Shang Xiaoling, Zhang Chenyue, Lv Yuanyuan, Zhang Xiaoxiao, Guo Kaiyue, Li Huijuan, Wang Haiyong
Shandong Cancer Hospital and Institute, Shandong University, Jinan, 250117, People's Republic of China.
Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, People's Republic of China.
Immunotargets Ther. 2024 Oct 26;13:571-583. doi: 10.2147/ITT.S483093. eCollection 2024.
Immune checkpoint inhibitors (ICIs) has prolonged survival in patients with extensive-stage small cell lung cancer (ES-SCLC) as first-line treatment. However, whether ICI rechallenge could bring survival benefit to patients with ES-SCLC following its failure as first-line treatment remains unknown. Therefore, we aim to address the issue and identify the cohort of patients that may derive such benefit.
Patients with ES-SCLC from both the IMpower133 study and Shandong Cancer Hospital and Institute (shanzhong cohort) who failed first-line ICI were included. Kaplan Meier analysis was performed to compare overall survival (OS). Both univariate and multivariate Cox regression analyses were conducted to identify factors affecting survival. Tumor immune cell infiltration was evaluated by the CIBERSORT algorithm and detected by multiplex immunofluorescence (mIF).
A total of 125 ES-SCLC patients undergoing atezolizumab and 161 patients undergoing ICI as first-line treatment were recruited from IMpower133 and shanzhong cohort. Those receiving ICI rechallenge had a longer OS than those without in IMpower133 ( = 0.08) and shanzhong cohort ( = 0.013). In IMpower133 cohort, subgroup analyses found that patients with <4 metastatic sites derived more survival benefit from atezolizumab ( = 0.008). For patients with ES-SCLC harboring <4 metastatic sites, there was significant OS difference between atezolizumab versus non-atezolizumab as retreatment ( = 0.036). Moreover, for ES-SCLC patients with <4 metastatic sites, atezolizumab improved survival compared with non-atezolizumab (hazard ratio [HR]: 0.457; 95% CI: 0.256-0.817; = 0.008). These findings were confirmed in shanzhong cohort. Those harboring <4 metastatic sites had fewer M2 macrophage and more CD4 naïve T cells infiltration, which was further confirmed by mIF of ES-SCLC samples from shanzhong cohort.
Our study provides rationale for ICI rechallenge among ES-SCLC patients with <4 metastatic sites, suggesting beneficial outcome by reshaping TME.
免疫检查点抑制剂（ICIs）作为一线治疗已延长了广泛期小细胞肺癌（ES-SCLC）患者的生存期。然而，ICI再挑战在一线治疗失败后的ES-SCLC患者中是否能带来生存获益仍不清楚。因此，我们旨在解决这一问题并确定可能从中获益的患者群体。
纳入来自IMpower133研究以及山东肿瘤医院和研究所（山中队列）一线ICI治疗失败的ES-SCLC患者。采用Kaplan-Meier分析比较总生存期（OS）。进行单因素和多因素Cox回归分析以确定影响生存的因素。通过CIBERSORT算法评估肿瘤免疫细胞浸润，并通过多重免疫荧光（mIF）检测。
从IMpower133和山中队列中招募了总共125例接受阿替利珠单抗治疗的ES-SCLC患者和161例接受ICI一线治疗的患者。在IMpower133队列（P = 0.08）和山中队列（P = 0.013）中，接受ICI再挑战的患者OS长于未接受再挑战的患者。在IMpower133队列中，亚组分析发现转移部位<4个的患者从阿替利珠单抗中获得更多生存获益（P = 0.008）。对于转移部位<4个的ES-SCLC患者，阿替利珠单抗与非阿替利珠单抗作为再治疗的OS存在显著差异（P = 0.036）。此外，对于转移部位<4个的ES-SCLC患者，阿替利珠单抗与非阿替利珠单抗相比改善了生存（风险比[HR]：0.457；95%CI：0.256 - 0.817；P = 0.008）。这些发现在山中队列中得到证实。转移部位<4个的患者M2巨噬细胞较少且CD4幼稚T细胞浸润较多，这在山中队列的ES-SCLC样本的mIF中得到进一步证实。
我们的研究为转移部位<4个的ES-SCLC患者进行ICI再挑战提供了理论依据，表明通过重塑肿瘤微环境可带来有益结果。
