Navigating first-line therapies for extensive-stage small-cell lung cancer: a frequentist network meta-analysis and systematic review

Abstract

Aim: To identify the optimal first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC).

Materials & methods: We conducted a network meta-analysis (CRD42023486863) to systematically evaluate the efficacy and safety of eight first-line treatment regimens for ES-SCLC, including 15 clinical trials.

Results: Our analysis showed that the PD-1/PD-L1 + etoposide combined with platinum (EP) and PD-L1 + vascular endothelial growth factor (VEGF) + EP regimens significantly enhanced overall survival and progression-free survival, with subgroup analysis revealing that serplulimab ranked as the most promising option for improving overall survival. Integrating anti-angiogenesis drugs into immunochemotherapy presents potential benefits, with an increased incidence of adverse events necessitating further investigation.

Conclusion: Our findings offer valuable insights for future research and for developing more effective treatment strategies for ES-SCLC, underscoring the critical need for continued innovation in this therapeutic area.

Plain language summary

Article highlights.

• Immunochemotherapy has changed the treatment landscape of extensive-stage small-cell lung cancer (ES-SCLC), but the efficacy of this strategy still needs improvement.

• Compared with chemotherapy, immunochemotherapy has demonstrated a significantly enhanced overall survival (OS) and progression-free survival in patients with ES-SCLC. Furthermore, integrating anti-angiogenesis drugs into immunochemotherapy regimens has shown an additional benefit.

• The efficacy and safety of PD-1 inhibitors and PD-L1 inhibitors have no significant difference.

• Serplulimab ranked as the most promising option combined with chemotherapy for improving the OS of ES-SCLC patients.

• Combining anti-angiogenesis targeted therapy with immunochemotherapy presents a promising direction for future studies, which need further exploration.

• Notably, combining anti-angiogenesis targeted therapy with immunochemotherapy was associated with increased grade ≥3 TRAEs.

• Our study indicated multidisciplinary treatment strategies that could potentially transform the therapeutic landscape for ES-SCLC, underscoring the need for continued innovation and research in this field.

• The findings have significant implications for clinical decision-making, potentially guiding the development of more effective treatment strategies for this highly challenging form of lung cancer.

1. Background

Small-cell lung cancer (SCLC), which comprises approximately 15% of all lung cancer cases [1], is distinguished by rapid doubling time, high growth fraction and early development of widespread metastases [2]. Despite SCLCs high sensitivity to initial chemotherapy and radiotherapy [3,4], most patients present with hematogenous metastases and ultimately succumb to recurrent disease [5]. There is also a big gap in the screening and early diagnosis of SCLC. At present, there is no effective screening method to detect early SCLC. Most patients have distant metastasis at initial diagnosis and are diagnosed as extensive-stage SCLC (ES-SCLC) [6,7]. ES-SCLC is classified as stage IV (T any, N any, M1a/b/c) or T3-4 due to multiple lung nodules, encompassing about two-thirds of all SCLC cases [8]. For patients with extensive-stage disease, systemic therapy can alleviate symptoms and extend survival in most cases. However, long-term survival is uncommon [2], rendering ES-SCLC a therapeutically challenging disease [4].

In the past 30 years, the first-line treatment of ES-SCLC is usually a dual-drug chemotherapy regimen (EP regimen) of etoposide combined with platinum [9,10]. During this period, lung cancer treatment experts around the world have tried other chemotherapy regimens, such as irinotecan [11], paclitaxel [12], etc., and the efficacy is not superior to the EP regimen. Until the emergence of IMpower133 [13], the world saw the potential of immunotherapy targeting PD-1/PD-L1. The advent of immune checkpoint inhibitors (ICIs), specifically those targeting the PD-1/PD-L1 axis, has radically transformed the treatment landscape for various cancers, including ES-SCLC. Numerous clinical trials have consistently shown improved overall survival (OS) and a tolerable safety profile with combined chemotherapy and immunotherapy, thereby establishing this approach as a new standard of care [13–16]. The National Comprehensive Cancer Network SCLC Panel endorses certain combinations of chemotherapy and immunotherapy as preferred treatment options for patients with ES-SCLC [13].

