Abstract
Background
The combination of immune checkpoint inhibitors and chemotherapy is the standard first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, predictive biomarkers for treatment efficacy are lacking. This study aimed to investigate the association between clinical characteristics, particularly liver metastasis, and survival outcomes in patients with ES-SCLC treated with chemoimmunotherapy.
Methods
We conducted a retrospective analysis of 279 patients with ES-SCLC treated at the Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (102 receiving chemoimmunotherapy and 177 receiving chemotherapy alone). The association of clinical features with progression-free survival (PFS) and overall survival (OS) was assessed via Cox regression. Furthermore, a meta-analysis of five randomized controlled trials (IMpower133, CAPSTONE-1, CASPIAN, ETER701, and RATIONALE-312) was performed to confirm the effect of liver metastases on the efficacy of chemoimmunotherapy.
Results
The cohort of 279 patients with ES-SCLC was predominantly male (92.1%), and the vast majority had a smoking history (85.7%). The median age was 61.4 years, and 18.6% of cases included involvement of more than three organs. The prevalence of brain, liver, and bone metastases was 22.2%, 25.1%, and 32.3%, respectively. Patients without liver metastases derived significantly greater survival benefit from chemoimmunotherapy than from chemotherapy alone (PFS: 8.9 vs. 6.6 months; OS: 21.8 vs. 12.9 months); in contrast, despite a numerical increase, patients with liver metastases showed no significant improvement from chemoimmunotherapy in PFS (6.4 vs. 4.8 months) or OS (10.8 vs. 9.5 months). Multivariate analysis identified liver metastases as an independent prognostic factor among patients treated with chemoimmunotherapy for worse PFS [hazard ratio (HR) =2.71, 95% confidence interval (CI): 1.62–4.51] and OS (HR =2.64, 95% CI: 1.49–4.70). The meta-analysis confirmed that while immunotherapy benefited both groups, the HRs of OS were consistently higher in patients with liver metastases.
Conclusions
The presence of liver metastases is a critical prognostic factor for outcomes in patients with ES-SCLC. These patients derive limited benefit from the current standard of care, underscoring the urgent need for novel therapeutic strategies to improve the prognosis of this subgroup.
Keywords: Small-cell lung cancer (SCLC), liver metastases, immune checkpoint inhibitors (ICIs), programmed death ligand-1 (PD-L1), immunotherapy
Highlight box.
Key findings
• This study found that liver metastases significantly limit the survival benefits of first-line chemoimmunotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC). Patients without liver metastases showed significantly greater improvements in progression-free survival (PFS) and overall survival (OS) with chemoimmunotherapy than with chemotherapy alone. However, those with liver metastasis did not experience similar benefits. Liver metastasis was identified as an independent prognostic factor for worse outcomes in both PFS and OS. This was confirmed through both the cohort study and a meta-analysis of previous randomized controlled trials.
What is known and what is new?
• It is known that chemoimmunotherapy improves survival outcomes in patients with ES-SCLC, but liver metastasis is a factor associated with a poor prognosis.
• A novel finding of this study is that liver metastasis limits the efficacy of chemoimmunotherapy among patients with ES-SCLC, suggesting that this subgroup may not benefit from the current standard treatment approach.
What is the implication, and what should change now?
• Given the limited benefit of chemoimmunotherapy for patients with ES-SCLC and liver metastasis, novel treatment strategies are urgently needed for this high-risk group. Future research should focus on developing alternative therapies and clarifying the underlying mechanisms that contribute to the poor treatment responses in these patients.
Introduction
Lung cancer has the highest incidence and mortality rates among all malignant tumors worldwide (1). Pathologically, lung cancer can be classified into non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), with NSCLC accounting for approximately 87% of all lung cancer cases (2). With the advent of targeted therapies such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (3,4) and immune checkpoint inhibitors (ICIs), NSCLC treatment has entered the era of precision medicine. In contrast, SCLC, despite constituting only about 13% of all lung cancer cases, exhibits a higher degree of malignancy and invasiveness as compared to NSCLC, resulting in a generally poorer prognosis (2). Moreover, effective targeted therapies for SCLC remain lacking. For patients newly diagnosed with extensive-stage SCLC (ES-SCLC), despite some studies supporting the benefit of combining antiangiogenic agents in first-line therapy (5), the standard first-line treatment continues to be ICIs combined with chemotherapy. In recent years, numerous studies have attempted to divide SCLC into subtypes based on genomic, transcriptomic, and proteomic profiling and have examined correlations between different subtypes and therapeutic responses (6). However, these classifications have yet to be translated into effective treatment guidance. In this context, identifying risk factors associated with chemoimmunotherapy in SCLC could provide valuable insights into developing personalized treatment strategies for this aggressive cancer type.
