Etoposide–Platinum Rechallenge in Small Cell Lung Cancer Worth More Application: A Multicenter Study and Web-Based Predictive Model

Etoposide–Platinum Rechallenge in Small Cell Lung Cancer Worth More Application: A Multicenter Study and Web-Based Predictive Model | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Etoposide–Platinum Rechallenge in Small Cell Lung Cancer Worth More Application: A Multicenter Study and Web-Based Predictive Model Zhonghui Wei, Yang Liu, Zhaoqin Huang, Xiaoyu Luo, Guoyu Li, Xiaoli Liu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9293073/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Objective Guidelines generally recommend platinum rechallenge for patients with small cell lung cancer (SCLC) who progress more than 6 months after first-line platinum-based chemotherapy. However, clinical practice indicates therapeutic benefit in patients with a 3-6-month chemotherapy-free interval (CTFI), warranting re-evaluation particularly in the immunotherapy era. This study aimed to investigate the efficacy and safety of etoposide plus platinum rechallenge ± immunotherapy in this controversial population to provide evidence to fill this clinical gap, and a user-friendly online tool was constructed to facilitate personalized prognostic management. Methods This real-world study enrolled SCLC patients from three hospitals (August 2018–May 2025) who progressed 3–6 months after first-line etoposide-platinum (± immunotherapy) treatment. Patients were stratified based on whether they received etoposide-platinum rechallenge after relapse. We systematically evaluated the efficacy and safety. Based on 44 clinical features, this study assessed three machine learning models to generate survival prediction curves. An interactive online platform was established to facilitate convenient prognostic evaluation. Results Between 2018 and 2025, we enrolled 313 limited- or extensive-stage SCLC patients who experienced disease progression with a CTFI of 3–6 months; the median follow-up was 26.3 months. Etoposide plus platinum rechallenge (± immunotherapy) improved mOS (15.0 vs 12.1 months; HR = 0.57; P< 0.001) and mPFS (5.1 vs 3.6 months; HR = 0.68; P = 0.004). The rechallenge significantly improved ORR compared to other regimens (46.3% vs. 35.6%), especially in patients who achieved a complete or partial response (CR/PR) during first-line (54.2% vs. 34.0%). Notably, survival benefits from the rechallenge regimen were consistently observed across different recurrence patterns (local or distant progression) and disease stages. Regardless of first-line immunotherapy exposure, rechallenge with combination immunotherapy (concurrent/consolidation) conferred significant benefits, with a median OS of 18.1 months. Grade ≥ 3 adverse events were comparable between cohorts. Finally, a multi-time-point survival prediction model (3 months to 3 years) was developed for the rechallenge cohort (mean AUC = 0.858) to facilitate prognostic assessment and enhanced monitoring, with a web-based visualization tool: http://43.154.9.125:3838/ . Conclusions As an inexpensive and widely accessible regimen with controllable adverse events, the etoposide-platinum rechallenge (± immunotherapy) in relapsed SCLC with a CTFI of 3–6 months after first-line therapy offers significant clinical benefits and a manageable safety profile. Small Cell Lung Cancer Relapse Rechallenge Platinum Immunotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Small cell lung cancer accounts for roughly 15% of newly diagnosed lung cancers( 1 – 3 ). This malignancy is defined by its high-grade aggressive biology and a profound tendency for early systemic dissemination, which leads to poor prognosis for patients( 1 – 5 ). While first-line treatment with platinum-based chemotherapy typically elicits a high initial response rate, this therapeutic benefit is often transient. Unfortunately, most patients relapse in 6 months or less( 6 , 7 ). Numerous clinical