In addition to PD-1/PD-L1 inhibitors, cytotoxic T lymphocyte antigen 4 (CTLA-4) is also used in clinical practice, but analysis shows that the efficacy and safety of CTLA-4 are not as good as PD-1/PD-L1 inhibitors, and there are differences in efficacy and safety between different ICIs [17]. Among them, a PD-1 inhibitor (serplulimab), and three PD-L1 inhibitors (atezolizumab, adebrelimab and durvalumab) are recommended as first-line treatment for ES-SCLC, as supported by the ASTRUM-005 study [15], the IMpower133 study [18], the CAPSTONE-1 study [19] and the CASPIAN trial [14]. These treatment options have significantly improved OS and progression-free survival (PFS) while maintaining a management safety profile. While various anti-PD-1/PD-L1 antibodies have been tested as first-line treatments for ES-SCLC, no new drugs have been approved. Compared with the revolutionary effect of immunotherapy on non-small cell lung cancer (NSCLC), its effectiveness in treating SCLC has been less impressive, highlighting the need for ongoing research and development in this area.

Additionally, anti-angiogenesis drugs have increasingly become a focus for researchers. Currently, vascular endothelial growth factor (VEGF) inhibitors are categorized into three main types: monoclonal antibodies (bevacizumab, ramucirumab, aflibercept, etc.), tyrosine kinase inhibitors (lenvatinib, anlotinib, apatinib, etc.) and pan-target angiogenesis inhibitors-recombinant human endostatin. The integration of anti-angiogenesis drugs has proven effective for NSCLC [20]*, gastric cancer [21], colorectal cancer [22] and other cancers. In the context of SCLC treatment, based on the results of the ALTER1202 trial (NCT03059797), anlotinib as a third-line treatment demonstrated improvements in both OS and PFS in Chinese patients with SCLC [23]. Furthermore, at the 2023 World Lung Cancer Conference (WCLC), our team presented findings on the clinical effectiveness of combining benmelstobart (a PD-L1 inhibitor) or placebo with anlotinib, etoposide and carboplatin in the first-line treatment of stage III ES-SCLC. These results indicate that the integration of immunotherapy with anti-angiogenesis therapy and chemotherapy could lead to superior outcomes. However, there are still several questions remain for exploration: the comparative benefits of PD-1 versus PD-L1 inhibitors; the variability in treatment efficacy across different regimens; the efficacy differences among similar therapeutic agents; and the potential enhanced benefits and safety profiles associated with the combination of anti-angiogenesis drugs.

In this study, our primary objective is to identify the optimal first-line treatment for patients with ES-SCLC by systematically comparing and ranking the efficacy and safety profiles of various treatment regimens. Through this analysis, we aim to provide a well-informed direction for future exploration and development of treatment strategies for ES-SCLC, ultimately guiding clinicians in making evidence-based decisions that optimize patient outcomes.

2. Materials & methods

This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and the PRISMA Network Meta-Analysis Extension (PRISMA-NMA) standards, as detailed in Supplementary Table S1. Our research protocol has been prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42023486863.

2.1. Literature search

Our literature search strategy was exhaustive, encompassing databases such as PubMed, Embase, Cochrane Library, Web of Science and Scopus, as well as proceedings from significant oncology conferences, including the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), the American Association for Cancer Research (AACR) and the WCLC. The time frame for the collected literature spanned from the inception of each database to 30 November 2023. We further augmented our search by manually reviewing the reference lists of all included articles to unearth additional relevant studies. Our search terms were comprehensive, including phrases like “extensive stage small cell lung cancer”, “first-line treatment” and “randomized controlled trial”, among others. We imposed no language or location restrictions, ensuring a broad and inclusive scope for our analysis. The complete search strategy is outlined in Supplementary Table S2.

