Small cell lung cancer (SCLC) constitutes approximately 15% of all lung cancer cases and is distinguished by its aggressive growth, high propensity for metastasis, and substantial mortality rate (1, 2). Previous research has indicated that the 5-year survival rate for SCLC patients remains below 5% (3, 4). SCLC is typically classified into two stages: limited stage and extensive stage, as defined by the Veterans Affairs Lung Study Group staging system. Notably, at the time of diagnosis, the majority of SCLC cases are identified as extensive stage SCLC (ES-SCLC) (5), and the prognosis for these patients is generally poor. Recurrence of cancer is common in ES-SCLC patients post-first-line treatment, largely due to the development of drug-resistant tumor cells, despite an initial high sensitivity to first-line therapies (6). Currently, effective second-line treatment options for ES-SCLC are scarce. Topotecan is the standard second-line therapeutic agent, but its objective response rate (ORR) is relatively low, and the significant adverse effects associated with its administration often curtail its clinical utility (7–9). Moreover, prior studies have shown that the overall survival (OS) for patients treated with topotecan is approximately 26 weeks (10).

The advent of immune checkpoint inhibitors (ICIs) has markedly altered the therapeutic paradigm and improved survival outcomes for ES-SCLC patients. The incorporation of the PD-L1 inhibitor atezolizumab into platinum-etoposide chemotherapy as a first-line treatment has significantly extended OS in ES-SCLC patients, establishing it as the preferred first-line treatment regimen (11). Supporting the ICI-based approach, durvalumab, another PD-L1 inhibitor, combined with chemotherapy, has also been endorsed as a first-line treatment for ES-SCLC (12). Furthermore, PD-1 inhibitors such as nivolumab and pembrolizumab have been approved for use in the third-line setting (13, 14). However, it is important to recognize that the efficacy of ICI monotherapy in second-line or subsequent settings is limited to a small subset of unselected ES-SCLC patients, with ORR ranging from 10% to 30%. Thus, there remains a critical need for more effective therapeutic strategies in this clinical context (13, 14).

Combining ICIs with anti-angiogenic agents has emerged as a promising strategy to enhance cancer immunotherapy’s effectiveness (15, 16). Anlotinib, a new multi-target small molecular polytyrosine kinase inhibitor, has shown potential in inhibiting several key receptors, including vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor α and β (PDGFRα/β), and c-kit (17). This broad inhibition disrupts tumor angiogenesis and growth, contributing to its anti-cancer properties. Camrelizumab, a PD-1 inhibitor, works by blocking the PD-1/PD-L1 pathway, which tumors exploit to evade immune detection. By inhibiting this pathway, camrelizumab reactivates effector T cells, enhancing the body’s immune response against cancer cells (18). Recent studies have indicated that the combination of PD-1 inhibitors with anti-angiogenic drugs can produce synergistic anti-tumor effects. Abnormalities in the tumor microenvironment (TME), driven by VEGF-mediated angiogenesis, contribute to immunosuppression and reduced efficacy of PD-1/PD-L1 blockade (19). VEGF-induced abnormal vasculature in tumors creates hypoxic and acidic conditions, which inhibit effective T cell responses (20). By normalizing the tumor vasculature, anti-angiogenic agents like anlotinib can enhance T cell infiltration and improve the effectiveness of ICIs (21). Given these findings, our study aims to evaluate the effectiveness and safety of combining camrelizumab with anlotinib as a second-line treatment for ES-SCLC, compared to standard chemotherapy regimens.

To the best of our knowledge, this study is the first to report that camrelizumab combined with anlotinib outperforms standard chemotherapy in the second-line treatment for patients with ES-SCLC. This finding is distinct from previous reports, such as the case report by Yuqi Jiang et al., which involved a patient with limited-stage SCLC (22). Our study specifically focuses on ES-SCLC, providing comprehensive evidence of efficacy and safety. The median PFS for the combination therapy was a notable 7 months, significantly surpassing the median PFS observed in the chemotherapy group and those reported in previous second-line treatment studies (7–9, 23). Although the differences in the ORR and DCR did not reach statistical significance, positive trends were observed. Moreover, the combined treatment regimen demonstrated a manageable safety profile with fewer grade 3 or higher TRAEs compared to chemotherapy. These outcomes suggest that the camrelizumab and anlotinib combination could be a favorable option for second-line treatment in the ES-SCLC context.

