PD-1 Blockade Plus Chemotherapy for EGFR-Mutant, EGFR Tyrosine Kinase Inhibitor-Pretreated Non-Small Cell Lung Cancer: A Multicenter Retrospective Study on Efficacy and Biomarker Exploration

Background: Patients with non-small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations respond poorly to immune checkpoint inhibitors (ICI). Our retrospective study evaluated the efficacy and explored potential biomarker for ICIs combined with chemotherapy in patients with EGFR -mutated NSCLC who were not detected with actionable mutations after progressing from EGFR-targeted therapies.Methods: Our study included 226 patients with NSCLC who were not detected with actionable mutations following disease progression with EGFR inhibitors. Of whom, 117 received chemotherapy plus anti-PD-1 inhibitor (Chemo + ICI) and 109 received platinum-based chemotherapy (with or without bevacizumab; Chemo/Chemo + Bev). Baseline whole blood lymphocytes subsets using six biomarkers were analyzed by flow cytometry in 46 patients treated with Chemo + ICI (training group, Group 1) to access the efficacy. Simultaneously, baseline whole blood lymphocytes subsets of 62 patients receiving first line chemo + ICI treatment (validation group, Group 2, enrolled in clinical trials [ORIENT 12/11, CAMEL/CAMEL-Sq, CHOICE-1]) were also analyzed. An optimal cutoff value was determined using the Youden index.Findings: Compared with the Chemo/Chemo + Bev group, patients treated with Chemo + ICI had significantly longer progression-free survival (PFS, 6 vs. 4 months; p<0.0001). No statistical difference was observed for overall survival between the two groups (14 vs. 11 months; p=0.06). The objective response rate (ORR) was 34.2% for Chemo + ICI group and 22.0% for Chemo/Chemo + Bev group. Univariate and multivariate analyses both indicated that Chemo + ICI was an independent factor for predicting better clinical outcomes. Lymphocytes subset model (LSM) showed good performance in predicting PFS. Patients with LSM-low had significantly higher ORR (p=0.007), significantly longer PFS (p<0.001) and overall survival (p=0.004).Interpretation: Our study provides real-world clinical evidence that patients with EGFR -mutant, EGFR inhibitor-resistant NSCLC benefit from chemotherapy combined with anti-PD-1 inhibitor. Lymphocyte subsets model might serve as a novel, routine, cost-effectiveness, and non-invasion strategy in selecting patients who would benefit from this combination regimen.Funding: This work received financial support from the National Natural Science Foundation of China (grant numbers: 82003206, 82173338, 82102747, and 82160489) and Natural Science Foundation of Hunan Province (grant numbers: 2020SK2031, 2020SK2030, 2021RC4040, and 2020JJ3025). Declaration of Interest: All authors declare no conflict of interest.Ethical Approval: Approval was obtained from the Hunan Cancer HospitalInstitutional Review Board Committee (2020YYQ-SSB-651).