Neoadjuvant or conversion anti-PD-1/PD-L1 immunotherapy combined with chemotherapy improves 2-year survival and achieves high pathological complete response rate in patients with stage IIB-IIIB small-cell lung cancer.

Introduction
Lung cancer is the most frequently diagnosed malignancy and the primary cause of cancer-related mortality (1). Small-cell lung cancer (SCLC)—a subtype of lung cancer characterized by its aggressive, poorly differentiated, high-grade neuroendocrine features (2)—accounts for approximately 13–15% of all lung cancer cases (3,4). Among these cases, approximately 30% include a diagnosis of limited-stage SCLC (LS-SCLC) (5). For decades, the standard treatment paradigm for inoperable LS-SCLC has been concurrent chemoradiotherapy (cCRT)—typically comprising 4–6 cycles of platinum-etoposide chemotherapy with synchronous thoracic radiotherapy—followed by prophylactic cranial irradiation (PCI) in patients demonstrating treatment response (6). However, the majority of patients receiving this treatment regimen experience disease recurrence within 2 years of therapy initiation, with a median overall survival (OS) of 25–30 months and a 5-year survival rate of merely 29–34% (7-9). Therefore, developing more effective and higher-quality treatment modalities is of paramount importance.
The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape for extensive-stage SCLC (ES-SCLC), as demonstrated by the CASPIAN and IMpower133 trials (10,11). Recently, the ADRIATIC study—the first phase III trial to evaluate immune consolidation therapy following cCRT in patients with LS-SCLC—established a new standard of care. It demonstrated that following cCRT, consolidation therapy with the PD-L1 inhibitor durvalumab significantly prolonged median OS (55.9 vs. 33.4 months with placebo) and progression-free survival (16.6 vs. 9.2 months with placebo) (12). This landmark clinical study demonstrated significant improvements in both OS and PFS among patients with LS-SCLC. Based on these results, durvalumab has been incorporated as a consolidation therapy into the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Small-Cell Lung Cancer (2025 version), establishing it as part of the standard of care for this patient population.
Since the 1960s, it has been widely accepted that surgical treatment does not provide additional benefits for patients with SCLC, which has resulted in a prolonged stagnation in the development of surgical therapies for SCLC (13). However, this perception has been challenged in recent years by large-scale retrospective analyses focusing on LS-SCLC (14). For instance, multiple studies of the Surveillance, Epidemiology, and End Results (SEER) database have demonstrated that surgical intervention, particularly lobectomy, is associated with significantly prolonged survival in selected patients with LS-SCLC as compared to nonsurgical treatment approaches (15-18). This challenges the traditional view and opens new avenues for a multimodal approach that integrates surgery.
Neoadjuvant therapy represents a promising additional strategy. In patients with resectable non-SCLC (NSCLC), the efficacy and safety of neoadjuvant chemoimmunotherapy have been well-established (19-25). Translating this success to SCLC, a pioneering, multicenter, single-arm study (NEO-SCI) investigated neoadjuvant or conversion atezolizumab combined with chemotherapy in patients with resectable LS-SCLC. The efficacy outcomes are encouraging. In the intention-to-treat (ITT) population, the pathological complete response (pCR) and major pathological response (MPR) rates were 47.1% and 70.6%, respectively; these rates were further improved in the per-protocol (PP) population, reaching 61.5% and 92.3%, respectively. These data provide preliminary confirmation of the favorable efficacy and safety profile of this treatment regimen (26).
However, while the short-term outcomes provide a cause for optimism, the ultimate value of any oncologic intervention hinges on its ability to translate into long-term survival benefits. The long-term clinical significance of this novel approach in LS-SCLC remains inadequately characterized. Notably, the 2025 NCCN guidelines already recommend surgical resection as the preferred option for patients with stage IA–IIA SCLC, while cCRT remains the standard for other LS-SCLC cases. To address this dearth in data, we conducted a real-world retrospective study enrolling patients with stage IIB–IIIB SCLC who received neoadjuvant or conversion anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) chemoimmunotherapy, focusing primarily on long-term outcomes including event-free survival (EFS) and OS. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1496/rc).

Methods

Patients and study design
Patients with SCLC who were admitted to the Department of Thoracic Surgery at Tangdu Hospital, The Fourth Military Medical University, between May 2020 and January 2024, were screened for study eligibility.
The inclusion criteria for patients were as follows: age ≥18 years with histopathologically confirmed clinical stage IIB–IIIB LS-SCLC (according to the American Joint Committee on Cancer 8th edition staging system), imaging evaluation [all patients underwent positron emission tomography (PET)/computed tomography (CT) and some patients additionally received contrast-enhanced CT, brain magnetic resonance imaging (MRI), and/or bone scan to complete the staging evaluation] confirming no distant metastasis, and completion of neoadjuvant or conversion anti-PD-1/PD-L1 immunotherapy combined with chemotherapy, followed by surgery. Patients with incomplete clinical or pathological data were excluded.
The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Tangdu Hospital (No. K202511-10) and informed consent was taken from all the patients.