Biomarkers that have previously been identified as prognostic or predictive in NSCLC appear to have limited utility in SCLC. For instance, programmed death ligand-1 (PD-L1) expression is a well-established predictive biomarker for immunotherapy response in patients with NSCLC. However, multiple studies have reported no clear association between PD-L1 expression and prognosis in SCLC (7,8). Meanwhile, the IMpower133 trial found that tumor mutational burden, another commonly used predictive marker for immunotherapy response, could be potentially associated with benefit (9). However, few studies have examined how clinical features impact the efficacy of immunotherapy in patients with SCLC.
In this study, we included patients with ES-SCLC who received chemoimmunotherapy at the Guangdong Lung Cancer Institute (GLCI) and focused on various clinical characteristics, including smoking history, number of metastatic organs, brain metastases, liver metastases, bone metastases, and expression of chromogranin A (CgA) and synaptophysin (Syn). Our objective was to investigate the association between these clinical features and progression-free survival (PFS) and overall survival (OS) in patients with ES-SCLC. Furthermore, we incorporated data from five successful prospective clinical trials—IMpower133 (10), CAPSTONE-1 (11), CASPIAN (12), ETER701 (5), and RATIONALE-312 (13)—to further assess the relevance of these clinical characteristics to immunochemotherapy outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0193/rc).
Methods
Data sources and study population
A retrospective analysis of 279 patients with ES-SCLC treated at the Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital was conducted. For patients receiving chemotherapy alone, we collected information from 177 patients with ES-SCLC who were treated between January 2004 and December 2017. These patients had received at least two cycles of chemotherapy and were available for follow-up. For patients receiving chemotherapy combined with immunotherapy, we collected information from 102 patients with ES-SCLC who were treated between January 2020 and December 2023. These patients had received at least two cycles of chemotherapy combined with immunotherapy and were available for follow-up. The patients with missing clinical information or those who could not be followed up were excluded. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Guangdong Provincial People’s Hospital [No. GDREC2016175H(R2)]. Informed consent was obtained from all patients involved in the study.
Confirmation of SCLC and prognosis
All enrolled patients underwent pathological biopsy to confirm the diagnosis of SCLC. Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The best response was determined based on the optimal radiologic response during treatment. PFS was defined as the time from the initiation of treatment to disease progression or the last follow-up. OS was defined as the time from the initiation of treatment to death or the last follow-up.
Clinical features
In this study, the clinical features examined included sex, age, smoking history, number of metastatic organs, brain metastases, liver metastases, bone metastases, and expression of CgA and Syn. Sex was categorized as male or female. Age was recorded at the time of SCLC diagnosis. Smoking history was classified as either a history of smoking or a lack of it. The number of metastatic organs was classified as fewer than three or three or more metastatic sites. Brain, liver, and bone metastases were categorized based on the presence or absence of metastases at these sites. Relevant information about metastasis was obtained through computed tomography or positron emission tomography-computed tomography. The expression status of CgA and Syn was categorized into four groups: double negative, single positive, double positive, and unknown. This indicator was assessed after immunohistochemical staining.
Statistical analyses
All analyses were performed with R v.4.4.1 (The R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org) and Free Statistics analysis platform (Version 2.0, Beijing, China). Analysis of baseline characteristics included the mean, standard error (SE), or frequency, as appropriate. Normally distributed continuous variables were compared with the t-test or analysis of variance. Categorical variables were analyzed with the Chi-squared test or the Fisher’s exact test. Univariate and multivariate Cox proportional hazards regression models were used to assess the relationships between clinical features and survival outcomes, with OS and PFS serving as end points. Kaplan-Meier survival curves were also used to analyze the associations between clinical characteristics and survival outcomes. The hazard ratio (HR) was used to estimate the association between clinical features and the prognosis for SCLC immunotherapy, and the strength of these associations was evaluated with 95% confidence intervals (CIs). We examined several randomized controlled trials (RCTs) related to immunotherapy in patients with ES-SCLC and liver metastases. The HRs and corresponding 95% CIs of each study were analyzed. Heterogeneity was assessed via the I2 statistic, with values greater than 50% being considered moderate to high, which we defined as substantial heterogeneity. A random-effects model was applied when the I2 exceeded 50%; otherwise, a fixed-effects model was used. Furthermore, subgroup analyses were conducted to evaluate the prognostic impact of programmed death-1 (PD-1)/PD-L1 inhibitors in ES-SCLC patients with and without liver metastasis. Funnel plots and leave-one-out analyses were used to assess the robustness of the results. The threshold for statistical significance was set at P<0.05.