2.2. Eligibility criteria

Upon completion of the literature search, two investigators (Ying Liu and Jing Zhu) independently assessed the titles, abstracts, and full texts of retrieved articles to determine their eligibility for inclusion in our study. Discrepancies between the investigators were adjudicated by consulting a third investigator (Tian-Ying Du), who facilitated a consensus. The criteria for inclusion and exclusion of studies are detailed in Table 1.

Table 1.

The criteria for inclusion and exclusion of studies.

Inclusion Criteria	Exclusion criteria
Study design: Randomized controlled trials (RCTs), including Phase II and Phase III clinical trials.	Study design: Nonrandomized studies such as observational studies, case reports, single-arm studies, and retrospective cohort studies.
Participants: Individuals diagnosed with extensive-stage small-cell lung cancer (ES-SCLC).	Publications: Duplicate studies or those with overlapping data from other selected research.
Interventions: A. The control arm received a combination of etoposide and platinum-based chemotherapy (EP regimen). B. Regimens incorporating PD-1 or PD-L1 inhibitors with chemotherapy. C. Targeted therapy and other immunotherapeutic approaches. D. Additional immunotherapy combinations with chemotherapy.	Data reporting: Studies lacking adequate treatment or outcome data, or insufficient statistical data for comparative analysis.
Primary outcomes: Overall survival (OS) and progression-free survival (PFS).	Participants: Studies not exclusively involving patients with ES-SCLC or control groups not receiving etoposide with platinum-based chemotherapy.
Secondary outcomes: Efficacy evaluations (e.g., objective response rate, ORR) and safety assessments.	Interventions: Studies not focused on first-line treatments, or those only examining maintenance or subsequent lines of therapy post-first-line treatment.
	Others: Studies with irrelevant research types or focus.

2.3. Data extraction

Data extraction was meticulously conducted for each study included in our analysis. We collated essential information such as trial name, first author, publication year, publication source, demographic details of participants (age and sex distribution), sample size, smoking status, Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores and histological types. The primary end point was OS, defined as the time from randomization to death from any cause. Hazard ratios (HRs) and 95% confidence intervals (CIs) for these outcomes were meticulously extracted. Secondary end points included PFS, objective response rate (ORR) and the incidence of grade ≥3 adverse events (AEs). PFS was the time from randomization to disease progression or death, regardless of cause. ORR was determined by the proportion of patients achieving complete response (CR) or partial response (PR) as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or the modified WHO’s best overall response rate (mWHO-BORR). AEs were classified according to the Common Terminology Criteria for Adverse Events (CTCAE).

2.4. Quality & risk of bias assessment

In our analysis, the included studies’ quality and risk of bias were rigorously assessed utilizing the Cochrane Collaboration’s risk of bias tool. This assessment was performed independently by two authors (Ying Liu and Jing Zhu). Any discrepancies in the evaluation were resolved through collegial discussion with a third author (Xian-Hong Liu) to ensure a unified consensus. The outcomes of this critical appraisal are presented in Supplementary Figure S1.

2.5. Statistical analysis

Our statistical analysis computed HRs for continuous outcomes and odds ratios (ORs) for dichotomous outcomes using the ‘netmeta’ package in R Studio. OS and PFS were quantified as HRs with corresponding 95% CIs. Similarly, ORR and the incidence of grade ≥3 AEs were expressed as ORs with 95% CIs. To evaluate the consistency among the included studies regarding their design and clinical characteristics, we employed the I² statistic. A value of I² greater than 50% indicated significant heterogeneity, prompting the use of a random-effects model. Conversely, an I² of 50% or less suggested a lack of heterogeneity, justifying the use of a fixed-effects model. Subgroup analyses were conducted on treatments that demonstrated superiority in OS to determine the optimal first-line therapy for patients with ES-SCLC. Furthermore, the ‘netmeta’ package facilitated the ranking of treatments through p-scores, calculating the probability of each intervention being the most effective.