studies have shown that the CTFI after first-line therapy substantially influences both the selection and the efficacy of second-line treatments in SCLC( 8 , 9 ). Owing to the lower cost, high accessibility, and favorable tolerability upon re-administration, etoposide-platinum rechallenge regimens are widely utilized after first-line recurrence and have demonstrated favorable clinical efficacy( 10 , 11 ). Although current guidelines recommend etoposide-platinum rechallenge for SCLC patients with a CTFI of ≥ 6 months, a recent prospective Japanese study including patients with a CTFI > 3 months demonstrated that carboplatin plus etoposide was significantly superior in PFS and non-inferior to topotecan in OS ( 12 ). Another study based on data from 2007–2011 indicated that platinum rechallenge achieved a mOS of 7.9 months in platinum-sensitive relapsed SCLC, though lacking control-arm validation( 13 ). These findings indicate the potential of earlier rechallenge of etoposide–platinum therapy; however, conclusive evidence comparing different treatment regimens in relapsed or metastatic SCLC patients with a CTFI of 3–6 months after first-line therapy is currently lacking. Additionally, given the widespread use of immunotherapy in the first-line treatment of SCLC today, it is essential to re-evaluate the value of etoposide cisplatin/carboplatin (EP/EC) rechallenge regimens in the immunotherapy era, with particular attention to whether rechallenge with concurrent or consolidation immunotherapy can translate into significant survival benefits. Our study is the first real-world study focusing specifically on relapsed patients with a CTFI of 3–6 months following first-line platinum-based therapy, comparing outcomes based on the receipt of etoposide-platinum rechallenge (with or without immunotherapy). As the first study of its kind to include patients who received immunotherapy during the first-line or rechallenge phases, it closely reflects current clinical practice. We systematically evaluated differences in objective response rate (ORR), progression-free survival (PFS), overall survival (OS) among different post-relapse treatments, aiming to identify populations likely to benefit and predictive factors for EP/EC ± immunotherapy efficacy, thus providing evidence to guide subsequent management. In summary, we conducted the largest multi-center real-world study to date evaluating EP/EC rechallenge (± immune checkpoint inhibitors, ICIs) in the clinically contentious patients relapsing with a CTFI of 3–6 months. This study further addresses the evidence gap by comparing the efficacy of rechallenge combined with immunotherapy against other chemo-immunotherapy regimens. We also investigated pressing clinical questions in the management of relapsed SCLC, such as the influence of varying relapse/progression patterns on outcomes and treatment selection after first-line immunotherapy failure. To further refine the rechallenge strategy, we identified the optimal subgroup for rechallenge and developed a highly accurate prognostic model evaluating machine learning algorithms with over 40 variables. We aim to provide evidence-based support to guide the clinical application of EP/EC rechallenge, both as a standalone therapy or in combination with immunotherapy. Methods Patients This retrospective cohort study enrolled patients with limited- or extensive-stage SCLC who experienced disease progression with a CTFI of 3–6 months after first-line EP/EC ± immunotherapy at 3 medical centers between August 2018 and May 2025. Patients who received ≤ 2 cycles of chemotherapy or who were lost to follow-up immediately after first-line relapse were excluded. Collected variables included demographics, performance status, details of first-line therapy and response, subsequent treatments, and outcomes. Tumor response was evaluated per RECIST v1.1. Follow-up assessments were performed regularly to record recurrence and survival. The study was