According to the National Cancer Institute (NCI), the rate of new cases of lung and bronchus cancer was 52.0 per 100,000 persons per year. The death rate was 35.0 per 100,000 persons per year in 2019; there were an estimated 236,740 new cases in 2022 (1). According to the estimates of the National Cancer Center (NCC) of China, approximately 549,800 newly diagnosed lung cancer cases were reported in 2016; 29.7% of all deaths from cancer were ascribed to lung cancer in men and 22.9% in women (2). Small cell lung cancer (SCLC) represents approximately 15% of all lung cancers, which was a high-grade neuroendocrine carcinoma defined by its aggressiveness, poor differentiation, and somber prognosis (3, 4). The veteran’s administration lung cancer study categorizes SCLC into limited or extensive-stage disease according to whether the disease is limited to one hemithorax in a field amenable to radiation therapy (5). Despite divergent active treatment, SCLC has a bleak prognosis, with a 5-year survival rate of only approximately 7% due to factors like a high proliferative index, a quick doubling time, and a strong propensity to metastasis (5). Throughout the course of the disease, 50% of patients with SCLC will develop central nervous system (CNS) metastasis (6, 7).

For several decades, platinum drugs (cisplatin or carboplatin) plus etoposide, namely, EP protocol, have been established as the first-line standard treatment protocol for ES-SCLC. However, because of the quick emergence of resistance, the transient benefit of therapy, and the limited efficacy of subsequent lines, the survival outcomes benefit remained poor (8–10). Although some trials in Japan demonstrated that an irinotecan-based regimen as a first-line treatment for ES-SCLC had better PFS, its OS advantage was still vague (11). Thus, the above situation compels physicians and scientists to seek better first-line treatments.

One of the most significant advancements in the treatment of cancer was immunotherapy (IO), particularly immune checkpoint inhibitors (ICIs) that obstruct co-inhibitory molecules such as programmed cell death protein-1 (PD-1) and the associated programmed death ligand 1 (PD-L1) (12–15). Clinical evidence has revealed that anti-PD-L1 monoclonal antibodies like atezolizumab and durvalumab provided additional benefits in both OS and progression-free survival (PFS) when compared with platinum-based chemotherapy as the first-line treatment for patients with ES-SCLC (16–18). The National Comprehensive Cancer Network (NCCN) SCLC panel recommended certain chemotherapy plus immunotherapy regimens as preferred alternatives for patients with ES-SCLC in 2018 (9, 19).

Undoubtedly, randomized controlled trials (RCTs) with placebo are the gold standard for determining the efficacy of novel pharmaceutical treatments (20). Until now, there have been numerous regimens treating ES-SCLC, up to now, simultaneously physicians were trapped with making clinical decisions on which regimen to choose owing to the lack of direct/indirect comparisons among those agents, urgently entailing the launch of relevant studies.

Hence, we conducted a Bayesian network meta-analysis comparing the efficacy and safety of immunotherapy combinations with chemotherapy in treating ES-SCLC to provide more evidence for clinical practice.

We conducted this meta-analysis in accordance with the Preferred Reporting Items for Systemic Review and Meta-analyses (PRISMA) checklist ( Supplementary Table 1 ). This network meta-analysis (NMA) was performed and reported in accordance with the PRISMA Extension version (PRISMA-NMA) (21). This study protocol has been registered on the international prospective register of systematic review (PROSPERO) (CRD42022373291).

To the best of our knowledge, this was the first network meta-analysis to compare the relative efficacy of all current available first-line immunotherapy combinations for ES-SCLC, which is more comprehensive than previously published studies (22, 23). In addition, this was the first network meta-analysis to make comparisons among the first-line systemic regimens on OS and PFS in ES-SCLC by each time node.

