Clinical outcomes and safety of continuous immunotherapy beyond progression in patients with extensive-stage small cell lung cancer: a retrospective real-world study.

Introduction
Lung cancer was the most frequently diagnosed cancer in 2022, accounting for nearly 2.5 million new cases, which was equivalent to about one out of every eight cancers diagnosed globally, making up 12.4% of all cancer cases around the world. Additionally, lung cancer was the primary cause of cancer-related deaths, with an approximate 1.8 million fatalities, representing 18.7% of all cancer deaths (1). Small-cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma arising predominantly in current or former smokers and has an exceptionally poor prognosis (2). The Veterans Administration Lung Cancer Study Group (VALSG) staging system is widely used in both designing clinical trials and presenting data of SCLC, as it effectively distinguishes patients treated primarily with chemoradiotherapy (limited-stage disease) from those treated with systemic chemotherapy or chemoimmunotherapy (extensive-stage disease). At the time of diagnosis, approximately two-thirds of all cases of SCLC would present with extensive-stage disease (ES-SCLC) (3).
Until 2019, the combination of etoposide and platinum had been the standard treatment for ES-SCLC (4, 5). However, in 2019, evidence showed that adding anti-programmed death-ligand 1 (anti-PD-L1) immunotherapies such as atezolizumab (6, 7) and durvalumab (3, 8) to etoposide/platinum chemotherapy could improve survival, which were recommended as first-line therapeutic options for ES-SCLC. Then several immune-checkpoint inhibitors (ICIs) such as pembrolizumab (9), ipilimumab (10), tremelimumab (8), adebrelimab (11), serplulimab (12), tislelizumab (13) and toripalimab (14) were also investigated in the first-line treatment of ES-SCLC. And also, anti-angiogenic agents including bevacizumab (15–17) and anlotinib (18) were also explored for combination immunochemotherapy, indicating positive synergistic effects. Nevertheless, even though immunochemotherapy, with or without anti-angiogenic therapy, has demonstrated potential by providing an overall survival (OS) benefit of 2 to 4 months for patients with ES-SCLC when compared to chemotherapy alone, the goal of enhancing survival still remains an unfulfilled need. Moreover, progression after previous anti-Programmed Cell Death-1/Programmed Cell Death Ligand-1 (anti-PD-1/PD-L1) inhibitors is inevitable, and if continuous immunotherapy leads to more favorable prognosis were still undefined.
After progression during chemotherapy combined with immunotherapy, a potential approach to address drug resistance is to modify the type of chemotherapy drug, aiming to restore the responsiveness to immunotherapy and enable its continued effectiveness. However, most previous studies have mainly focused on the rechallenge of immunotherapy, neglecting the impact of continuous immunotherapy after progression. According to a subgroup study of Checkmate 025, continuing immunotherapy beyond progression has reduced tumor burden by ≥ 30% in patients with advanced or metastatic clear-cell renal-cell carcinoma (19). OAK study also demonstrated the survival benefit of continued atezolizumab after progression for advanced non-small cell lung cancer (NSCLC) patients (20). To the best of our knowledge, there are limited data on whether continuous ICIs beyond progression can be adopted in SCLC. This study aimed to investigate the role of continuous immunotherapy and addition of anti-angiogenic agents beyond progression after first-line immunochemotherapy in ES-SCLC patients, identifying the optimal treatment strategy and specific subgroups that may derive greater benefits from this strategy.

Methods

Patients
We retrospectively collected patients with ES-SCLC that received ICIs plus chemotherapy as first-line therapy from January 2020 to December 2024 in the Department of Medical Oncology of Qilu Hospital of Shandong University (Jinan, Shandong), the Department of Medical Oncology of Qilu Hospital of Shandong Province (Qingdao, Shandong), and Shandong Cancer Hospital. Given that the study is retrospective, there is no need to provide written informed consent. Our multicenter and retrospective study was carried out in compliance with the amended Declaration of Helsinki and got approval from the appropriate ethical committees.