Efficacy
The standard hematoxylin and eosin staining was used to assess the percentage of residual viable tumor cells in primary tumors for pathological evaluation. MPR was defined as ≤10% viable tumor cells, while pCR was confirmed when no viable tumor cells were detected. In accordance with the NCCN guidelines recommendations, we conducted follow-up visits every 3–4 months during the first 1–2 years after treatment completion, every 6 months from year 3 to 5, and annually thereafter. Each follow-up included comprehensive medical history review, physical examination, and either chest CT or MRI. The primary end point was OS, and the secondary end points were EFS, pCR, and MPR. OS was defined as the time from the initiation of neoadjuvant/conversion therapy to death from any cause. EFS was defined as the interval from the initiation of neoadjuvant/conversion therapy to the earliest occurrence of disease progression, either local or distant recurrence.

Statistical analysis
The Kaplan-Meier method was used to calculate OS and EFS and to estimate the survival curve. The log-rank test was used to compare the OS and EFS rates between the subgroups. The P values were two-sided, and 0.05 was considered as the significance level. All statistical analyses were performed with SPSS software version 27.0 (IBM Corp., Armonk, NY, USA).

Results

Patients
According to the inclusion and exclusion criteria, a total of 34 patients with stage IIB–IIIB SCLC who received neoadjuvant or conversion anti-PD-1/PD-L1 immunochemotherapy were enrolled and followed up. Of the 34 patients, 8 received 2 cycles, 15 received 3 cycles, and 11 received 4 cycles of neoadjuvant or conversion therapy. During the neoadjuvant or conversion treatment phase, patients received ICIs, including PD-1 inhibitors (pembrolizumab, tislelizumab, and serplulimab) and a PD-L1 inhibitor (atezolizumab), in combination with chemotherapy consisting of etoposide and platinum-based agents (nedaplatin, carboplatin, cisplatin, or lobaplatin). Detailed information on the specific medication regimens is provided in Table S1. The demographics and baseline characteristics of these 34 patients are shown in Table 1. Among the 34 patients, 15 (44.1%) were over 60 years old; 24 (70.6%) were male, 19 (55.8%) were overweight or obese, 12 (35.3%) had stage IIB disease, and 22 (64.7%) had stages IIIA and IIIB disease. Furthermore, the ICIs administered varied: 23 (67.6%) patients received the PD-L1 inhibitor atezolizumab, while the other 11 (32.4%) patients were treated with PD-1 inhibitors, including pembrolizumab (n=1), camrelizumab (n=1), tislelizumab (n=1), and serplulimab (n=8).

Efficacy
All 34 patients were followed up until May 30, 2025, and the median follow-up duration was 34.2 months. Among these patients, 7 (20.6%) died, including 5 (14.7%) who succumbed to cancer metastasis or recurrence, while 9 patients 26.5%) developed progressive disease. Moreover, 23 (67.6%) patients were in stable condition with no disease progression (Figure 1). The 2-year EFS rate of the patients was 72.1% [95% confidence interval (CI): 53.1–84.5%] (Figure 2A), and the 2-year OS rate was 82.4% (95% CI: 64.9–91.7%) (Figure 2B). Neither the median EFS nor OS was reached.

