Abstract

RATIONALE

Extensive-stage small cell lung cancer (SCLC) carries a poor prognosis and has limited therapeutic options. The addition of immune-checkpoint inhibitors (ICIs) to platinum-etoposide (PE) chemotherapy has become an important first-line treatment strategy. However, the comparative benefits and harms of different first-line chemotherapy-based regimens, including ICI-containing combinations, remain unclear.

OBJECTIVES

To evaluate the comparative benefits and harms of immunotherapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4), plus chemotherapy and other relevant first-line systemic chemotherapy-based regimens, for the first-line systemic treatment of extensive-stage SCLC with a network meta-analysis; to rank the interventions according to their benefits and harms; and to explore the potential role of biomarkers or clinical factors, where data are available.

SEARCH METHODS

We used CENTRAL, MEDLINE, and Embase, together with clinical trial registries, to identify studies that were included in the review. The latest search date was 12 December 2025.

ELIGIBILITY CRITERIA

We included randomised controlled trials (RCTs) comparing first-line systemic chemotherapy-based regimens, including chemotherapy alone, chemotherapy combined with ICIs, and other relevant combination strategies, in adults (≥ 18 years) with previously untreated extensive-stage SCLC.

OUTCOMES

Critical outcomes were overall survival (OS) and adverse events (AEs). These include any grade AEs, serious AEs, and grade ≥ 3 AEs. Important outcomes were progression-free survival (PFS), objective response rate (ORR), and health-related quality of life (HRQoL).

RISK OF BIAS

We assessed the risk of bias using the Cochrane RoB 2 tool. We judged most studies to have low risk of bias or some concerns across key domains. Some concerns mainly related to measurement of the outcome in open-label trials and selection of the reported result where protocols or registry entries were unavailable or incomplete. The extent to which these limitations may have influenced the critical outcomes of OS and AEs remains uncertain.

SYNTHESIS METHODS

We synthesised results for each outcome using meta-analysis where possible, using a contrast-based random-effects network meta-analysis with a common heterogeneity parameter. For network meta-analysis, we assessed the certainty of the evidence using the GRADE approach, informed by the CINeMA framework.

INCLUDED STUDIES

Fourteen RCTs were included, with 7541 participants contributing to the critical outcome of OS. The evidence network comprised a total of 17 treatment regimens. Most studies compared PE chemotherapy combined with ICIs targeting programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1). Some trials evaluated additional immune-checkpoint pathways, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), or incorporated anti-angiogenic agents.

SYNTHESIS OF RESULTS

For OS, based on a network meta-analysis of 14 studies (7541 participants), PE + benmelstobart + anlotinib reduced the hazard of death most compared with PE (hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.47 to 0.79; high-certainty evidence), followed by PE + serplulimab (HR 0.63, 95% CI 0.49 to 0.82), PE + durvalumab (HR 0.71, 95% CI 0.59 to 0.85), and PE + adebrelimab (HR 0.72, 95% CI 0.58 to 0.90). Several other regimens, including PE + tislelizumab, PE + atezolizumab, PE + pembrolizumab, PE + toripalimab, and PE + durvalumab + tremelimumab, also reduced the hazard of death compared with PE. For PFS, based on 14 studies (7541 participants), the largest reductions in the hazard of progression were with PE + benmelstobart + anlotinib (HR 0.32, 95% CI 0.25 to 0.40) and PE + anlotinib (HR 0.44, 95% CI 0.36 to 0.54; high-certainty evidence). Several other regimens, including PE + tislelizumab, PE + serplulimab, PE + toripalimab, PE + adebrelimab, PE + pembrolizumab, PE + atezolizumab, and PE + durvalumab, also reduced the hazard of progression compared with PE. For ORR, based on 14 studies (7385 participants), PE + benmelstobart + anlotinib (RR 1.22, 95% CI 1.09 to 1.35), PE + anlotinib (RR 1.22, 95% CI 1.09 to 1.35), PE + pembrolizumab (RR 1.14, 95% CI 1.00 to 1.31), and PE + serplulimab (RR 1.14, 95% CI 1.03 to 1.26) increased the ORR compared with PE (high-certainty evidence), whereas most other regimens showed little or no difference compared with PE. Safety profiles varied across regimens. For any AEs, based on 11 studies (6249 participants), the risk was higher with PE + serplulimab (RR 1.25, 95% CI 1.08 to 1.43; high-certainty evidence) and was also increased with PE + ipilimumab and PE + atezolizumab-based combinations. For serious AEs, based on 10 studies (4264 participants), several regimens showed higher risks compared with PE. The largest increases were with PE + tislelizumab (RR 1.75, 95% CI 1.25 to 2.45) and PE + durvalumab + tremelimumab (RR 1.42, 95% CI 1.14 to 1.77). Higher risks were also seen with PE + adebrelimab, PE + benmelstobart + anlotinib, PE + toripalimab, and PE + socazolimab. For grade ≥ 3 AEs, based on 12 studies (6446 participants), differences between most regimens and PE were small, with increases for PE + atezolizumab + tiragolumab, PE + durvalumab + tremelimumab, PE + anlotinib, and PE + benmelstobart + anlotinib. HRQoL data were insufficient for quantitative synthesis because measurement instruments and reporting formats differed across studies; therefore, we summarised the findings narratively.

AUTHORS' CONCLUSIONS

In people with extensive-stage SCLC, several ICI-based combinations with PE chemotherapy improve OS compared with PE alone (high-certainty evidence), although the magnitude of benefit varies across regimens. Some combinations probably or may have little to no effect on OS. Effects on PFS and ORR vary across treatments, and some combinations increase the risk of AEs whereas others result in little to no difference. HRQoL data were insufficient for quantitative synthesis, and so we are unable to draw conclusions about this outcome. The certainty of the evidence varies across outcomes and comparisons, reflecting differences in study design, variability in safety reporting, and limited direct head-to-head comparisons. Further RCTs directly comparing commonly used first-line regimens, with consistent reporting of AEs and patient-reported outcomes including HRQoL, are needed to reduce uncertainty and inform treatment decisions.

FUNDING

Takeshi Hasegawa and Hisashi Noma were supported by the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239).

REGISTRATION

Protocol available via doi.org/10.1002/14651858.CD015738.

MeSH

Registries, Cells, Research Design, Bias, Quality Of Life, Lung, Neoplasms, Drug Therapy, Lung Neoplasms, Network Meta-Analysis, Small Cell Lung Carcinoma, Research, Therapeutics, T-Lymphocytes, Chemotherapy