Xiaoling Shang,1,* Chenyue Zhang,2,* Yuanyuan Lv,3,* Xiaoxiao Zhang,3,* Kaiyue Guo,4 Huijuan Li,3 Haiyong Wang5 

1Shandong Cancer Hospital and Institute, Shandong University, Jinan, 250117, People’s Republic of China; 2Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, People’s Republic of China; 3Department of Clinical Drug Research, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China; 4Department of Radiation Oncology, Qilu Hospital of Shandong University, Shandong University, Jinan, 250117, People’s Republic of China; 5Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Huijuan Li, Department of Clinical Drug Research, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China, Email ywb234@126.com Haiyong Wang, Department of internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China, Tel +860531-87984777, Fax +86531-87984079, Email wanghaiyong6688@126.com

Background: 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.
Methods: 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).
Results: 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 (P = 0.08) and shanzhong cohort (P = 0.013). In IMpower133 cohort, subgroup analyses found that patients with < 4 metastatic sites derived more survival benefit from atezolizumab (P = 0.008). For patients with ES-SCLC harboring < 4 metastatic sites, there was significant OS difference between atezolizumab versus non-atezolizumab as retreatment (P = 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; P = 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.
Conclusion: Our study provides rationale for ICI rechallenge among ES-SCLC patients with < 4 metastatic sites, suggesting beneficial outcome by reshaping TME.

Keywords: extensive stage small cell lung cancer, ICI rechallenge, survival, metastatic sites, tumor microenvironment