Our analysis results indicated that the immunotherapy–chemotherapy combination strategy showed significant efficacy for OS compared with placebo, except ipilimumab and tiragolumab plus atezolizumab. According to Bayesian ranking profiles, serplulimab had the highest probability for better OS, followed by atezolizumab and durvalumab, with the same results as before (23). In addition, we proved for the first time that among the first−echelon regimens compared to placebo from a longitudinal perspective, serplulimab, atezolizumab, and durvalumab were first-echelon regimens at the 3rd to 24th month on OS. These findings indicated that they may be related to better long-term survival benefits of patients with ES-SCLC. As for PFS, the immunotherapy combinations revealed better PFS than chemotherapy. The only exception was also tiragolumab plus atezolizumab, which was found to have the worst PFS of all treatments. According to Bayesian ranking profiles, serplulimab had the highest probability for better PFS, with the same results as before (23). Furthermore, in our study, serplulimab and nivolumab were first-echelon drugs from the 1st to the 12th month in PFS and had a faster onset of action compared with placebo.

In this study, efficacy and safety were well balanced in the serplulimab group, which ranked first for OS, PFS, and ORR, and fourth for grade greater than or equal to 3 AEs across all immunotherapy combinations. Serplulimab recently became the first anti-PD-1 antibody, when combined with chemotherapy, demonstrates significant improvement in the survival rates of patients with ES-SCLC (24, 25). According to our research results, serplulimab could be a first-echelon regimen because, first, it takes effect sooner and, second, the patients who benefit from it can experience long-lasting effects. Recently, serplulimab received its first approval in China for the treatment of adult patients with advanced unresectable or metastatic microsatellite instability-high (MSI-H) solid tumors that have failed to respond to previous standard treatments (26). Prior to our study, PD-L1 inhibitors might be preferred for patients with ES-SCLC, and atezolizumab and durvalumab were approved by Food and Drug Administration (FDA) as first-line treatment for patients with ES-SCLC based on the primary data from IMpower133 (27, 28) and CASPIAN (29, 30). Our study also found that the addition of atezolizumab to chemotherapy was associated with the best benefit in survival outcomes but not in ORR, with the same results as before (23). The ORR of the atezolizumab and placebo was 60.2% vs. 64.4%, respectively (17). In addition, the 3-year OS rate of durvalumab was 17.6%, which was nearly three times higher than that of chemotherapy, and the long-term survival benefit was significant. The results showed that the combination of durvalumab and EP regimen could significantly improve the OS of patients, while the combination of durvalumab and tremelimumab plus the EP regimen did not further improve the survival prognosis of ES-SCLC (10.4 vs. 10.5 months; HR = 0.81, 95% CI: 0.67 to 0.97) (31). A final analysis of a recent phase 3 clinical trial (CAPSTONE-1) showed that adebrelimab combined with carboplatin and etoposide improved the OS and PFS of ES-SCLC patients (32). In contrast, the experimental results are not very ideal for PD-1 antibody pembrolizumab and nivolumab; in terms of PFS, the efficacy of pembrolizumab and nivolumab was significantly increased compared with chemotherapy, and the secondary endpoint of OS was also improved. However, there was no significant difference between the two groups (33, 34). In terms of safety and toxicity, consistent with expectations, the immunotherapy–chemotherapy combination strategy did not observe unexpected safety events; all adverse events were controllable. A review of the included studies revealed that anti-PD-1/PD-L1 combinations with chemotherapy were relatively safe. However, toxicity increased, but remained tolerable, when anti-CTLA4/TIGIT and chemotherapy were combined (35–38). Furthermore, inclusion of nivolumab may significantly increase AEs according to our results. The PD-1 and PD-L1 antibodies were the most typical inhibitors of immunological checkpoints, with the primary function of the PD-1/PD-L1 pathway being to induce tumor cells to evade immune attacks (27). Preclinical research showed that chemotherapy altered the immune response against tumor cells and increased PD-L1 expression on tumor cells; additionally, while not reducing the number of T cells in the tumor, chemotherapy can lessen the activation and proliferation of T cells in peripheral blood (39). Head-to-head comparisons are still needed to confirm the efficacy of PD-1 and PD-L1 antibodies for patients with ES-SCLC.