Inclusion and exclusion criteria
The main inclusion criteria were as follows: 1) patients with pathologically or histologically diagnosed ES-SCLC; 2) patients who received at least two cycles of anti-PD-1 or anti-PD-L1 agents in combination with chemotherapy during the first-line therapy; 3) at least one measurable lesion. The primary exclusion criteria are listed below: 1) limited-stage small cell lung cancer; 2) patients who did not receive anti-PD-1 or anti-PD-L1 agents during the first-line therapy; 3) no measurable lesions; 4) incomplete medical data; 5) exclusion due to other diseases or causes.

Data collection
The basic information of the patients before treatment was collected, including age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), smoking status, etc. Clinical characteristics included the date of diagnosis, location of metastasis, as well as the specific medications used during first-line treatment, the number of treatment cycles, the mode of second-line treatment, and follow up indicators including efficacy evaluation, follow-up time, progression-free survival (PFS), OS, adverse events (AEs), and immune-related adverse events (irAEs) during the entire treatment period. Continuous immunotherapy beyond progression refers to class continuation allowing ICI agents different from those used in the first-line therapy or continuation of the same ICI agent. Patient information was retrieved and summarized from the hospital medical records.

Endpoints
The primary endpoints included first-line PFS, second-line PFS, and OS. First-line PFS is defined as the time from the start of first-line therapy to progression. Second-line PFS is defined as the duration from the start of second-line therapy to the date of disease progression or death due to any cause. OS is defined as the duration from the date of treatment initiation to the date of death due to any cause. Radiological data were used to assess tumor response based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, classifying tumor response to treatment as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). CR refers to the disappearance of all target lesions; PR indicates that the sum of the diameters of target lesions has decreased by more than 30% from the baseline; PD refers to an increase of 20% or more in the sum of the diameters of target lesions compared to the smallest recorded value, with an absolute increase of at least 5 millimeters, or the appearance of new lesions; SD means that the change in the sum of the diameters of target lesions that falls within the range of a 30% decrease to a 20% increase. The objective response rate (ORR) is defined as the proportion of patients achieving CR or PR. All patients were actively followed up until May 1, 2025, and follow-up information was obtained via phone or directly from electronic medical record system files. AEs and irAEs were assessed and graded according to the scores defined the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).

Statistical analysis
We stratified the included patients based on age, gender, ECOG PS, smoking status, location of metastatic lesions, and treatment modality for baseline characteristics and analyzed the differences between baseline characteristics using Chi-square test and Fisher’s exact test. The best response status during first-line treatment was statistically analyzed. Kaplan-Meier method was employed to evaluate the PFS during first-line and second-line therapy as well as OS. The log-rank test was used to compare the differences in survival curves between groups, and the corresponding 95% confidence interval (95%CI) was calculated. All tests yielded two-sided P values, and those with a value <0.05 were regarded as statistically significant. Statistical analysis was performed using SPSS software (version 26.0), the graphs were generated using R software (version 4.4.1) and GraphPad Prism software (version 9.0).

Results

Patient clinical characteristics
From January 2020 to December 2024, a total of 354 ES-SCLC patients treated with first-line immunochemotherapy who suffered disease progression were enrolled (Figure 1). The median age of the cases was 62 years (range, 36–84 years) and most patients had a performance status score of 0-1. There were 303 males (85.6%) and 230 (65.0%) with a history of smoking. As for metastatic sites, 96 (27.1%) cases presented with brain metastases, 125 (35.3%) with liver metastases, 123 (34.7%) with bone metastases. Among these, 241 (68.1%) patients received anti-PD-L1 antibody including atezolizumab, durvalumab, adebrelimab and envafolimab, 113 (31.9%) received anti-PD-1 antibody including serplulimab and others (Table 1). Pleural effusion was present in 145 patients (41.0%), and 24.9% of patients received locoregional thoracic radiotherapy. A minority of patients had the comorbidity of hypertension, diabetes, and coronary heart disease.

Efficacy of first-line therapy
Among 354 patients who received first-line immunochemotherapy and suffered disease progression, 3 cases achieved CR, PR was accomplished in 218 cases, and SD was observed in 126 cases. The median PFS (mPFS) of first-line therapy was 6.60 (95%CI: 6.28-6.92) months (Supplementary Table 1, Figure 2).

Subgroup analysis of PFS during first-line therapy
Subgroup analysis in Figure 3 showed that younger (p = 0.016, Figure 3A) and female (p = 0.017, Figure 3B) patients had longer first-line mPFS than older and male patients. Patients who have never smoked have a longer first-line PFS (p = 0.003, Figure 3C). Additionally, patients without bone metastasis showed better efficacy in first-line immunochemotherapy (p < 0.001, Figure 3D), as did those without liver metastasis (p < 0.001, Figure 3E). No significant differences of PFS were observed in the other subgroups including brain metastasis (p = 0.262, Figure 3F), immunotherapy regimen (p = 0.861, Figure 3G) and pleural effusion (p = 0.841, Figure 3H).

Second-line therapy strategies
To further investigate the efficacy of continuous immunotherapy beyond disease progression after first-line immunochemotherapy, we excluded patients who showed primary immune resistance. Here, primary immune resistance refers to a PFS of less than 3 months following first-line therapy. Finally, a total of 206 patients were enrolled to compare the efficacy of second-line therapy. Among these 206 patients, 149 (72.3%) patients received continuous immunotherapy beyond progression, including 122 cases with immunochemotherapy, and other 27 cases with anti-angiogenic therapy plus immunotherapy (11 cases) or plus immunochemotherapy (16 cases). A total of 57 (27.7%) patients received chemotherapy without immunotherapy as second-line therapy, and among them 17 cases received anti-angiogenic agents at the same time. The subsequent strategies administered for patients after progression on first-line therapy were showed in Figure 1 and the baseline clinical characteristics of 206 patients were showed in Supplementary Table 2.

Second-line therapy efficacy among different groups
We categorized patients into five groups based on different second-line treatment regimens: chemotherapy alone (C, 40 cases), chemotherapy + anti-angiogenic therapy (C+A, 17 cases), immunochemotherapy (I+C, 122 cases), immunotherapy + anti-angiogenic therapy (I+A, 11 cases) and immunochemotherapy + anti-angiogenic therapy (I+C+A, 16 cases). The second-line PFS and OS among different groups are showed in Figure 4. Therein, I+C+A group obtained the longest second-line PFS of 4.60 months compared with other groups, next was the C+A group with a second-line PFS of 4.03 months. The second-line PFS of I+C group was longer than that of the C group, which were 3.50 months and 2.33 months respectively. The I+A group also showed poorer second-line PFS of 2.83 months compared with other groups (Figure 4A). As for OS, I+A group achieved best OS of 22.00 months, while I+C+A group showed the worst OS of 19.33 months. The other groups showed similar OS (20.97 months for C+A group, 20.03 months for C group and 19.53 months for I+C group) (Figure 4B). However, there were no statistical differences in second-line PFS and OS among the groups. Since chemotherapy and immunotherapy are the basic treatments, we further grouped C and C+A as C ± A, and grouped I+C and I+C+A as I+C ± A. It was found that I+C ± A showed the longest second-line PFS of 3.53 months (p = 0.827, Figure 5A), and I+A showed the longest OS of 22.00 months (p = 0.101, Figure 5B).

Comparison between immunochemotherapy group and chemotherapy group
Since immunochemotherapy and chemotherapy were the main second-line treatment options, we subsequently compared the efficacy of immunochemotherapy (I+C, 122 cases) and chemotherapy (C, 40 cases) alone during second-line treatment. The baseline characteristics were well balanced according to the Table 2. The I+C group showed a longer second-line mPFS of 3.50 months compared with 2.33 months for chemotherapy group (p = 0.249, Supplementary Figure 1). Whereas, our data indicated that continuous immunotherapy did not show a longer mOS compared with chemotherapy without immunotherapy (19.53 vs. 20.03 months, p = 0.070, Supplementary Figure 1). There were no statistical differences in second-line PFS and OS between these two groups.

The subgroup analysis of second-line PFS and OS between the immunochemotherapy group and chemotherapy group
During the subgroup analysis of second-line PFS, we noted that the I+C group showed significant advantages over the C group in subgroups such as female patients, non-smokers, patients without pleural effusion, and patients treated with anti-PD-1 antibody, with statistical differences observed (Figure 6A). However, for OS, the C group demonstrated a significant advantage over I+C group in patients without brain metastasis, with pleural effusion and those did not receive locoregional thoracic radiotherapy (Figure 6B).

The univariate and multivariate Cox regression analysis of second-line PFS and OS in immunochemotherapy and chemotherapy group
We used the univariate and multivariate Cox models to evaluate the effects of different variables on survival to determine which clinical characteristics are linked to the survival of ES-SCLC patients, which were summarized in Tables 3, 4. The outcomes of the univariate analysis revealed that liver metastases, bone metastases and brain metastases were significantly associated with worse second-line PFS. Variables with a P-value between 0.05 and 0.10 were also incorporated into the subsequent multivariate Cox regression model. The multivariate analysis showed that liver metastases was a reliable predictive factor (Table 3). The univariate analysis also showed that liver metastases and bone metastases were significantly correlated with poorer OS. Upon conducting the multivariate analysis, liver metastases, bone metastases and second-line therapeutic regimen were identified as independent prognostic factors for OS, which was presented in Table 4.

Safety
In terms of safety, we analyzed the AEs throughout the entire treatment process. The most common AEs of any grade in the immunochemotherapy group were anemia and fatigue, while the incidence of fatigue was higher in the chemotherapy group. For grade ≥3 AEs, we found that neutropenia predominated in both two groups. Furthermore, we analyzed the incidences of common irAEs in the two groups, noting that immune-related pneumonia was the most common irAE. However, the difference between the rates of AEs (including irAEs) in the two groups were not statistically significant (Table 5).