conducted in accordance with the Declaration of Helsinki and received approval from the institutional review boards/independent ethics committees of the participating centers. Outcomes The primary endpoints of this analysis were overall survival (OS) and progression-free survival (PFS). In this study, PFS was defined from the initiation of second-line therapy to disease progression, death or last follow-up, while OS was defined from the initiation of second-line therapy to death or last follow-up. One-, two-, and three-year survival rates were also estimated. Efficacy and safety served as important comparative endpoints in this study. Radiographic assessment of treatment response was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). To identify subpopulations potentially benefiting from rechallenge therapy, exploratory subgroup analyses were performed based on multiple covariates. Univariate and multivariate Cox proportional-hazards models were applied to assess prognostic factors in relapsed SCLC patients after first-line therapy and to further identify determinants associated with benefit from rechallenge regimens. To predict the prognosis of the rechallenge cohort and facilitate personalized management, a multivariate prognostic prediction model was constructed. By evaluating Random Survival Forest (RSF)( 14 ), XGBoost-Cox( 15 ), and the Cox Proportional Hazards (COXPH) model, key prognostic variables were identified, leading to the development of an interactive prediction tool. The performance of each model was robustly evaluated on the training dataset using a repeated 5-fold cross-validation scheme (10 repetitions). The models' predictive accuracy was assessed based on their discrimination and calibration. Discrimination was quantified using metrics such as the Area Under the Receiver Operating Characteristic (ROC) curve (AUC)( 16 ) and the Concordance Index (C-index)( 17 ). Developed using the Shiny R platform and deployed on a public web server, this tool is conveniently accessible to both clinicians and patients. Statistical analyses Categorical variables were compared using the χ² test or Fisher’s exact test, as appropriate. Continuous variables were compared using the Wilcoxon rank-sum test, and correlations between continuous variables were assessed with Pearson’s correlation coefficient. Overall OS and PFS were estimated by the Kaplan–Meier method and compared using the log-rank test. Exploratory subgroup analyses were performed with unstratified Cox proportional-hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs); results are presented as forest plots. Univariate and multivariate Cox proportional-hazards models were used to identify prognostic factors. Two-sided p values < 0.05 were considered statistically significant. All analyses were conducted using R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria) and SPSS version 23.0 (IBM Corp., Armonk, NY, USA). Results Patient characteristics Between August 2018 and May 2025, a total of 991 patients with limited-stage or extensive-stage SCLC experienced disease progression after first-line EP/EC and were subsequently followed up. This study focused on the 313 patients with CTFI of 3–6 months to evaluate the feasibility of EP/EC rechallenge (with or without immunotherapy). The study flowchart is shown in Fig. 1 . In the overall cohort, patients were predominantly male (74.4%), most had an ECOG performance status of 0–1 (92.7%), 55.6% were younger than 65 years, and 68.7% presented with extensive-stage disease. A best overall response of complete or partial response to first-line therapy was achieved in 213 patients (68.1%). Baseline clinical characteristics were balanced between the rechallenge and non-rechallenge groups (Table 1 ). Second-line treatments were further classified as EP/EC + IO, EP/EC, other chemo-IO combinations, and other chemotherapy; baseline remained well balanced across these cohorts (Supplementary Fig. 1). Treatment