Results
The baseline characteristics of selected participants
Ultimately, the GLCI cohort consisted of 279 patients with ES-SCLC. Figure 1 shows the flowchart of patient enrollment, and Table 1 presents the baseline characteristics of patients who received chemotherapy or chemoimmunotherapy. It should be noted that the baseline characteristics including age, smoking status, number of metastatic organs, CgA expression, Syn expression, and best response were imbalanced between the chemotherapy and chemoimmunotherapy groups. In the chemotherapy group, 66.1% of patients received an etoposide plus platinum-based regimen, while 28.8% received an irinotecan plus platinum-based regimen. In contrast, all patients in the chemoimmunotherapy group were treated with an etoposide plus platinum-based regimen, with the majority receiving PD-L1 inhibitors. The median PFS for all participants was 6.6 months (chemotherapy: 6.1 months; chemoimmunotherapy: 7.3 months), and the median OS was 12.9 months (chemotherapy: 12.4 months; chemoimmunotherapy: 19.0 months). Meanwhile, the median follow-up time was 34.2 months (chemotherapy: 96.0 months; chemoimmunotherapy: 22.9 months). In the chemotherapy group, 153 patients died, while in the chemoimmunotherapy group, 61 patients died. Due to the different time periods of diagnosis between the chemoimmunotherapy and chemotherapy groups, patients in the chemotherapy group were diagnosed earlier. As lung cancer screening was not widely implemented at that time, it is understandable that these patients exhibited more typical clinical features.
Figure 1.
Flowchart of the selection of patients with ES-SCLC. ES-SCLC, extensive-stage small-cell lung cancer.
Table 1. The baseline characteristics of the included patients.
| Variable | Total (n=279) | Chemotherapy (n=177) | Chemoimmunotherapy (n=102) |
|---|---|---|---|
| Male | 257 (92.1) | 164 (92.7) | 93 (91.2) |
| Age (years) | 61.4±9.3 | 60.6±10.2 | 62.9±7.3 |
| Smoking | 239 (85.7) | 161 (91.0) | 78 (76.5) |
| Number of metastatic organs | |||
| <3 | 227 (81.4) | 158 (89.3) | 69 (67.6) |
| ≥3 | 52 (18.6) | 19 (10.7) | 33 (32.4) |
| Brain metastasis | 62 (22.2) | 37 (20.9) | 25 (24.5) |
| Liver metastasis | 70 (25.1) | 43 (24.3) | 27 (26.5) |
| Bone metastasis | 90 (32.3) | 56 (31.6) | 34 (33.3) |
| Best response | |||
| PR/CR | 175 (62.7) | 108 (61.0) | 67 (65.7) |
| SD | 64 (22.9) | 35 (19.8) | 29 (28.4) |
| PD | 40 (14.3) | 34 (19.2) | 6 (5.9) |
| CgA & Syn | |||
| Double negative | 12 (4.3) | 7 (4.0) | 5 (4.9) |
| Single positive | 72 (25.8) | 52 (29.4) | 20 (19.6) |
| Double positive | 161 (57.7) | 86 (48.6) | 75 (73.5) |
| Unknown | 34 (12.2) | 32 (18.1) | 2 (2.0) |
| Type of chemotherapy | |||
| Etoposide plus platinum-based | 219 (78.5) | 117 (66.1) | 102 (100.0) |
| Irinotecan plus platinum-based | 51 (18.3) | 51 (28.8) | 0 (0.0) |
| Others | 9 (3.2) | 9 (5.1) | 0 (0.0) |
| Type of ICI | |||
| PD-1 | 4 (1.4) | 0 (0.0) | 4 (3.9) |
| PD-L1 | 98 (35.1) | 0 (0.0) | 98 (96.1) |
Data are presented as n (%) or mean ± standard deviation. CgA, chromogranin A; CR, complete response; PD, progressive disease; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PR, partial response; SD, stable disease; Syn, synaptophysin.
