Multidimensional comparative evaluation of first-line therapies for extensive-stage small cell lung cancer: a systematic review and network meta-analysis of clinical efficacy and safety profiles

Abstract

Background: The first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) has evolved from chemotherapy alone to chemoimmunotherapy. However, the improvements in overall survival (OS) and progression-free survival (PFS) have been modest. Therefore, this study employs a comprehensive multidimensional evaluation framework to identify optimized therapeutic combinations with enhanced efficacy and improved safety profiles in the immunotherapy era.

Methods: An adaptive search strategy was employed to retrieve all relevant literature from electronic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, from database inception to November 2024. The retrieved studies were carefully screened according to pre-designed inclusion and exclusion criteria. Clinical research articles and their supplementary materials that met the criteria were obtained and thoroughly reviewed. Manual data extraction was conducted, with the safety data and efficacy outcomes. A network meta-analysis of all acquired data for each outcome was performed. The study protocol was pre-registered in PROSPERO, CRD42024612944.

Results: This network meta-analysis included 6,473 patients from 14 head-to-head randomized controlled trials (RCTs). Compared with etoposide-platinum chemotherapy combined with a programmed cell death ligand 1 inhibitor (the Chemo + PD-L1 regimen), the addition of anlotinib (the Chemo + PD-L1 + Anlo regimen) resulted in better PFS (hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.33-0.54) and objective response rate (ORR) (odds ratio (OR), 1.81; 95% CI, 1.13-2.91). Moreover, adding BMS-986012 (anti-fucosyl-GM1 antibodies) to the Chemo + PD-L1 regimen ranked first in the surface under the cumulative ranking curve (SUCRA, 0.96) analysis for OS. Compared with the Chemo + PD-L1 regimen, the addition of an anti-CTLA-4 inhibitor (the Chemo + PD-L1 + CTLA-4 regimen) was associated with an increased risk of treatment-related adverse events (TRAEs) of grades ≥ 3 (risk ratio (RR), 1.19; 95%CI, 1.04-1.36).

Conclusions: Incorporating anlotinib into the Chemo + PD-L1 regimen can be a viable first-line option for patients with high tumor burden, but cannot fully replace the current first-line standard-of-care (SOC). Chemoimmunotherapy combined with immune-related targeting drugs demonstrates the potential to improve overall survival.

Keywords: Angiogenesis; Chemoimmunotherapy; Extensive-stage; Immune checkpoint inhibitor; Network meta-analysis; Small cell lung cancer.

Fig. 1

The Flowchart of Literature Screening Process

Fig. 2

Network meta-analysis for efficacy. #1. The red squares along the diagonal represent the conventional and new first-line SOC for patients with ES-SCLC. The blue squares along the diagonal indicate experimental treatment modalities added to the SOC, which are not included in the first-line SOC. The differently colored squares on either side of the diagonal correspond to distinct clinical outcome measures, as indicated in the legend at the bottom left. All statistically significant results are shown in bold. #2. Effect sizes were considered statistically significant if the 95% confidence interval (CI) did not include 1, which was also marked. #3. A treatment modality with an HR for OS or PFS less than 1, or an OR for ORR or DCR greater than 1, was deemed more favorable. #4. Abbreviations: Chemo, Etoposide-Platinum (Cisplatin or Carboplatin) Chemotherapy; CTLA-4, Cytotoxic T-lymphocyte associated protein 4; PD-L1, programmed cell death ligand 1; PD-1, programmed cell death 1; Anlo, anlotinib; Bev, bevacizumab; SOC, Standard of Care

Fig. 3

Network meta-analysis for safety. A Overall toxicity and gastrointestinal symptoms. B Hematology toxcity. #1. The red squares along the diagonal represent the conventional and new first-line SOC for patients with ES-SCLC. The blue squares along the diagonal indicate experimental treatment modalities added to the SOC, which are not included in the first-line SOC. The differently colored squares on either side of the diagonal correspond to distinct clinical outcome measures, as indicated in the legend at the bottom left. All statistically significant results are shown in bold. #2. Effect sizes were considered statistically significant if the 95% confidence interval (CI) did not include 1, which was also marked. #3. An RR greater than 1 for TRAEs suggested a higher toxicity risk. #4. When collecting data, prioritize using “Leukopenia; Neutropenia; Thrombocytopenia”. If these specific data are unavailable, use the corresponding “Decreased white-cell count; Decreased neutrophil count; Decreased platelet count” data. #5. When collecting data, if TRAEs data are not reported, use AEs (Adverse Events) data instead. #6. Abbreviations: Chemo, Etoposide-Platinum (Cisplatin or Carboplatin) Chemotherapy; CTLA-4, Cytotoxic T-lymphocyte associated protein 4; PD-L1, programmed cell death ligand 1; PD-1, programmed cell death 1; Anlo, anlotinib; Bev, bevacizumab; SOC, Standard of Care

Fig. 4

The ranking probabilities of First-Line Treatment Regimens for Patients with ES-SCLC. #1. Each cell in the heatmap is colored based on the Surface Under the Cumulative Ranking (SUCRA) value of the corresponding treatment and outcome. Blue indicates a 100% probability of being ranked first, while yellow indicates a 0% probability of being ranked first. #2. Abbreviations: NA, Not Applicable; Chemo, Etoposide-Platinum (Cisplatin or Carboplatin) Chemotherapy; CTLA-4, Cytotoxic T-lymphocyte associated protein 4; PD-L1, programmed cell death ligand 1; PD-1, programmed cell death 1; Anlo, anlotinib; Bev, bevacizumab