Extensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive subtype of lung cancer, diagnosed in approximately 70% of SCLC patients, and is associated with poor prognosis and a significant disease burden (1). Among patients with ES-SCLC, liver metastasis is particularly common, occurring in around 20-30% of cases (2). Notably, liver metastases tend to develop early in the disease course (3) and are correlated with a significantly worse prognosis compared to other metastatic sites (4). Patients frequently suffer from severe complications due to the extensive nature of liver involvement, including hepatic dysfunction (5). This subset of patients experiences shorter progression-free survival (PFS) and overall survival (OS), poorer performance status, and reduced quality of life (6). Liver metastasis is also often associated with a less favorable response to traditional chemotherapy, further challenging disease control (6). The progression of the disease and resulting comorbidities significantly impact patients’ quality of life, frequently leading to increased symptom burden, higher levels of palliative care needs, and substantial healthcare costs (7, 8).

Current therapeutic strategies for ES-SCLC generally incorporate immunotherapy in combination with platinum-based chemotherapy as the first-line treatment (9, 10). Compared to chemotherapy alone, chemo-immunotherapy demonstrated superior efficacy in prolonging OS in ES-SCLC patients with liver metastasis (11). However, liver metastases have been shown to attenuate the therapeutic benefits. ES-SCLC patients with liver metastases often demonstrate less pronounced clinical improvements from immunotherapy compared to those without liver involvement. It is likely due to the unique immunologic and vascular characteristics of the liver that may hinder effective immune response activation against tumor cells (12).

In recent years, serplulimab, a novel PD-1 inhibitor, has been approved in China for SCLC treatment (13). The ASTRUM-005 clinical trial demonstrated that serplulimab combined with platinum-based chemotherapy improved outcomes for ES-SCLC patients with liver metastases, achieving a median OS of 10.8 months and a median PFS of 6.9 months (14). However, the efficacy of this regimen may vary in real-world settings, where patients often have poorer baseline performance status and greater comorbidities than those in clinical trials. Although guidelines have incorporated serplulimab plus platinum-based chemotherapy for first-line ES-SCLC treatment, there remains a lack of real-world data to assess its safety and effectiveness comprehensively, particularly in patients with liver metastases. This study aims to fill this gap by evaluating the real-world effectiveness and safety of this combination therapy in ES-SCLC patients with liver metastases.

This study substantiates the clinical use of serplulimab combined with platinum-based chemotherapy in treating ES-SCLC liver metastases, demonstrating an ORR of 63.3% and a DCR of 83.3%. The median PFS was 5.9 months, and the median OS was 9.1 months. Subgroup analyses indicated that the depth of remission is a critical factor influencing survival outcomes. Notably, patients achieving a depth of remission of ≥30% in primary lung lesions had significantly longer PFS and OS, while a depth of remission of ≥30% in liver metastases was also associated with prolonged OS. Additionally, the manageable safety profile of this combination supports its feasibility for broad clinical application in ES-SCLC liver metastases.

The advent of PD-1/PD-L1 ICIs has significantly altered the therapeutic landscape for SCLC, challenging the long-standing reliance on chemotherapy as the primary treatment modality (15, 16). PD-1/PD-L1 inhibitors enhance T cell responses and improve the immune system’s ability to target cancer cells by blocking the PD-1/PD-L1 pathway (17). However, this immunological enhancement may have a limited impact in patients presenting with liver metastases, as liver metastases are often characterized by a lower infiltration of cytotoxic T lymphocytes compared to metastases located in the lung, bone, or brain (18). A meta-analysis synthesizing data from four randomized controlled trials highlighted a modest discrepancy in the efficacy of ICIs, revealing that SCLC patients with liver metastases experienced lesser OS benefits from ICI therapy compared to patients without such metastases (HR, 1.22; 95% CI, 1.01-1.46; P = 0.036) (12). This was further supported by a meta-analysis of 14 real-world studies, which identified the presence of liver metastases as an independent adverse prognostic factor for OS in SCLC patients undergoing ICI therapy (P<0.0001) (12). Moreover, outcomes from the CASPIAN study underscored these observations, showing that the addition of durvalumab to a standard EP chemotherapy regimen did not significantly enhance OS in patients with liver metastases compared to those without (HR = 0.87, 95% CI 0.66-1.16) (19). Similar findings were reported in the CAPSTONE-1 study of adebrelimab plus EC, where the OS HR for patients with liver metastases was 0.92 (95% CI 0.55-1.31), suggesting no substantial survival advantage (20). These collective results from various studies illustrate a nuanced landscape where, despite the revolutionary potential of PD-L1 inhibitors (10), their benefits in ES-SCLC patients with liver metastases are inconsistent and limited.

The clinical benefit of serplulimab for SCLC with liver metastases may not be consistent with other PD-1 inhibitors, such as pembrolizumab (21). Serplulimab and pembrolizumab exhibited similar performance in vitro and in vivo studies, but serplulimab demonstrated consistently superior anti-tumor activity compared to pembrolizumab upon co-administration with anti-TIGIT or anti-LAG3 inhibitors (22). Serplulimab robustly induces PD-1 receptor endocytosis while fostering weaker PD-1-CD28 cis interactions, leading to sustained and robust T cell activation. Therefore, the serplulimab combination effectively reduces tumor microenvironment Treg cell populations, augments effector and memory T cell populations, and more potently modulates genes associated with diverse facets of the immune system, surpassing the effects of the pembrolizumab combination (22). These findings suggest that serplulimab may offer improved efficacy in ES-SCLC liver metastases, highlighting its potential for enhanced therapeutic response in this challenging patient subset.