According to the result of CA184-041 and CA184-156 studies, ipilimumab could significantly improve the PFS of patients with ES-SCLC; however, it could not significantly improve the OS in our study; this study confirmed the feasibility of immunotherapy combination strategy for ES-SCLC (37, 40). Ipilimumab was a monoclonal antibody (IgG1) that blocks cytotoxic T-lymphocyte-associated protein 4 (CTLA4) through its association with CD28 and enhances the T-cell response (41). SKYSCRAPER-02 evaluated the addition of tiragolumab to atezolizumab plus carboplatin and etoposide (CE), which did not provide an antitumor effect and survival benefits in patients with untreated ES-SCLC with or without brain metastases. Although the remission rate of tiragolumab was higher, it was of little significance and did not meet the prediction of ES-SCLC response rate for first-line treatment (42). Comparing Impower133 and SKYSCRAPER-02, the control arm outperformed expectations in the SKYSCRAPER-02 study, which was likely the cause of negative endpoints, in addition to the fact that an enhanced benefit in the tiragolumab arm was not seen. However, the reason for this is unclear, and further research is needed (43). TIGIT was an inhibitory receptor expressed on CD4+T cells, effector CD8+T cells, and NK cells. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumor cells to downregulate T-cell and natural killer (NK) cell functions; moreover, anti-TIGIT may synergize with other immunotherapies, such as PD-L1/PD-1 inhibitors, and further amplify the immune response to improve clinical outcomes (44). However, increasing only TIGIT antibody does not appear to increase the efficacy in the tumor microenvironment where there are fewer tumor-infiltrating lymphocytes, according to some studies (45). In conclusion, adding immunosuppressive drugs to the immunological checkpoint alone does not appear to be a breakthrough in the treatment of ES-SCLC without the supervision of biomarkers.

For subgroup analysis, single metastatic sites were favorable prognostic factors in patients with ES-SCLC (5). These data support the idea that patients with asymptomatic CNS metastasis can receive first-line systemic treatment (15, 42). More ongoing clinical trials will shed further light on the safety and efficacy of immunotherapy combination with chemotherapy strategy in patients with CNS metastasis (46, 47).

Immunotherapy combination was the focus of ES-SCLC treatment, and it had higher tumor mutation load (TMB) and higher total immune cell infiltration, suggesting that it may show a greater benefit trend in immunotherapy (48, 49). Whether there were differences in tumor microenvironments between different molecular subtypes of SCLC is also a matter of concern. Recently, some real-world research findings with large sample sizes have further validated the notion that the differential expression of immune genes and predictive biomarkers in various SCLC subtypes might serve as vulnerable areas where rational and personalized treatment strategies can be targeted (50, 51). At the same time, increasing lines of evidence prove that SCLC has different cell origins, suggesting that SCLC was a heterogeneous disease. It might be a feasible strategy to improve the treatment dilemma of SCLC by molecular typing of SCLC through differences in molecular expression, exploring the characteristics of the tumor microenvironment of different molecular subtypes of SCLC, and formulating accurate treatment (50, 52). Therefore, patients with SCLC still urgently need therapeutic drugs with different mechanisms of action. In the realm of future exploration, a crucial direction lies in establishing an organic connection between key factors of SCLC molecular typing and tumor evolution. This could be accomplished through comprehensive multi-group research, aiming to identify targeted treatment strategies.

According to our findings from this research, serplulimab combined with standard chemotherapy appears to be the best course of treatment. More head-to-head clinical trials are needed to confirm these findings.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

TZ wrote the manuscript and contributed to the data analysis and interpretation. WL and DD extracted data and ensured the accuracy of the data analysis. LC and XC contributed to the data interpretation and critical revision of the manuscript for important intellectual content. HW obtained funding and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.