Discussion
ICIs combined with etoposide-platinum is recommended as standard first-line therapy for ES-SCLC (21, 22). Several ICIs including atezolizumab (6), durvalumab (3), adebrelimab (11), tislelizumab (13), toripalimab (14), serplulimab (12) and benmelstobart plus anlotinib (18) has been approved for the first-line treatment of ES-SCLC in China. Other ICIs such as pembrolizumab (9), ipilimumab (10) and tremelimumab (8) were also investigated in the first-line treatment of ES-SCLC. Despite immunochemotherapy has shown OS benefits in ES-SCLC compared with chemotherapy (23), improving second-line PFS and OS remains an unmet need for this lethal malignancy. For first-line immunotherapy-based combination therapy, there is no conclusive conclusion on whether to continue immunotherapy or not in the second-line treatment.
Patients with relapsed SCLC have globally dismal prognosis. Retreatment with original or similar platinum-based chemotherapy in patients with sensitive relapse has been widely adopted as routine practice, mostly because of the lack of highly active alternative treatment options (24). In the past, oral or intravenous topotecan was the drug approved for second line SCLC. This was based mainly on the results from two randomized phase III trials in which topotecan showed extended OS compared with best supportive care (25), and the noninferiority result in symptom control compared with cyclophosphamide, doxorubicin, and vincristine in patients relapsing after 60 days from first-line chemotherapy (26). However, the ORRs of topotecan regimen did not typically exceed 25%, and the median OS only ranged between 6–9 months (27). Irinotecan, lurbinectedin, paclitaxel, temozolomide and gemcitabine are among other modestly active drugs as single agents in the relapse setting. They are commonly used in routine clinical practice in second or further lines of treatment because of a better tolerability profile and somehow comparable clinical activity with topotecan. Anlotinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) which demonstrated anti-tumour effects in various cancers and has been approved for later-line treatment of SCLC in China (28). Up to now, second-line or further lines treatment options for relapsed ES-SCLC after first-line immunochemotherapy are still controversial with limited overall survival benefit. Whether cross-line ICIs will improve clinical outcome for relapsed ES-SCLC remains ambiguous.
Continuous immunotherapy beyond progression for malignancies remains controversial as some studies have shown opposite results. In non-small cell lung cancer, results from the OAK study (29) found that the median post-PD OS was 12.70 months in 168 patients with continuing atezolizumab treatment beyond progression, while 8.80 months in 94 patients switching to non-protocol therapy. EMPOWER-Lung 1 explored first-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced NSCLC and found that for 64 patients who had disease progression on single-agent cemiplimab, second-line therapy with cross-line cemiplimab resulted in an ORR of 31.3% and a median OS of 15.10 months, which was superior to historical OS of 8.40 months with second-line chemotherapy alone (30). However, Enomoto et al. showed no remarkable advantages relevant to continuation of nivolumab for advanced NSCLC patients (15.60 vs. 13.40 months, P = 0.400) (31). Xu et al. found there were no significant benefits associated with continuation of original ICIs for advanced NSCLC patients beyond first-line immunotherapy progression (32). For small cell lung cancer, previous study have shown that rechallenging of PD-(L)1 inhibitors may offer benefits, especially for the first-line immunochemotherapy subgroup or those who had a SD or PD response to initial immunochemotherapy (33). The study of Liu et al. explored the clinical pattern of immunotherapy resistance in ES-SCLC and found that cross-line immunotherapy rechallenge had a better prognosis (34). Another study from Japan suggested the effectiveness of continuous ICIs beyond progression in clinical practice for SCLC and the strategy provided a favorable prognosis in selected cases of SCLC (35). The IMfirst Study explored the role of atezolizumab treatment beyond progression in ES-SCLC, supporting the continuous use of atezolizumab therapy after first-line immunotherapy progression (36). Another study assessed second-line outcomes for patients with ES-SCLC following progression after initial etoposide/platinum plus immunotherapy and found the overall second-line mOS (n=111) was 5.80 months (95%CI: 4.60-6.40). The mOS of non-rechallenge (n=88) group was 5.00 months (95%CI: 4.10-6.40) and that of rechallenge (n=23) group was 6.20 months (95%CI: 5.10-9.40), without statistically significance (p = 0.180) (37). In our study, we compared the efficacy of immunochemotherapy with chemotherapy alone during second-line therapy. The immunochemotherapy group showed a longer second-line mPFS of 3.50 months compared with 2.33 months for chemotherapy group (p = 0.249). Moreover, continued immunotherapy did not improve the OS of patients (19.53 vs. 20.03 months, p = 0.070), which might be partially due to the influence of immunotherapy rechallenge during subsequent-line treatment in the chemotherapy group.