The ASTRUM-005 study, which assessed serplulimab as a first-line therapy for ES-SCLC, has significantly contributed to the evolving landscape of treatment options for patients with liver metastases. Notably, the subgroup analysis focusing on patients with concomitant liver metastases revealed that serplulimab offers considerable OS benefits, with an HR of 0.58 (95% CI 0.40-0.84), aligning closely with outcomes observed in patients without liver metastases (14, 23). This finding positions serplulimab as a potentially preferred immunotherapy option for treating ES-SCLC patients with liver metastases. Despite these promising clinical trial results, a noticeable gap remains in real-world evidence regarding the effectiveness of immune combination therapies in ES-SCLC liver metastases. The current study, which reported an OS of 9.1 months, highlights this gap, especially considering the poorer ECOG performance scores and the universal presence of metastatic disease among patients.

In contrast to the ASTRUM-005 trial, which studied a diverse group of ES-SCLC patients, including brain and liver metastases, our study population focused on ES-SCLC patients with liver metastases. Patients in this real-world study were older and had poorer ECOG scores. These disparities highlight a patient population with a more advanced disease state and a generally poorer health status, factors that typically predict a diminished response to treatment (24). Moreover, our study was conducted amidst the unprecedented challenges posed by the COVID-19 pandemic. The pandemic’s pervasive impact on healthcare systems worldwide led to logistical hurdles for many of our patients, resulting in treatment delays for 3 patients, discontinuation for 2 patients, and COVID-19-related deaths for 2 patients among those who contracted the virus (n=17, 56.7%). Such disruptions could have potentially skewed our results, given the critical importance of uninterrupted treatment in oncology, particularly for patients with ES-SCLC. Therefore, it is plausible that the therapeutic effectiveness observed in our study may have been underestimated due to these adverse effects of the pandemic. Nevertheless, the fact that our study still managed to secure a substantial antitumor response and a DoR not far off from those observed in a controlled clinical trial setting underscores the potential robustness of the treatment regimen utilized. This comparison not only reaffirms the effectiveness of the therapeutic approach employed in the ASTRUM-005 but also suggests that similar outcomes can be anticipated in real-world settings, even among populations with generally poorer prognostic factors.

Depth of remission has been extensively studied in non-small cell lung cancer (NSCLC) as a predictor of survival outcomes (25, 26), but to date, no comparable research has been conducted for SCLC. In this study, we uniquely evaluated the depth of remission separately for primary lesions and liver metastases, a method that diverges from the single, unified approach typically used in NSCLC studies. Our findings demonstrate that the depth of remission of primary lesions is significantly associated with both PFS and OS, suggesting that the response of primary tumors to immunotherapy reflects the overall systemic response and can serve as a predictor of long-term prognosis. Additionally, depth of remission of liver metastases was correlated with OS, with a similar trend observed for PFS, indicating that depth of remission of liver metastases may also have predictive value for treatment effectiveness. These findings imply that the response mechanisms of primary lesions and liver metastases to serplulimab are aligned, further highlighting the potential of depth of remission as a meaningful marker in SCLC.

In our study, AEs of any grade were reported in 63.3% of patients, predominantly nausea, leukopenia, and neutropenia. The occurrence of grade 3 or higher AEs was limited to 6.7% of patients. Notably, irAEs were observed in 26.7% of participants, which is considerably lower than the rates reported in pivotal trials such as IMpower133, where 39.9% of patients experienced irAEs, primarily rash and hypothyroidism (9). Comparatively, the CASPIAN study reported higher incidences of severe neutropenia and anemia, with irAEs in up to 36% of patients, emphasizing more frequent thyroid-related irAEs (19). Similarly, in the ASTRUM-005 trial, 33.2% of patients experienced significant treatment-related adverse events, such as decreased neutrophil and white blood cell counts (23). The CAPSTONE-1 (20) and KEYNOTE-604 (20) studies also reported substantial hematological AEs and irAEs, including a notable incidence of hypothyroidism. Our study’s relatively low incidence of irAEs, combined with a manageable range of other AEs, underscores the favorable safety profile of the treatment regimen employed, especially when considering its application in patients with typically poor prognoses and advanced disease stages. However, it is important to consider that the incidence of AEs might be underestimated due to the retrospective nature of our study.

Our study has several limitations. A significant constraint is the relatively small sample size, which limits the generalizability of our findings. Additionally, the absence of a control group restricts our ability to draw more definitive causal inferences regarding the effectiveness and safety of the treatment regimen. The retrospective design of our study also introduces potential biases, which could affect the robustness of our conclusions. Notably, while prolonged survival was associated with both the receipt of maintenance therapy and completion of more than four treatment cycles, these associations should be interpreted in the context of inherent immortal-time bias. Patients who remained progression-free and survived longer had a greater opportunity to receive subsequent therapies, indicating that extended treatment exposure is intrinsically linked to longer pre-existing survival. The results require validation using more robust methods, such as time-dependent covariate modeling or landmark analysis in future studies. Furthermore, the follow-up period in our study may not have been sufficient to fully assess long-term outcomes and late-emerging adverse events. These limitations underscore the need for larger, prospective, randomized controlled trials to more accurately evaluate the benefits and risks of this therapeutic approach in a more diverse patient population.

Our study provides valuable real-world clinical evidence demonstrating promising effectiveness and a manageable safety profile for the combination of serplulimab with platinum-based chemotherapy in treating ES-SCLC liver metastases. The remission depth of primary lung lesions and liver metastases hinted at prognosis. The findings demonstrate that this combination can offer a durable antitumor response and a favorable safety profile, highlighting its potential as a viable treatment option for ES-SCLC liver metastases.