The association between clinical features and ES-SCLC prognosis
We first compared the impact on prognosis between chemoimmunotherapy and chemotherapy, and the results showed that the chemoimmunotherapy group had better PFS and OS than did the chemotherapy group (Figures S1,S2). Furthermore, univariate Cox regression analysis was conducted to determine the association between clinical characteristics and PFS. It was found that patients with ≥3 metastatic organs, liver metastasis, bone metastasis, and stable disease (SD) or progressive disease (PD) as the best response, and those treated with chemotherapy had a significantly shorter PFS. As for OS, liver metastases, chemotherapy, and SD or PD as the best response were associated with a significantly shorter OS. Multivariate regression further confirmed the significant impact of liver metastases, best response, and treatment strategy on both PFS and OS (Table S1). We further examined the prognostic significance of liver metastases. In both the chemoimmunotherapy and chemotherapy groups, patients with liver metastases had worse PFS and OS (Figure 2A-2D). Among patients with liver metastases, despite a numerical increase in survival outcomes, the addition of immunotherapy to chemotherapy did not appear to provide a survival benefit in terms of PFS (median: 6.4 vs. 4.8 months) or OS (median: 10.8 vs. 9.5 months) (Figure 2E,2F). However, in patients without liver metastases, adding immunotherapy significantly improved both PFS (median: 8.9 vs. 6.6 months) and OS (median: 21.8 vs. 12.9 months) (Figure 2G,2H).
Figure 2.
Kaplan-Meier survival curves for the impact of liver metastasis on (A) OS and (B) PFS in the chemotherapy group. The impact of liver metastasis on (C) OS and (D) PFS in the immunochemotherapy group. The impact of immunotherapy on (E) OS and (F) PFS in the liver metastases group. The impact of immunotherapy on (G) OS and (H) PFS in the non-liver metastasis group. Chemo, chemotherapy; IO, immunotherapy; LM, liver metastasis; NLM, no liver metastasis; OS, overall survival; PFS, progression-free survival.
Meta-analysis of RCTs on liver metastasis subgroups
Furthermore, a meta-analysis of five RCTs that included subgroup analyses based on liver metastasis status was conducted to assess the impact of liver metastases. While chemoimmunotherapy demonstrated survival benefits over chemotherapy regardless of metastasis status, the hazard ratios for both OS and PFS were favorable in patients without liver metastases (Figure 3A-3D). Further subgroup analyses based on ICI type (PD-1 or PD-L1) showed consistent OS benefits (Figure 3E,3F). Regarding PFS in the liver metastasis subgroup, PD-L1 inhibitors showed no significant improvement, and limited data precluded a pooled analysis for PD-1 inhibitors (Figure 3G,3H). Sensitivity analyses are presented in Figures S3-S10.
Figure 3.
Results of the meta-analysis. (A) OS outcomes in patients with liver metastasis. (B) OS outcomes in patients without liver metastasis. (C) PFS outcomes in patients with liver metastasis. (D) PFS outcomes in patients without liver metastasis. (E) Subgroup analysis of OS by ICI type (PD-1 vs. PD-L1) in patients with liver metastasis. (F) Subgroup analysis of OS by ICI (PD-1 vs. PD-L1) in patients without liver metastasis. (G) Subgroup analysis of PFS by ICI (PD-1 vs. PD-L1) in patients with liver metastasis. (H) Subgroup analysis of PFS by ICI (PD-1 vs. PD-L1) in patients without liver metastasis. CI, confidence interval; df, degrees of freedom; HR, hazard ratio; ICI, immune checkpoint inhibitor; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PFS, progression-free survival; SE, standard error.