regimens In this cohort, 136 patients (43.5%) received EP/EC rechallenge with or without immunotherapy as second-line treatment. The non-rechallenge control group (n = 177, 56.5%) received more heterogeneous chemotherapy regimens, most commonly nab-paclitaxel plus platinum agent (n = 77, 43.5%), irinotecan monotherapy (n = 36, 20.3%), and temozolomide (n = 31, 17.5%). Temozolomide was predominantly used for patients who subsequently developed brain metastases, reflecting its role in CNS-directed therapy. A total of 127 patients (40.6%) received ICIs in the second-line setting; of these, 61 (48.0%) received ICIs combined with EP/EC rechallenge. Table 1 Baseline and therapeutic characteristics of patients. Characteristics EP/EC ± IO cohort Other cohort p-value n = 136 (%) n = 177 (%) Gender 0.645 Female 33(24.3%) 47(26.6%) Male 103(75.7%) 130(73.4%) Age, years 0.216 < 65 81(59.6%) 93(52.5%) ≥ 65 55(40.4%) 84(47.5%) ECOG PS 0–1 126(92.6%) 164(92.7%) 0.998 2 10(7.4%) 13(7.3%) Smoking 0.134 YES 53(39.0%) 84(47.5%) NO 83(61.0%) 93(52.5%) Progression patterns To limited-stage 47(34.6%) 51(28.8%) 0.277 To extensive-stage 89(65.4%) 126(71.2%) First-line chemotherapy EP 68(50.0%) 82(46.3%) 0.519 EC 68(50.0%) 95(53.7%) First-line radiotherapy NO 34(25.0%) 51(28.8%) 0.452 YES 102(75.0%) 126(71.2%) PCI NO 84(61.8%) 103(58.2%) 0.523 YES 52(38.2%) 74(41.8%) First-line immunotherapy NO 51(37.5%) 54(30.5%) 0.194 YES 85(62.5%) 123(69.5%) First-line efficacy 0.352 SD 40(29.4%) 60(33.9%) PR 83(61.0%) 107(60.5%) CR 13(9.6%) 10(5.6%) Brain metastasis 53(39.0%) 70(39.5%) 0.917 Liver metastasis 29(21.3%) 37(20.9%) 0.928 Bone metastasis 20(14.7%) 32(18.1%) 0.427 ECOG PS Eastern Cooperative Oncology Group performance status, CR complete response, PR partial response, CTFI chemotherapy-free interval, PCI prophylactic cranial irradiation Clinical efficacy: tumor response We collected the best tumor responses to first- and post-relapse therapy between the two cohorts. Figure 2 A shows best responses during initial EP/EC ± immunotherapy and following relapse with various salvage regimens. No significant difference in ORR was observed between groups during first-line treatment (P = 0.35). In the second-line setting, patients who received rechallenge had a higher ORR than the non-rechallenge cohort (46.3% vs. 35.6%) and a higher disease control rate (DCR: 81.6% vs. 74.0%; Fig. 2 A). Figure 2 B presents a Sankey diagram illustrating the relationship between first- and second-line responses, enhancing visualization of these associations. Patients who achieved CR or PR to first-line therapy and subsequently received rechallenge therapy had a second-line ORR of 54.2%, which was significantly greater than the non-rechallenge group (34.0%). Based on these findings, EP/EC ± immunotherapy rechallenge may be considered in the second-line setting, particularly for patients who attained CR or PR after first-line treatment. Survival analyses The median follow-up was 26.3 months (95% CI, 22.5–33.7). The median PFS was 5.1 months (95% CI, 4.4–6.7) in the rechallenge cohort versus 3.6 months (95% CI, 2.9–4.8) in the cohort receiving other therapies (HR = 0.68; 95% CI, 0.52–0.89; P = 0.004; Fig. 3A). To account for treatment and biological heterogeneity, we calculated the PFS2/PFS1 ratio using each patient as their own control. PFS1 and PFS2 were defined as the PFS following the initiation of first-line and relapse therapies, respectively. In this study, the PFS2/PFS1 ratio was significantly correlated with survival outcomes (Pearson correlation coefficient = 0.4, P 1 was 55.6% in the rechallenge cohort and 45.3% in the other-treatment cohort, with median values of 1.36 and 1.10 respectively, suggesting a greater probability of prolonged disease control, with a potential impact on overall survival. The median OS was 15.0 months (95% CI, 13.2–20.3) in the rechallenge cohort versus 12.1 months (95% CI, 10.0–13.4) in the non-rechallenge cohort (HR = 0.57; 95% CI, 0.44–0.76; P < 0.001; Fig. 3B). One- and two-year OS rates were 64.8% (95% CI, 57.0–73.7%) and 36.4% (95% CI, 28.2–46.9%) in the rechallenge group versus 50.5% (95% CI, 43.3–58.9%) and 17.6% (95% CI, 12.0–25.8%) in the other group. In summary, rechallenge with EP/EC ± immunotherapy was associated with superior short- and long-term survival rate, demonstrating improvements in both OS and PFS. Subgroup analyses were conducted to investigate the impact of rechallenge versus other regimens on OS and PFS across patients with varying characteristics (Supplementary Fig. 3–4). Rechallenge therapy demonstrated a trend toward clinical benefit in the majority of subgroups, supporting its recommendation as a superior therapeutic strategy (Supplementary Fig. 3). When stratifying by disease progression patterns, rechallenge of EP/EC ± immunotherapy showed significant survival benefits across all patients, including those progressing from initial limited-stage disease (to either limited-stage, HR = 0.57, 95% CI 0.33–0.97, P = 0.040; or to extensive-stage disease, HR = 0.64, 95% CI 0.42–0.97, P = 0.034) as well as those progressing from initial extensive-stage disease (HR = 0.52, 95% CI 0.31–0.87, P = 0.013). It is noteworthy that the benefit from rechallenge was particularly significant for patients who had achieved CR (HR = 0.28, 95% CI 0.09–0.84, P = 0.024) or PR (HR = 0.64, 95% CI 0.45–0.90, P = 0.011) to first-line therapy, while the benefit remained uncertain for those with SD. Additionally, patients with brain metastases at entry experienced a more pronounced benefit from rechallenge after first-line relapse (HR = 0.47, 95% CI 0.30–0.72, P< 0.001), a significant difference not observed in patients with other sites of metastasis. For relapsed SCLC, EP/EC + IO rechallenge provided greater survival benefit than other chemo-IO regimens (Supplementary Fig. 3). Given the increasing interest in immunotherapy for SCLC, we conducted a survival analysis comparing EP/EC + IO rechallenge, other chemo-IO, and EP/EC monotherapy in relapsed patients (Fig. 3C-D). The EP/EC + IO rechallenge group demonstrated a significantly longer median OS of 18.1 months (95% CI: 14.4–50.5, P = 0.033), compared to 14.6 months for other chemo-IO (95% CI: 13.2–20.7) and 13.0 months for EP/EC rechallenge monotherapy (95% CI: 11.2–17.3). A trend towards improved PFS was observed in the EP/EC + IO rechallenge group versus the other chemo-IO group (median PFS: 5.5 months [95% CI: 4.6–8.2] vs. 4.2 months [95% CI: 3.2–7.0]; P = 0.14). These results indicate that re-challenging with EP/EC plus immunotherapy provides a more substantial survival advantage for SCLC patients after first-line treatment relapse. Figure 3 Kaplan–Meier analysis of OS and PFS. (A, B) Post-relapse outcomes by treatment: EP/EC ± IO rechallenge versus alternative salvage regimens. (C, D) Post-relapse outcomes according to rechallenge therapy with or without immunotherapy.(E, F) Post-relapse outcomes by treatment in patients treated with first-line chemo-immunotherapy. To facilitate individualized application of rechallenge therapy, we conducted subgroup analysis to explore OS benefits from EP/EC rechallenge vs. EP/EC plus immunotherapy rechallenge across different patient characteristics (Supplementary Fig. 5–6). In addition to patients with extensive-stage disease at relapse, those who remained classified as limited-stage after progression also appeared to derive an overall survival benefit from EP/EC plus immunotherapy rechallenge (HR = 0.44, 95% CI 0.19–1.01, P = 0.050). In terms of progression-free survival, the analysis also indicated a supportive trend (HR = 0.57, 95% CI 0.29–1.12, P = 0.102). This finding is particularly relevant to the hot topics about immunotherapy strategies in LS-SCLC, suggesting that timely IO combination is advantageous. Critically, we also found that patients exposed to first-line immunotherapy still derived a significant survival advantage from a second-line