Topotecan is currently the conventionally recommended second-line treatment option for patients with ES-SCLC following initial chemotherapy. Previous research highlighted that OS associated with topotecan in the second-line setting was limited to an average of 26 weeks, alongside a modest ORR of 7% and a higher incidence of toxic effects (10). Furthermore, in a phase 3 clinical trial, SCLC patients given topotecan after failing first-line therapy reported a 16.9% ORR, with a median PFS of 3.5 months and an OS of 7.8 months (7). More recently, the approval of lurbinectedin as a new second-line agent for SCLC resulted in a median PFS of 3.5 months and an OS of 9.3 months (24). Given the suboptimal outcomes of the established second-line regimens, the need for more effective treatments is urgent. Our research showcases a promising alternative; the combination of camrelizumab with anlotinib achieved a median PFS of 7 months in our study, which exceeds the PFS seen with the current standard second-line therapies.

The introduction of PD-1/PD-L1 inhibitors has significantly transformed the therapeutic landscape for ES-SCLC. The integration of PD-L1 inhibitors with platinum-based chemotherapy has become a standard first-line treatment, substantially improving OS for ES-SCLC patients (11, 12). Similarly, for advanced NSCLC, the combination of PD-1/PD-L1 inhibitors with platinum-based chemotherapy has received approval for first-line use (25). Moreover, the IMPOWER 150 trial demonstrated that anti-PD-L1 agents, when combined with bevacizumab and platinum-based chemotherapy, can enhance the prognosis of advanced NSCLC (26). These advancements highlight the potential of PD-1/PD-L1 inhibitor combination therapies to enhance the efficacy of immunotherapy.

Combining ICIs with angiogenesis inhibitors has shown promise as a therapeutic strategy. A phase 1 clinical trial reported an ORR of 19.6% for metastatic melanoma patients treated with ipilimumab, an anti-CTLA-4 antibody, in combination with the angiogenesis inhibitor bevacizumab (27). Similarly, other studies have demonstrated encouraging ORRs in patients with renal and urothelial cancers when ICIs are combined with angiogenesis inhibitors (28, 29). Supporting these findings, research by Fan et al. demonstrated that the combination of camrelizumab, a PD-1 inhibitor, with apatinib, an angiogenesis inhibitor, significantly improved ORR and PFS in ES-SCLC patients (23). Given the generally low ORR associated with ICI monotherapies, adding an angiogenesis inhibitor could offer a viable and relatively safe combination therapy. Our results align with this approach, suggesting that the combination of the PD-1 inhibitor camrelizumab with the oral VEGFR inhibitor anlotinib achieved an ORR of 52.9% and a DCR of 82.4%. These outcomes are noteworthy compared to a recent phase 2 trial that reported a confirmed ORR of 33.9% and a DCR of 69.5% with a regimen of camrelizumab and apatinib (23). One potential reason for the superior results in our study could be the inclusion of more patients treated with anlotinib, which previous research has indicated may be more effective and better tolerated than apatinib, especially in third-line or subsequent treatment settings for ES-SCLC (30). The relatively small number of participants in our study might also have influenced the results. Furthermore, the treatment regimen analyzed here achieved a median PFS of 7 months, a significant improvement compared to the 3-month PFS observed in the chemotherapy group (p<0.001). This finding supports the notion that combining ICIs with oral VEGFR inhibitors could be a viable and effective treatment option for ES-SCLC patients who do not respond to first-line therapy.

Patients who have received extensive prior treatment often present with a lower ECOG PS, which can indicate a reduced ability to tolerate later-line treatments, particularly chemotherapy. This trend was also noted in our study, where we observed that patients receiving chemotherapy experienced a higher incidence of TRAEs of all grades, including grade 3 or above TRAEs. However, these differences did not reach statistical significance. Previous research suggests that combination therapies are generally associated with a higher frequency of adverse events compared to monotherapies (31, 32). Nevertheless, in our study, the chemotherapy group exhibited a different safety profile, influencing the comparative assessment. As a result, the combination of camrelizumab and anlotinib demonstrated a more manageable safety profile. Our data suggest that the camrelizumab and anlotinib combination may offer a more tolerable and effective treatment alternative.

It is important to acknowledge certain limitations of this study. Firstly, due to its retrospective design, the findings should be interpreted with caution. Additionally, the limited sample size may introduce selection bias. Therefore, conclusions drawn from this study require validation through larger, randomized controlled trials.

In summary, the results of our study suggest that the combination of camrelizumab and anlotinib offers superior efficacy and a manageable safety profile compared to conventional systemic therapy for patients with ES-SCLC in a second-line treatment setting. Our research provides valuable insights for the treatment of ES-SCLC patients failing first-line therapy. Nonetheless, future research is necessary to further corroborate these findings.

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

The studies involving humans were approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because of the retrospective design and individuals information will not be published, hence informed consent was exempted.

SS: Data curation, Formal analysis, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing. XL: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Writing – original draft, Writing – review & editing. SG: Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing. LX: Conceptualization, Data curation, Formal analysis, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. NY: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing.