registered with PROSPERO, CRD420251081707.

该研究已在PROSPERO注册，注册号为CRD420251081707。

Results

The initial search yielded 1026 results, and six randomised clinical trials met the eligibility criteria and were included.

初步检索产生了1026个结果，六项随机临床试验符合纳入标准并被纳入。

Among the 2881 patients eligible for analysis (838 [29·1%] female and 2043 [70·9%] male), 1282 received dual CTLA-4 and PD-L1 or PD-1 blockade and 1599 received single PD-L1 or PD-1 blockade.

在2881名符合分析资格的患者中（女性838名[29.1%]，男性2043名[70.9%]），1282名接受了CTLA-4和PD-L1或PD-1双重阻断治疗，而1599名接受了单药PD-L1或PD-1阻断治疗。

Patients treated with dual CTLA-4 and PD-L1 or PD-1 blockade had similar median overall survivalcompared with those treated with single PD-L1 or PD-1 inhibition (16·1 months [95% CI 15·0-17·8] vs 16·9 months [15·5-18·3]; HR 0·95 [95% CI 0·87-1·03], p=0·19).

接受双CTLA-4和PD-L1或PD-1阻断治疗的患者与接受单PD-L1或PD-1抑制治疗的患者总生存期中位数相似（16.1个月 [95% CI 15.0-17.8] 对比 16.9个月 [15.5-18.3]；HR 0.95 [95% CI 0.87-1.03]，p=0.19）。

Median overall survivalwas significantly longer with dual CTLA-4 and PD-L1 or PD-1 blockade among patients with PD-L1 TPS less than 1% versus those treated with single PD-L1 or PD-1 inhibition (15·5 months [95% CI 13·6-18·5] vs 14·5 months [13·4-15·9]; HR 0·85 [95% CI 0·74-0·98], p=0·021), with 5-year overall survivalrates of 16·6% (95% CI 13·4-20·6) versus 9·3% (7·0-12·3), respectively.

在PD-L1 TPS小于1%的患者中，接受双CTLA-4和PD-L1或PD-1阻断治疗的总生存期中位数显著长于接受单PD-L1或PD-1抑制治疗的患者（15.5个月 [95% CI 13.6-18.5] 对比 14.5个月 [13.4-15.9]；HR 0.85 [95% CI 0.74-0.98]，p=0.021），5年总生存率分别为16.6%（95% CI 13.4-20.6）和9.3%（7.0-12.3）。

Median overall survivalin patients with tumours harbouring STK11 mutations was also significantly longer with dual CTLA-4 and PD-L1 or PD-1 blockade compared with single PD-L1 or PD-1 inhibition (13·9 months [95% CI 9·8-20·8] vs 7·8 months [6·4-12·9]; HR 0·67 [95% CI 0·49-0·91], p=0·012).

在携带STK11突变的肿瘤患者中，双靶向CTLA-4和PD-L1或PD-1阻断的中位总生存期也显著长于单一PD-L1或PD-1抑制（13.9个月 [95% 置信区间 9.8-20.8] 对比 7.8个月 [6.4-12.9]；风险比0.67 [95% 置信区间 0.49-0.91]，p=0.012）。

However, no significant differences in overall survivalwere found between treatment groups by tumour histology (squamous vs non-squamous NSCLC) or by KRAS mutational status.

然而，在治疗组之间，无论是按肿瘤组织学（鳞状细胞癌对比非鳞状NSCLC）还是按KRAS突变状态分层，均未发现总生存期有显著差异。

interpretation

Compared with single PD-L1 or PD-1 inhibition, dual immune checkpoint blockade with CTLA-4 and PD-L1 or PD-1 inhibitors was associated with improved overall survivalin patients with advanced NSCLC and PD-L1 TPS less than 1% and in those with STK11 mutations, but not in the overall population.

与单一PD-L1或PD-1抑制相比，同时阻断CTLA-4和PD-L1或PD-1的双重免疫检查点阻断在PD-L1 TPS小于1%的晚期非小细胞肺癌患者以及STK11突变患者中与总生存期改善相关，但在整体人群中并未显示出这种效果。

Prospective validation of these results in clinical trials is warranted.

在临床试验中前瞻性验证这些结果是有必要的。

funding

NextGenerationUE.

下一代UE。