Subgroup analysis
The pathological response may serve as a predictive biomarker. Of the 34 patients, 16 (47.1%) and 24 (70.6%) achieved pCR and MPR, respectively. We categorized the patients into pCR and non-pCR groups, as well as MPR and non-MPR groups, based on their postoperative pathological results. In the MPR group, one death and four disease progression events were observed. These patients were identical to those who died or experienced progressive disease in the pCR group. The 2-year EFS rates were 75.0% (95% CI: 46.3–89.8%) in the pCR group and 83.3% (95% CI: 61.5–93.4%) in the MPR group. Two-year OS rates were both 100% for the pCR and MPR groups. Meanwhile, the non-PCR group had a 2-year EFS rate of 68.2% (95% CI: 38.6–85.7%) and a 2-year OS rate of 66.7% (95% CI: 40.4–83.4%) (Figure 3A,3B). For the non-MPR group, the 2-year EFS rate was 28.1% (95% CI: 1.6–67.8%), and the 2-year OS rate was 40.0% (95% CI: 12.3–67.0%) (Figure 3C,3D). The pCR group and non-pCR group both failed to reach the median EFS and OS end points. In the non-MPR group, the median EFS was 22.5 months (95% CI: 7.044–37.956), and the median OS was 16.8 months (95% CI: 15.715–17.885), whereas neither the median EFS nor OS was reached in the MPR group. Patients with pCR exhibited a significantly higher OS rate than did those without pCR (log-rank P=0.04). Patients with MPR exhibited significantly higher EFS and OS rates than did those without MPR (EFS: log-rank P=0.008; OS: log-rank P<0.001).
We additionally conducted subgroup analyses based on patients’ age, gender, body mass index (BMI), ICI categories, and tumor-node-metastasis (TNM) staging (Figures 4,5). However, no statistically significant differences were observed in the estimated 2-year EFS and OS rates between these stratification factors. Interestingly, in the BMI-stratified analysis (cutoff: 25.0 kg/m2), a consistent survival advantage was observed for normal-weight patients (BMI <25.0 kg/m2) as opposed to overweight/obese patients (BMI ≥25.0 kg/m2), with hazard ratios (HRs) of 0.538 (95% CI: 0.146–1.988; P=0.37) for EFS and 0.181 (95% CI: 0.041–0.795; P=0.07) for OS (Figure 4E,4F). This may suggest that overweight/obese status may adversely impact survival outcomes. Similarly, patients with stage II disease demonstrated improved survival outcomes compared to patients with stage III (EFS: HR =0.188, 95% CI: 0.050–0.714, P=0.08; OS: HR =0.267, 95% CI: 0.058–1.223, P=0.19) (Figure 5A,5B). Collectively, these data indicate that elevated BMI (≥25.0 kg/m2) and stage III disease may be associated with inferior survival, whereas patients with a BMI <25.0 kg/m2 and stage II disease may experience prolonged survival.