3. Results

3.1. The included studies in network meta-analysis

Our comprehensive literature search identified 15 clinical trials from over 780 articles that met our inclusion and exclusion criteria, encompassing a total of 5,881 participants for the NMA. The selection process for these studies is depicted in Supplementary Figure S2. We categorized the treatment regimens of these 15 included trials as follows: PD-1 + EP: This group includes five studies: ASTRUM-005, KEYNOTE-604, EA5161, RATIONALE-312 and EXTENTORCH. Except for EA5161, which is a Phase II trial, the rest are Phase III RCTs. PD-L1 + EP: Comprising three Phase III RCTs: CAPSTONE-1, CASPIAN and IMpower133. PD-L1 + CTLA-4 + EP: Including one Phase III RCT, the CASPIAN trial. CTLA-4 + EP: Including one Phase III RCT. VEGF + EP: This group includes three clinical studies, with two Phase II trials and one Phase III trial. CDK + EP: Including one Phase II clinical study. CXCR4 + EP: Including one Phase II clinical study. PD-L1 + VEGF + EP: Including one Phase III trial. The detailed characteristics of all the included studies are presented in Supplementary Table S3.

3.2. Analysis of OS in ES-SCLC

In our NMA, all included studies were assessed for OS using the most recently reported data and analyzed via a fixed effects model (Figure 1A). The results have demonstrated a clear OS benefit of the PD-1 + EP, PD-L1 + EP, PD-L1 + CTLA-4 + EP and PD-L1 + VEGF + EP regimens compared with EP chemotherapy alone (Figure 1B). Relative treatment effects revealed no significant differences among these three regimens, but network ranking indicated that the PD-L1 + VEGF + EP regimen is most likely to benefit ES-SCLC patients in first-line treatment (Figure 1C).

Figure 1.

Overall survival network meta-analysis of included studies. (A) Network meta-analysis of included studies based on treatment regimens. (B) Forest plot comparing each treatment regimen to EP chemotherapy alone. (C) Relative treatment effects among various treatment regimens and network ranking of treatment strategies based on p-scores. (D) Studies included in the OS subgroup analysis. (E) Forest plot of the comparison of various drug combinations with EP chemotherapy alone. (F) Relative treatment effects between drug combinations and network ranking of treatment strategies according to p-scores.

OS: Overall survival.

To further explore this superiority in OS, we conducted subgroup analyses to identify the optimal first-line drug combination for ES-SCLC patients. Nine studies were included in these subgroup analyses (Figure 1D), all showing a significant OS advantage over the EP regimen alone (Figure 1E). While relative treatment effects indicated no significant differences in OS among these combinations, network ranking identified the serplulimab + EP regimen as most likely to improve OS, followed by the benmelstobart + anlotinib and nivolumab combinations with EP (Figure 1F). These findings from a frequentist NMA align with previous Bayesian NMA results, reinforcing the established superiority of the serplulimab and EP combination in treating ES-SCLC [24,25].

3.3. Analysis of PFS in ES-SCLC

In parallel with the OS analysis, all included studies were also analyzed for PFS using the latest reported data through a fixed effects NMA (Figure 2A). The results indicated a significant PFS benefit for the PD-1 + EP, PD-L1 + EP, CTLA-4 + EP, VEGF + EP and PD-L1 + VEGF + EP regimens compared with EP chemotherapy alone (Figure 2B). The relative treatment effects revealed that within these five regimens, the PD-1 + EP regimen outperformed the PD-L1 + EP and VEGF + EP regimens, whereas the PD-L1 + VEGF + EP regimen surpassed all others (Figure 2C). Network ranking identified the PD-L1 + VEGF + EP regimen as the most likely to improve PFS in ES-SCLC patients (Figure 2C).

Figure 2.

Progression-free survival network meta-analysis of included studies. (A) Network meta-analysis of included studies based on treatment regimens. (B) Forest plot comparing each treatment regimen to EP chemotherapy alone. (C) Relative treatment effects among various treatment regimens and network ranking of treatment strategies based on p-scores. (D) Studies included in the PFS subgroup analysis. (E) Forest plot of the comparison of various drug combinations with EP chemotherapy alone. (F) Relative treatment effects between drug combinations and network ranking of treatment strategies according to p-scores.

PFS: Progression-free survival.

Subgroup analysis for PFS was conducted on nine studies focusing on the PD-1 + EP, PD-L1 + EP, PD-L1 + CTLA-4 + EP and PD-L1 + VEGF + EP regimens (Figure 2D). This analysis revealed that most combinations showed significant PFS benefits over the EP regimen alone, except for durvalumab + tremelimumab combined with the EP regimen (Figure 2E). Relative treatment effects indicated no PFS differences among the tislelizumab, nivolumab, toripalimab, adebrelimab, pembrolizumab, atezolizumab and durvalumab combinations; however, the serplulimab + EP regimen significantly outperformed the toripalimab, adebrelimab, pembrolizumab, atezolizumab, durvalumab, durvalumab + tremelimumab, with the benmelstobart + anlotinib and EP combination surpassing all other regimens; network ranking suggested the benmelstobart + anlotinib and EP combination as the most likely to benefit patients' PFS, followed by the serplulimab and EP, and the tislelizumab and EP combinations (Figure 2F).

3.4. Analysis of ORR in ES-SCLC

Our analysis of ORR encompassed 11 studies, covering seven treatment regimens: PD-1 + EP, PD-L1 + EP, PD-L1 + CTLA-4 + EP, CTLA-4 + EP, VEGF + EP, CDK + EP and CXCR4 + EP (Figure 3A). The PD-1 + EP regimen was represented by two RCTs (ASTRUM-005 and KEYNOTE-604), while the PD-L1 + EP regimen included three RCTs (CAPSTONE-1, CASPIAN and IMpower133). The CTLA-4 + EP and PD-L1 + CTLA-4 + EP regimens comprised one clinical study, respectively. The VEGF + EP regimen included three clinical studies. The CDK + EP and CXCR4 + EP regimens had one clinical trial, respectively. Our findings indicated that only the PD-1 + EP regimen significantly improved patients’ ORR compared with EP chemotherapy alone, with no statistical differences observed in ORR for the other regimens (Figure 3B & C). Network ranking further suggested that the PD-1 + EP regimen was the most likely to benefit ES-SCLC patients in ORR (Figure 3C).

Figure 3.

Objective response rate network meta-analysis of included studies. (A) Network meta-analysis of included studies based on treatment regimens. (B) Forest plot comparing each treatment regimen to EP chemotherapy alone. (C) Relative treatment effects among various treatment regimens and network ranking of treatment strategies based on p-scores. (D) Studies included in the ORR subgroup analysis. (E) Forest plot of the comparison of various drug combinations with EP chemotherapy alone. (F) Relative treatment effects between drug combinations and network ranking of treatment strategies according to p-scores.

ORR: Objective response rate.

As protocol, we planned to conduct ORR subgroup analyses for nine studies involving the PD-1 + EP, PD-L1 + EP, PD-L1 + CTLA-4 + EP and PD-L1 + VEGF + EP regimens. However, due to missing data, the analysis was limited to the PD-1 + EP (two clinical studies), PD-L1 + EP (three clinical studies) and PD-L1 + CTLA-4 + EP (one clinical study) regimens (Figure 3D). The results demonstrated that combinations of serplulimab, durvalumab and pembrolizumab with EP significantly outperformed the EP regimen alone in ORR (Figure 3E & F). Furthermore, relative treatment effects revealed that these combinations were also superior to the atezolizumab and EP combination, and network ranking indicated that the serplulimab + EP was most likely to benefit patients’ ORR, followed by durvalumab + EP and pembrolizumab + EP (Figure 3F).

