Immunotherapy in Extensive Stage Small-Cell Lung Cancer in First-Line and Second-Line Setting

Objectives: Despite a good response to first-line chemotherapy, small-cell lung cancer (SCLC) has high relapse rates and a poor prognosis. We conducted a systematic review and meta-analysis to assess the role of immune checkpoint inhibitors (ICIs) in the treatment of extended stage SCLC (ES-SCLC), in different lines of therapy. Methods: Medline (PubMed), EMBASE, and Cochrane Library databases between January 2010 and March 2025 and conference proceedings between 2018 and 2025 were searched for RCTs assessing ICIs versus chemotherapy in patients with ES-SCLC. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and grade 3+ adverse events. Pooled hazard ratios (HR) for OS and PFS were meta-analyzed using the generic inverse variance method, and random-effect models were used to compute pooled estimates. Subgroup analyses compared survival by line of therapy, sex, age, and ECOG status. Results: ICIs decreased risk of death by 19% (HR: 0.81, 95% CI: 0.76-0.86). OS benefit was regardless of age, sex, or ECOG, but only in first-line treatment. ICIs decreased the risk of disease progression by 22% (HR: 0.78, 95% CI: 0.67-0.91), with PFS benefit restricted to first-line treatment with a detrimental effect in the second line. ICIs improved ORR (OR: 0.79, 95% CI: 0.66-0.95), but were associated with increased grade 3+diarrhea (OR: 3.63, 95% CI: 1.46-9.02). Conclusions: ICIs conferred efficacy benefits and an acceptable safety profile in the treatment of patients with ES-SCLC in the first-line, but should not be used in the second-line as single agents. Biomarkers predicting long-term benefit are needed to further improve outcomes.