The association between clinical features and the prognosis of ES-SCLC patients treated with chemoimmunotherapy
This study further excluded patients who received chemotherapy alone to examine how other clinical characteristics affect the prognosis of chemoimmunotherapy in SCLC. Through univariate Cox regression analysis, we investigated the association between clinical characteristics and PFS. The results demonstrated that patients with ≥3 metastatic organs, liver metastases, and PD as best response had a significantly shorter PFS. Meanwhile, patients with a smoking history, bone metastases, hypokalemia, and SD as the best response tended to have a relatively shorter PFS. Similarly, patients with ≥3 metastatic organs, liver metastases, and SD or PD as best response had significantly shorter OS (Table 2). A swimmer plot is presented in Figure S11 for the five patients with the longest and shortest OS, facilitating a clear comparison of individual survival and progression dynamics. Multivariable Cox regression was employed for prognostic analysis to further confirm the impact of clinical characteristics on outcomes. All clinical features identified in the univariable analysis as exerting a significant or potential impact on PFS or OS were incorporated into the multivariable model. The independent prognostic factors for PFS were liver metastasis (HR =2.71, 95% CI: 1.62–4.51) and SD or PD as best response (SD: HR=1.70, 95% CI: 1.03–2.80; PD: HR=25.76, 95% CI: 9.55–69.49) (Figure 4A). Meanwhile, the independent prognostic factors for OS were liver metastases (HR =2.64, 95% CI: 1.49–4.70) and SD or PD as the best treatment response (SD: HR =2.33, 95% CI: 1.31–4.16; PD: HR=39.62, 95% CI: 12.62–124.42). The analysis indicated that hypokalemia may exert an influence on OS (HR =1.74, 95% CI: 1.00–3.02) (Figure 4B).
Table 2. The association between clinical features and outcomes of patients with ES-SCLC according to univariable Cox regression analyses.
| Clinical feature | OS | PFS | |||
|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | ||
| Sex | |||||
| Female | 1 | 1 | |||
| Male | 1.25 (0.45–3.46) | 0.67 | 1.03 (0.52–2.05) | 0.94 | |
| Age | 0.99 (1.00–1.03) | 0.70 | 1.00 (0.97–1.03) | 0.90 | |
| Smoking | |||||
| No | 1 | 1 | |||
| Yes | 1.21 (0.66–2.20) | 0.53 | 1.49 (0.93–2.41) | 0.10 | |
| Number of metastatic organs | |||||
| <3 | 1 | 1 | |||
| ≥3 | 1.78 (1.06–2.98) | 0.03 | 1.57 (1.02–2.42) | 0.04 | |
| Brain metastasis | |||||
| No | 1 | 1 | |||
| Yes | 1.21 (0.70–2.11) | 0.49 | 1.34 (0.85–2.12) | 0.21 | |
| Liver metastasis | |||||
| No | 1 | 1 | |||
| Yes | 2.50 (1.45–4.31) | 0.001 | 2.56 (1.58–4.14) | <0.001 | |
| Bone metastasis | |||||
| No | 1 | 1 | |||
| Yes | 1.12 (0.66–1.91) | 0.68 | 1.50 (0.98–2.29) | 0.06 | |
| CgA & Syn | |||||
| Double negative | 1 | 1 | |||
| Single positive | 3.03 (0.40–23.23) | 0.29 | 1.37 (0.47–4.03) | 0.56 | |
| Double positive | 2.41 (0.33–17.53) | 0.39 | 1.16 (0.42–3.18) | 0.78 | |
| Unknown | 3.80 (0.34–42.04) | 0.28 | 1.16 (0.21–6.36) | 0.87 | |
| Hyponatremia | |||||
| No | 1 | 1 | |||
| Yes | 0.76 (0.41–1.44) | 0.41 | 0.78 (0.47–1.29) | 0.34 | |
| Hypokalemia | |||||
| No | 1 | 1 | |||
| Yes | 1.77 (1.05–2.99) | 0.03 | 1.49 (0.96–2.30) | 0.08 | |
| Best response | |||||
| PR/CR | 1 | 1 | |||
| SD | 2.18 (1.26–3.77) | 0.01 | 1.56 (1.00–2.45) | 0.05 | |
| PD | 29.36 (10.26–84.04) | <0.001 | 15.53 (6.22–38.79) | <0.001 | |
CgA, chromogranin A; CI, confidence interval; CR, complete response; ES-SCLC, extensive-stage small-cell lung cancer; HR, hazard ratio; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; Syn, synaptophysin.
Figure 4.