3.5. Safety analysis: grade ≥3 AEs

In this study, we conducted a comprehensive safety analysis across all seven experimental treatment groups. Due to partial data unavailability, the analysis incorporated 12 clinical trials (Figure 4A). This included four trials for the PD-1 + EP regimen; three RCTs for the PD-L1 + EP regimen; one clinical study each for the PD-L1 + CTLA-4 + EP, CTLA-4 + EP and PD-L1 + VEGF + EP regimens; two trials for the VEGF + EP regimen; and one clinical trial for the CDK + EP regimen. The results indicated that, compared with EP chemotherapy alone, the PD-L1 + VEGF + EP and PD-L1 + CTLA-4 + EP regimens significantly increased the risk of grade ≥3 AEs. The safety profiles of the other regimens did not show statistical differences from EP chemotherapy alone, and the PD-L1 + VEGF + EP and PD-L1 + CTLA-4 + EP regimens also increased grade ≥3 AEs risk compared with the PD-L1 + EP regimen (Figure 4B & C). Network ranking suggested that the VEGF + EP regimen was associated with the lowest risk of grade ≥3 AEs in first-line treatment of ES-SCLC patients, followed by EP chemotherapy alone and PD-L1 + EP (Figure 4C).

Figure 4.

Safety (grade ≥3 AEs) network meta-analysis of included studies. (A) Network meta-analysis of included studies based on treatment regimens. (B) Forest plot comparing each treatment regimen to EP chemotherapy alone. (C) Relative treatment effects among various treatment regimens and network ranking of treatment strategies based on p-scores. (D) Studies included in the safety subgroup analysis. (E) Forest plot of the comparison of various drug combinations with EP chemotherapy alone. (F) Relative treatment effects between drug combinations and network ranking of treatment strategies according to p-scores.

AE: Adverse event.

According to the preprotocol, the subgroup analysis was conducted including eight clinical trials (Figure 4D). The result revealed that the benmelstobart + anlotinib + EP and durvalumab + tremelimumab + EP regimens increased the risk of grade ≥3 AEs compared with EP chemotherapy alone. Other drugs with EP demonstrated no statistical differences in safety compared with EP chemotherapy alone. Moreover, the benmelstobart + anlotinib + EP and durvalumab + tremelimumab + EP combinations also showed a higher risk of grade ≥3 AEs than durvalumab + EP (Figure 4E & F). Network ranking indicated that the tislelizumab + EP had the lowest risk for grade ≥3 AEs, followed by the durvalumab + EP and EP chemotherapy alone (Figure 4F).

4. Discussion

ES-SCLC presents significant therapeutic challenges [4]. Historically, platinum-based chemotherapy, either with carboplatin or cisplatin combined with etoposide (EP), has been the cornerstone of first-line treatment for ES-SCLC [4]. Recent insights, particularly from the IMpower133 and CASPIAN trials, have highlighted similarities in the immune biology of SCLC with conditions such as triple-negative breast cancer and urothelial carcinoma [13]. The US FDA approved the additions of atezolizumab or durvalumab, both PD-L1 antibodies, to the EP regimen as first-line treatments for ES-SCLC, following the findings from the IMpower133 and CASPIAN trials [13,14]. ORIENTAL (NCT0449861) further validates the CASPIAN treatment model’s safety and efficacy in the Chinese population with ES-SCLC [26]. Additionally, the success of the ASTRUM-005 study demonstrated that the PD-1 inhibitor serplulimab also offers significant benefits for patients with ES-SCLC [15]. Subsequently, the 2022 guidelines from the Chinese Society of Clinical Oncology (CSCO) recommended combinations of atezolizumab, durvalumab and serplulimab with chemotherapy for ES-SCLC [24]. Notably, the China National Medical Products Administration (NMPA) approved the use of serplulimab or adebrelimab in combination with EP chemotherapy for first-line ES-SCLC treatment in January and February 2023 based on the ASTRUM-005 and CAPSTONE-1 trials, respectively. As a result, the 2023 CSCO guidelines included adebrelimab in their recommendations.

