ObjectiveFew data are available on the optimal treatment options after disease progression from first-line treatment of immune checkpoint inhibitors (ICIs) plus chemotherapy. This study aimed to describe the safety and efficacy of continuing ICIs beyond first progress disease (PD) in non-small cell lung cancer (NSCLC).MethodsPatients with NSCLC previously treated with first-line anti-PD-1 antibody plus platinum-doublet chemotherapy and hence had PD as per Response Evaluation Criteria in Solid Tumors v1.1 were enrolled. For the subsequent line, patients received physician’s choice (PsC) with or without an anti-PD-1 antibody. The primary outcome was progression-free survival after second-line treatment (PFS2). Secondary outcomes included overall survival (OS) from the initiation of first-line treatment, post-second-progression survival (P2PS), overall response rate (ORR), disease control rate (DCR), and safety during second-line treatment.ResultsBetween July 2018 and January 2021, 59 patients were included. A total of 33 patients received a physician-decided second-line regimen plus ICIs (PsC plus ICIs group), and 26 patients did not continue ICIs (PsC group). There was no significant difference in PFS2 between the PsC plus ICIs group and the PsC group (median, 6.5 vs. 5.7 months,p= 0.46). median OS (28.8 vs. 29.2 months), P2PS (13.4 vs. 18.7 months), ORR (18.2% vs. 19.2%), and DCR (78.8% vs, 84.6%) were also similar between the two groups. No new safety signals were observed.ConclusionIn this real-world setting, patients treated with continued ICIs beyond their first disease progression did not experience clinical benefit but without compromising safety.