Forest plots showing the associations between clinical characteristics and PFS (A) and OS (B). Model 1: unadjusted model. Model 2: adjusted for other variables. CI, confidence interval; HR, hazard ratio; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
Discussion
SCLC, characterized by its high degree of malignancy, rapid progression, tendency to drug resistance, and considerable heterogeneity, is associated with a short survival. It is widely believed that SCLC represents a category of diseases rather than a single disease, but thus far, no classification indicators capable of effectively guiding clinical decision-making have been proposed. After the publication of the IMpower133 study results, chemotherapy combined with immunotherapy became the new standard of care, opening a new chapter for the treatment of patients with ES-SCLC. Studies such as CASPIAN (12), CAPSTONE-1 (11), ASTRUM-005 (7), RATIONALE-312 (9), ETER-701 (5), and EXTENTORCH (14) trials successively confirmed that immunotherapy combined with chemotherapy can provide survival benefits to patients with ES-SCLC. The 3-year OS rates in the IMpower133 (15), CASPIAN (16), and CAPSTONE-1 trials were 16%, 17.6%, and 21.1%, respectively. At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, the findings of the ASTRUM-005 trial were announced, which included a 3-year OS rate of 25.3% at a median follow-up of 42.4 months. This demonstrates that the addition of ICIs can indeed provide survival benefits to a portion of patients, but the exact nature of this population has yet to be specified.
Our study analyzed patients with ES-SCLC receiving chemotherapy combined with immunotherapy based on clinical characteristics to identify the population that benefits most from immunotherapy. We found that patients with fewer than three metastatic organs, without liver metastasis, and with treatment efficacy of partial response or complete response received greater benefit from immunotherapy. Unlike patients with NSCLC, brain metastasis did not affect the survival of patients with ES-SCLC, and bone metastasis similarly had no significant impact on survival time. However, liver metastasis was associated with a poorer prognosis. The survival of patients with liver metastasis was significantly worse than that of patients without liver metastases, with a difference in PFS of 2.5 months (6.4 vs. 8.9 months; P<0.01) and a difference in OS of 11 months (10.8 vs. 21.8 months; P<0.01). Multivariate analysis also found that the population with liver metastases did not benefit from immunotherapy combined with chemotherapy. After incorporating data from the population receiving chemotherapy alone into the analysis, we discovered that patients without liver metastases had a significantly prolonged PFS and OS after combined immunotherapy, with PFS increasing from 6.6 to 8.9 months and OS increasing by 8.9 months (12.9 vs. 21.8 months). For patients with liver metastases, neither PFS (4.8 vs. 6.4 months) nor OS (9.5 vs. 10.8 months) showed significant improvement after combined immunotherapy.
Given that the above conclusions were derived from a single-center study, the level of evidence is relatively low. To validate these findings, we conducted a meta-analysis that included subgroup results of patients with liver metastases from five RCTs. Although the meta-analysis indicated that patients with liver metastases could also benefit from immunotherapy, the HRs for both PFS and OS were higher compared to those without liver metastases. This suggests that the benefit of immunotherapy may be less pronounced in this subgroup, which is consistent with the observational findings of this study. Furthermore, in the subgroup meta-analyses based on ICI type, neither PD-L1 nor PD-1 inhibitors appeared to have significant effect on PFS in patients with liver metastases. For OS, both PD-L1 and PD-1 inhibitors seemed to confer survival benefits in patients with liver metastases. Given the suboptimal survival benefit observed in this subgroup, intensifying treatment by combining chemoimmunotherapy with novel agents is warranted. In light of the impressive efficacy demonstrated in the ETER-701 study, we propose that adding anlotinib to chemoimmunotherapy represents a promising strategy for ES-SCLC patients with liver metastases. Furthermore, emerging therapies such as lurbinectedin and tarlatamab may also offer valuable therapeutic alternatives.
In 2023, Lin et al. (17) analyzed 3,501 patients with ES-SCLC from six major RCTs. A pooled analysis similarly found that chemotherapy combined with immunotherapy did not improve PFS or OS in patients with liver metastases, with HRs of 0.82 (95% CI: 0.68–1.00; P=0.05) and 0.89 (95% CI: 0.79–1.00; P=0.05), respectively. For patients without liver metastases, chemotherapy combined with immunotherapy significantly improved PFS and OS in patients with ES-SCLC, with HRs of 0.66 (95% CI: 0.57–0.77; P<0.01) and 0.74 (95% CI: 0.67–0.82; P<0.01), respectively, consistent with the conclusion drawn from our institute. In 2024, Wu et al. (18) analyzed 24,507 patients with ES-SCLC accompanied by liver, lung, bone, and brain metastases from the Surveillance, Epidemiology, and End Results (SEER) database. The 1-year OS rate for the overall population was 19.7%. The population with liver metastases had the worst prognosis, with a 1-year OS rate of only 14.5%, while the population with brain metastases had a 1-year OS rate of 21.6%.