Prior clinical trials have established that combining PD-1 and PD-L1 inhibitors with chemotherapy as a first-line treatment significantly prolonged OS and PFS in patients with ES-SCLC, compared with chemotherapy alone. The safety profiles observed in these trials align with the known safety data of the tested drugs [13–15,18,19,27–29]. Numerous preceding meta-analyses have underscored the efficacy of immunochemotherapy, particularly highlighting the PD-1 inhibitor serplulimab, which significantly reduces mortality and improves PFS and OS compared with chemotherapy alone in ES-SCLC patients [24,25]. This benefit is especially pronounced in patients under 65 years old, with a baseline ECOG PS of 0, and without central nervous system metastasis [24,25]. Our analysis extends beyond comparing ICIs plus chemotherapy to chemotherapy alone. It includes combinations of targeted therapy with chemotherapy and a novel combination of ICI + anti-VEGF drug + chemotherapy. Our findings highlight the combination of serplulimab and chemotherapy, demonstrating substantial survival benefits in terms of OS and showing a preferable PFS with manageable safety. Additionally, our results spotlight the potential efficiency of integrating anti-angiogenesis drugs into immunochemotherapy. This study updates and expands upon previous data, offering new insights into the choice of first-line treatments for ES-SCLC patients. Moreover, our analysis, grounded in frequentist statistics, corroborates and supplements findings from previous meta-analyses based on Bayesian theory.

PD-1/PD-L1 monoclonal antibodies (mAbs) can inhibit the binding of PD-1 to PD-L1 and B7.1 receptors on T-cell surfaces, leading to T-cell activation and an enhanced antitumor immune response [30]. Anlotinib, a targeted VEGF tyrosine kinase inhibitor, suppresses tumor angiogenesis and potentially remodel the tumor microenvironment by targeting VEGFR, FGFR, PDGFR and c-kit [31]. The IMbrave150 trial highlighted the enhanced efficacy of combining ICIs with anti-VEGF drugs in hepatocellular carcinoma patients [32], while the Impower150 study demonstrated significant survival benefits for treatment-naive metastatic nonsquamous NSCLC patients receiving a combination of atezolizumab (an anti-PD-L1 mAb), bevacizumab (an anti-VEGF mAb) and PC (paclitaxel plus carboplatin) [33]. The Phase III ETER701 trial represented the first prospective study exploring the efficacy of combining anti-angiogenesis targeted therapy with immunochemotherapy in ES-SCLC patients, suggesting the potential applicability of this strategy. Our analysis indicated that adding PD-1/PD-L1 inhibitors to chemotherapy improved OS and PFS, the efficacy showed further enhancement when anlotinib (an anti-VEGF drug) was included in the immunochemotherapy regimen. In fact, existing study has provided real-world evidence of the efficacy of this strategy in SCLC patients. A retrospective study by Yu et al. suggested that the combination of anlotinib and PD-1/PD-L1 blockade demonstrates promising efficacy and safety as a second-line or subsequent therapy for SCLC [34]. Moreover, the ALTER1202 trial (NCT03059797) indicated that anlotinib monotherapy as a third- or later-line treatment could improve outcomes for SCLC patients [23]. Our study reinforces the notion that combining anti-angiogenesis targeted therapy with immunochemotherapy is a promising strategy for ES-SCLC patients.