Discussion
In this follow-up study, we evaluated the efficacy of neoadjuvant or conversion anti-PD-1/PD-L1 immunotherapy combined with chemotherapy in 34 patients with stage IIB–IIIB SCLC over a mean follow-up period of 34.2 months. Among these 34 patients, 7 died, 9 developed progressive disease, and 23 were in stable condition with no disease progression. The 2-year EFS rate was 72.1%, and the 2-year OS rate was 82.4%. Pathological assessment revealed treatment responses with pCR and MPR rates of 47.1% and 70.6%, respectively. These pathological response outcomes are significantly higher than the less than 10% pCR and MPR rates observed with neoadjuvant chemotherapy alone (27,28).
SCLC is a highly aggressive malignancy with inherent resistance to conventional therapies, including chemotherapy and radiotherapy (29). Current NCCN guidelines recommend surgical resection only for patients with stage IA–IIA SCLC, yet fewer than 5% of newly diagnosed patients meet these criteria (30). For the majority of patients with LS-SCLC, concurrent chemoradiation remains the standard of care. However, despite an 80% initial response rate, over 50% experience disease recurrence within 6 months posttreatment (31), highlighting the urgent need for more effective therapeutic strategies. Multiple studies have conclusively demonstrated that combining ICIs with chemotherapy significantly improves OS in patients with ES-SCLC (32,33). The phase III CASPIAN trial reported that adding durvalumab to platinum-etoposide chemotherapy significantly improved OS in untreated patients with ES-SCLC (11). Consequently, combination regimens comprising ICIs and chemotherapy have now become the standard first-line treatment for those with ES-SCLC (34,35). The ADRIATIC trial evaluated the efficacy and safety of durvalumab as consolidation therapy following cCRT in patients with LS-SCLC. The durvalumab group demonstrated superior clinical outcomes, with a 2-year OS rate of 68% and a 2-year PFS rate of 46.2% (12,36). The findings from the ADRIATIC trial led to an immediate revision of the NCCN guidelines, with ICIs being established as part of the standard-of-care therapy for LS-SCLC.
The role of surgery in the management of LS-SCLC is undergoing a transition. Although it was historically considered to have limited efficacy, large-scale retrospective studies have validated its survival benefit for certain patient subgroups (15-18). Furthermore, the significant advantage in pathological response achieved with neoadjuvant or conversion chemoimmunotherapy in clinical exploration is paving a new direction for this comprehensive treatment strategy. The long-term survival outcomes of patients in our study provide stronger support for this evolving paradigm shift. The strategy of neoadjuvant or conversion therapy followed by radical resection may possess multiple advantages over nonsurgical consolidation approaches. First, in terms of long-term survival, the neoadjuvant or conversion chemoimmunotherapy achieved a 2-year EFS rate of 72.1% and a 2-year OS rate of 82.4%, representing a significant improvement compared to the 46.2% 2-year PFS rate and 68% 2-year OS rate reported in the ADRIATIC trial. Moreover, this survival outcome was significantly better than the approximately 37.5% 2-year OS rate observed in a SEER database study involving patients with stage IIB–IIIB SCLC treated with surgery alone (15). Notably, the ADRIATIC trial excluded patients with disease progression after cCRT, whereas our study included those with IIB–IIIB SCLC who underwent neoadjuvant or conversion chemoimmunotherapy followed by surgery, providing a basis for comparing the outcomes. Second, regarding surgical opportunity and pathological response, radical resection can completely eliminate primary lesions and resistant clones, significantly reducing the risk of local recurrence (37)—an advantage not observed in the ADRIATIC study, which relied solely on radiotherapy. Pathologically, pCR and MPR serve as real-time biomarkers for guiding subsequent treatment decisions. In our study, patients achieving pCR exhibited a remarkable 2-year OS rate of 100%, substantially superior to the 66.7% observed in non-pCR patients. The ability to achieve a high pCR rate followed by surgical removal of the primary tumor site represents a unique advantage of the multimodal approach incorporating surgery. Third, in terms of treatment timing, the neoadjuvant or conversion approach allows for the immediate initiation of immunotherapy combined with chemotherapy upon diagnosis, enabling earlier clearance of circulating tumor cells as compared to the consolidation therapy used in the ADRIATIC trial (38,39). Moreover, the intact tumor antigens preserved preoperatively help maintain immunogenicity, preventing the compromised immune response caused by microenvironmental fibrosis following chemoradiation (40-42). These collective advantages highlight the unique value of the neoadjuvant or conversion strategy in treating patients with LS-SCLC.
Based upon the successful experience of neoadjuvant or conversion immunotherapy in NSCLC, the therapeutic strategy for SCLC demonstrates potential for optimization while addressing several unique challenges. However, the immunologically “cold” tumor characteristic of SCLC (featured by low PD-L1 expression and an immunosuppressive microenvironment) (43,44) may constrain the efficacy of monotherapy, necessitating the development of innovative combination strategies that can overcome these limitations. Although the NSCLC experience provides valuable reference points for SCLC management, the distinct biological differences between these two malignancies necessitate the design of SCLC-specific clinical trials to validate optimal treatment paradigms. These investigative efforts may generate novel approaches for overcoming current therapeutic impasses in SCLC management.
Beyond tumor-intrinsic factors, patient-specific characteristics may also critically influence treatment outcomes. Notably, our subgroup analysis demonstrated an association between an elevated body mass index (BMI >25.0 kg/m2) and inferior clinical outcomes. This observation is consistent with findings from a retrospective cohort study by Ihara et al., which demonstrated that nonobese patients with advanced NSCLC receiving ICI therapy had a significantly reduced risk of mortality (45). Furthermore, accumulating evidence suggests that obesity may exacerbate the immunosuppressive tumor microenvironment and impair CD8+ T cell–mediated tumor killing (46). Taken together, these findings provide a strong rationale for optimizing patient selection and suggest that BMI-based individualized treatment strategies may warrant further investigation in future clinical practice.
This study involved several limitations which should be acknowledged. Primarily, our findings represent only preliminary real-world evidence. The limited sample size (n=34) and the enrollment of only patients who received neoadjuvant therapy plus surgery—though this design allows for a direct efficacy comparison with the ADRIATIC trial—have introduced a degree of selection bias, making it impossible to fully and truly reflect the regimen’s clinical effectiveness in real-world settings. Additionally, the single-arm design reduces the statistical power of subgroup analyses, and the absence of a chemotherapy-only control group precludes rigorous assessment of the incremental benefit of immunotherapy. Furthermore, the median follow-up duration of 34.2 months remains inadequate for assessing long-term survival outcomes or for fully characterizing the potential delayed treatment effects associated with immunotherapy. The study also lacked a systematic investigation of predictive biomarkers, including PD-L1 expression levels and tumor mutational burden, and their correlation with therapeutic response. Given these methodological limitations, we emphasize the necessity of conducting larger-scale, rigorously designed phase III randomized controlled trials in the future to validate the preliminary findings of this study. Such trials should adopt a prospective, multicenter design and include randomized control groups with sufficient statistical power to objectively evaluate the efficacy and safety of neoadjuvant or conversion chemoimmunotherapy in patients with LS-SCLC. Furthermore, future research should incorporate comprehensive biomarker analyses and standardized patient-reported outcome measures to provide more robust evidence.

Conclusions
In conclusion, this follow-up study demonstrates that neoadjuvant or conversion anti-PD-1/PD-L1 immunotherapy combined with chemotherapy is a promising therapeutic strategy for resectable LS-SCLC. The regimen achieved notable survival outcomes, with a 3-year OS rate of 82.4% and an EFS rate of 72.1%, surpassing historical benchmarks for conventional treatments. Moreover, pCR and MPR emerged as strong predictors of long-term survival, underscoring the potential of early immune activation and surgical resection in improving outcomes. These results contribute to the growing evidence supporting the integration of immunotherapy into LS-SCLC treatment paradigms and pave the way for further investigations aimed at transforming the prognosis for this aggressive malignancy.

Supplementary
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