As for anti-angiogenic agents, our study suggests that immunochemotherapy plus anti-angiogenic agents revealed the longest second-line PFS of 4.60 months versus other groups. The mOS of immunochemotherapy plus anti-angiogenic agents group is the longest with 22.00 months. The potential explanation is the synergistic effect of anti-angiogenesis, immunotherapy and chemotherapy in the reprogramming of the tumor microenvironment. This concept has been explored in patients with advanced non-small-cell lung cancer (38, 39). IMpower150 study demonstrated that the combination of ICIs plus anti-VEGF and chemotherapy was associated with superior OS than the combination of anti-VEGF and chemotherapy in NSCLC (19.20 versus 14.70 months, respectively). Phase 3 trial ETER701 investigated the efficacy and safety of benmelstobart (a novel PD-L1 inhibitor) with anlotinib and standard chemotherapy in treatment-naive ES-SCLC and achieved a median OS of 19.30 months which was longer than the reported OS in previous randomized clinical trials. The results suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious approach. And also, studies have revealed the synergistic effects of anti-angiogenic agents with immunotherapy could reprogram tumor microenvironment from an immunosuppressive one to an immune permissive microenvironment, and thus could be an opportunity to overcome immunotherapy resistance (40). A large number of studies have demonstrated that the combination therapy of anti-angiogenic agents and immunotherapy has good clinical application prospects, providing a hopeful solution to improve outcomes of cancer patients (41). Our study implied the potential benefits of anti-angiogenic agents in second-line setting. Compared with chemotherapy and immunochemotherapy, anti-angiogenic combinations showed no statistically significant difference in survival benefits, but a trend of second-line PFS and OS benefits. Certainly, the sample sizes in the I+A and I+C+A subgroups were limited, and additional studies with larger cohorts are warranted to confirm these findings.
Although immunotherapy and anti-angiogenic therapy can improve efficacy, chemotherapy still plays a cornerstone role. The second-line mPFS of I+A group is 2.83 months, while C ± A group is 3.03 months, and I+C ± A group is 3.53 months, indicating the important role of chemotherapy in second-line treatment. The role of later line chemotherapy in SCLC has been widely verified and is tolerable as monotherapy or combined therapy (4). Our findings suggest that chemotherapy represents the backbone of therapeutic management of SCLC, and the addition of immunotherapy or immunotherapy + anti-angiogenesis to chemotherapy during second-line therapy may contribute to PFS and OS prolongation.
The status of liver metastasis (LM) has been evaluated as a predictive biomarker in patients receiving ICIs, suggesting patients with LM derived limited benefit from immunotherapy independent of other established biomarkers of response (42). Mechanisms underlying hepatic immune tolerance included ineffective immune synapses resulting in T cell anergy, regulatory T cell induction or effector T cell elimination (42). Hepatocellular carcinoma is associated with hypoxic tumor conditions, high VEGF expression, and increased angiogenesis, which can contribute to the induction of immunosuppressive immune-cell types (e.g., myeloid-derived suppressor cells and regulatory T cells) and the promotion of immune tolerance in the tumor microenvironment (43). It has been reported that liver metastases diminish immunotherapy efficacy systemically in both preclinical models and cancer patients (42). In the present study, patients with LM showed worse first-line PFS from immunochemotherapy. Moreover, the univariate and multivariate analysis also showed that liver metastases was independent prognostic factors for poorer second-line PFS and OS. The explanation for these findings may lie in the immunosuppressive microenvironment within LM, which undermined the efficacy of immunotherapy (44).
It has been known that the presence of bone metastasis (BoM) was a negative prognostic factor in lung cancer (45). Bone metastasis, especially the occurrence of skeletal-related events (SREs), significantly reduces OS and quality of life (QoL) in patients. The lower efficacy of immunotherapy treatments in BoM patients could be induced by the presence of a particular immunosuppressive bone metastasis microenvironment (46, 47). Several studies suggested that bone involvement might be a negative prognostic factor and the presence of BoM could be predictive of poor response to ICIs (47–50). The present study also found poorer first-line PFS in patients with bone metastases. During second-line therapy, bone metastases were also significantly associated with worse second-line PFS and OS.
In terms of safety and toxicity, continuous immunotherapy beyond progression was not associated with unexpected safety events and all adverse events were generally manageable as previously reported. The combination of ICI and chemotherapy caused more ≥grade 3 adverse effects as fatigue, nausea, vomiting and diarrhea.
The present study showed that continuous immunochemotherapy beyond progression in patients with ES-SCLC does not enhance overall survival, which could be influenced by subsequent lines of therapy that patients may have received. It is important to acknowledge that the current study has innate limitations. First, this was a retrospective study with a comparatively small sample size. Thus, the results should be interpreted cautiously and should be further verified in future prospective randomized and controlled study with large sample size. Second, treatment heterogeneity could not be avoided in retrospective analysis, including the local treatments such as radiotherapy, and later-line medical treatments. Patient outcomes, especially the OS, might be partly impacted by these factors. Third, limited post-therapy scanning was unavoidable in a retrospective study analyzing data from real-world oncology clinical practice. The timing of the patient’s follow-up imaging examination following treatment or insufficient scans performed could have an influence on the results, especially PFS. Fourth, adverse events were retrospectively assessed based on medical records and reported for the entire treatment duration, with no stratification according to distinct treatment phases. Finally, patient selection bias was also one of the important limitations in this study. To exclude various biases, further large prospective randomized studies are warranted to confirm the effectiveness of continuous ICIs beyond progression in ES-SCLC.

Conclusions
Continuous immunotherapy beyond progression in extensive-stage small cell lung cancer shows the trend of prolonging second-line progression free survival, but does not improve the overall survival. Additionally, in the second-line treatment, chemotherapy remains an important cornerstone therapy and anti-angiogenic agent containing strategy may potentially improve survival.