However, our study results indicate that, compared with the combination of PD-1/PD-L1 inhibitors with EP chemotherapy, the multicombination regimen of ETER701 demonstrated superiority only in PFS, with no significant difference observed in OS. Notably, combining anti-angiogenesis targeted therapy with immunochemotherapy was associated with increased grade ≥3 treatment-related adverse events (TRAEs), although these TRAEs were generally manageable. The advantages of the multi-combination regimen bring several challenges, including limited study numbers, the incomprehensiveness of study designs, and unanticipated safety concerns, all requiring further exploration. Some previous meta-analyses have suggested that an increased occurrence of adverse events is associated with enhanced therapeutic efficacy in ICI-treated patients with various solid malignant tumors, including lung cancer [35,36]. These observations underscore the need for clinicians to monitor AEs when administering this multi-combination regimen to ES-SCLC patients. In other words, ES-SCLC patients with better ECOG may exhibit improved prognoses. Combining anti-angiogenesis targeted therapy with immunochemotherapy appears promising for ES-SCLC patients but requires further verification through clinical trials. This also suggests that serplulimab, the best ICI in OS of our analysis with a more manageable safety profile, could be a choice in combining anti-angiogenesis targeted therapy with immunochemotherapy.

Our analysis found no significant difference between PD-1 inhibitors and PD-L1 inhibitors in terms of efficacy and safety, which is consistent with the results of a recent retrospective study [37]. Notably, serplulimab (HLX10), a humanized immunoglobulin anti-PD-1 mAb, combined with chemotherapy which ranked the best in OS. Serplulimab was first approved for treating adult patients with advanced unresectable or metastatic microsatellite instability-high (MSI-H) solid tumors unresponsive to previous standard treatments in March 2022 [38]. It was subsequently approved in China for first-line therapy of ES-SCLC in combination with carboplatin and etoposide on January 2023, based on the ASTRUM-005 trial. A recent study has also demonstrated that serplulimab plus chemotherapy significantly benefits patients in the first-line treatment of advanced esophageal squamous cell carcinoma (ESCC) [16]. Additionally, a single-arm Phase II study highlighted the efficacy and safety of serplulimab plus nab-paclitaxel in previously treated patients with PD-L1-positive advanced cervical cancer [39]. Furthermore, multiple studies have shown that serplulimab represents a cost-effective first-line intervention compared with chemotherapy alone for ES-SCLC patients in both the US and China [40,41].

Our study has certain limitations, such as the reliance on a frequentist NMA and the specific focus of our research, that we have not included all previously explored first-line treatment strategies for ES-SCLC in the analysis. For instance, we excluded studies like the SKYSCRAPER-02 trial, which showed promising benefits of tiragolumab plus atezolizumab combined with EP chemotherapy, but had a control group receiving a placebo plus atezolizumab and EP chemotherapy. This exclusion potentially omits a discussion of some viable treatment strategies.

5. Conclusion

In conclusion, our study demonstrates that serplulimab combined with chemotherapy ranks as the most substantial survival benefit in OS, while PFS and safety profiles are comparable to other ICIs combined with chemotherapy. Although our analysis specifically revealed the PFS advantage of benmelstobart plus anlotinib in combination with EP chemotherapy for first-line treatment of ES-SCLC, the ETER701 trial’s strategy of combining anti-angiogenesis targeted therapy with immunochemotherapy presents a promising direction for future studies. This insight encourages further exploration into multimodal treatment strategies that could potentially transform the therapeutic landscape for ES-SCLC, underscoring the need for continued innovation and research in this field.

6. Future perspective

In summarizing these critical immunotherapy trials, it is evident that the first-line ICIs combined with platinum-based chemotherapy yield significant advantages in ES-SCLC patients. Kaplan-Meier survival curves from these studies indicated that a minor group of patients could experience profound and enduring responses to ICIs, but no robust prognostic factor can be used. Additionally, more high-quality real-world studies are needed.

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/14796694.2024.2376514

Author contributions

Y Liu: Writing – original draft, study design, literature search, data curation, methodology, software. J Zhu: Writing – original draft, software. T-Y Du: Writing – review & editing, data curation. X-H Liu: Methodology, validation. Y Xin: Analysis, writing – review & editing. Y Wang: Software, data Curation. Y-P Wang: Methodology, critical discussion. J-H Xu: Literature search, data curation. Y Chen: Literature search, Conceptualization. H-F Wei: Data curation, methodology. Y Cheng: Conceptualization, analysis, writing – review & editing, validation, critical discussion.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.