The incidence of liver metastasis in patients with SCLC is reported to be 17% (19), while that in those with NSCLC is only 4% (20). Data from our institute indicate that the proportion of the population with liver metastases is as high as 25%. In the ASTRUM-005 study (7), the proportion of patients with liver metastasis in the study and control groups was 25.4% and 26%, respectively. The proportions in the RATIONALE 312 study (13) were also quite similar, at 28% and 26% in the study and control groups, respectively. The ETER-701 study (5) had an even higher proportion of patients with liver metastasis, at 31.8% in the experimental group and 32% in the control group. Among patients with SCLC, those with liver metastasis have a poorer prognosis, which cannot be improved by the standard combination of chemotherapy and immunotherapy. Thus, there is an urgent need to develop novel treatment strategies for this population. There have been numerous ongoing and recently completed studies investigating the efficacy of combining immunotherapy, antiangiogenic therapy, and chemotherapy in SCLC. The ETER-701 study has reported promising results (5). In addition, Liu et al., in a single-arm study, evaluated camrelizumab in combination with apatinib and chemotherapy and similarly observed favorable therapeutic outcomes (21). Comparable findings have also been reported in clinical trials for ivonescimab (22). The CeLEBrATE study, which examined carboplatin, etoposide, atezolizumab, and bevacizumab, likewise demonstrated favorable responses (23). Highly anticipated data on the efficacy of emerging antitumor therapeutics in SCLC were presented at recent international conferences and included notable therapeutic promise. Tarlatamab is a bispecific T-cell engager (BiTE) immunotherapy targeting delta-like ligand 3 (DLL3). At the 2025 World Conference on Lung Cancer (WCLC), data presented on tarlatamab combined with PD-L1 inhibitor as first-line maintenance therapy indicated a significant extension of median OS to 25.3 months (95% CI: 20.3–not estimable) (24). In addition, tarlatamab demonstrated superior efficacy in the second-line setting in terms of median OS (tarlatamab: 13.6 months, 95% CI: 11.1–not reached; chemotherapy: 8.3 months, 95% CI: 7.0–10.2) (25). However, there are no reports on data specifically for the population with liver metastases. It has been reported that BNT327 (pumitamig; a PD-L1 × VEGF—a bispecific antibody) yields higher response rates and superior PFS in the first-line treatment of patients with ES-SCLC (26). Further data from other large-sample studies and subgroup analyses for patients with liver metastases are anticipated. Another study found that a B7-H3 targeted antibody-drug conjugate (ADC) demonstrated good efficacy and safety in previously treated patients with ES-SCLC (27). In research examining ABBV-706 [an ADC targeting seizure-related homolog 6 (SEZ6)], it was found that it produces high response rates, accelerated tumor shrinkage, and rapid symptom relief, with good efficacy and safety in relapsed/refractory patients with SCLC (28). It is hoped that these novel antitumor drugs can also effectively treat patients with liver metastasis.
This study involved certain limitations that should be addressed. First, as we employed a retrospective design, bias was inevitable. However, we conducted a meta-analysis that included several phase Ⅲ RCTs with high levels of evidence, which confirmed the reliability of the retrospective findings. Second, the study population was primarily composed of Asian patients; therefore, future studies involving other ethnic groups are needed to further validate the reliability and generalizability of our results. Thirdly, restricted by the retrospective design and limited data availability, we were unable to assess metabolic dysfunction-associated steatohepatitis, neuroendocrine transcription factors, or detailed toxicity profiles, precluding a comprehensive analysis of their correlations with safety and efficacy.
Conclusions
The presence of liver metastasis is a key prognostic factor in patients with ES-SCLC. Patients with liver metastasis receive limited benefit from standard chemoimmunotherapy, highlighting the urgent need for novel therapeutic strategies. Specifically, combinatorial regimens incorporating additional agents hold significant potential to improve the prognosis of this subgroup. Future studies should focus on optimizing treatment approaches and clarifying the biological mechanisms underlying the poor response in this subgroup.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Guangdong Provincial People’s Hospital [No. GDREC2016175H(R2)]. Informed consent was obtained from all patients involved in the study.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0193/rc
Funding: This work was supported by Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (No. 2017B030314120).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0193/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0193/dss
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