EP/EC + IO rechallenge. The median OS was longer in the EP/EC + IO rechallenge group than in the EP/EC rechallenge group (14.6 months, 95% CI, 13.03–NR vs. 11.3 months, 95% CI, 8.5–NR; P = 0.024, Fig. 3E-F). These results demonstrate the feasibility of immunotherapy-based rechallenge in patients who have developed resistance to first-line immunotherapy, and continued exposure to immunotherapy can still provide additional clinical benefit. Prognostic analysis of OS and PFS Univariate and multivariate Cox regression analyses identified several significant prognostic factors for OS (Table 2 ). In the multivariable analysis, first-line radiotherapy (HR = 0.7, 95% CI 0.49–0.98, P = 0.047) and achieving a CR to first-line treatment (HR 0.45, 95% CI 0.24–0.84, P = 0.013) were significantly associated with improved OS. Regarding post-relapse treatment, second-line rechallenge therapy (HR 0.57, 95% CI 0.42–0.75, P< 0.001) and immunotherapy consolidation (HR 0.56, 95% CI 0.35–0.90, P = 0.017) were also identified as significant prognostic factors. The presence of extrapulmonary metastases was significantly associated with a poorer OS prognosis, including liver metastases (HR = 2.38, 95% CI 1.66–3.42, P< 0.001) and bone metastases (HR = 1.75, 95% CI 1.15–2.59, P = 0.005). Additionally, those who were initially diagnosed with limited-stage disease exhibited longer PFS, regardless of whether they progressed to limited-stage disease (HR = 0.69, 95% CI 0.49–0.98, P = 0.037) or extensive-stage disease (HR = 0.72, 95% CI 0.52–1.01, P = 0.057; Table 2 ). Table 2 Univariable and multivariable analyses of OS and PFS. Characteristics Univariable (OS) Multivariable (OS) Univariable (PFS) Multivariable (PFS) p value HR (95% CI) p value p value HR (95% CI) p value Gender Female - - Male 0.001 1.46 (1-2.15) 0.053 0.095 1.17 (0.86–1.6) 0.312 Age, years < 65 - - ≥ 65 0.808 - - 0.708 - - ECOG PS 0–1 - - 2 0.037 1.71 (0.99–2.95) 0.056 0.223 - - Smoking NO - - YES 0.083 1.19 (0.86–1.65) 0.299 0.519 - - Progression patterns ES to ES - - LS to ES 0.014 1.03 (0.69–1.53) 0.893 0.014 0.72 (0.52–1.01) 0.057 LS to LS <0.001 0.86 (0.52–1.44) 0.578 0.009 0.69 (0.49–0.98) 0.037 First-line chemotherapy EC - - EP 0.605 - - 0.693 - - First-line radiotherapy NO - - YES 0.001 0.7 (0.49–0.98) 0.047 0.347 - - PCI NO - - YES 0.211 - - 0.958 - - First-line immunotherapy NO - - YES 0.991 - - 0.958 - - First-line efficacy SD - - PR 0.442 1.13 (0.84–1.53) 0.419 0.902 1.08 (0.81–1.45) 0.591 CR <0.001 0.45 (0.24–0.84) 0.013 0.078 0.75 (0.44–1.28) 0.292 Brain metastasis NO - - YES 0.006 1.15 (0.83–1.6) 0.392 0.820 - - Liver metastasis NO - - YES <0.001 2.38 (1.66–3.42) <0.001 0.011 1.53 (1.07–2.19) 0.021 Bone metastasis NO - - YES 0.001 1.75 (1.19–2.59) 0.005 0.164 - - Second-line rechallenge NO - - YES <0.001 0.57 (0.42–0.75) <0.001 0.004 0.68 (0.52–0.89) 0.005 Concurrent immunotherapy NO - - YES 0.001 0.85 (0.58–1.25) 0.408 0.004 1 (0.72–1.41) 0.978 Immunotherapy consolidation NO - - YES 0.002 0.56 (0.35–0.9) 0.017 < 0.001 0.48 (0.31–0.73) 0.001 ECOG PS Eastern Cooperative Oncology Group performance status, CR complete response, PR partial response, CTFI chemotherapy-free interval, PCI prophylactic cranial irradiation Safety A total of 284 patients (90.7%) experienced at least one treatment-related adverse event during post-relapse therapy. In the rechallenge cohort, 125 patients (92.0%) developed adverse events, compared with 89.8% in the other treatment group. The most common events were hematologic toxicities, with neutropenia being the most frequent treatment-related serious adverse event. Specifically, neutropenia occurred in 78 patients (57.4%) in the rechallenge cohort and in 96 patients (54.2%) in the other treatment group, with grade 3–4 events reported in 32 cases (23.5%) versus 38 cases (21.5%), respectively. We also evaluated treatment-related pneumonitis, which was observed in 25 patients (18.4%) in the rechallenge group and in 28 patients (15.8%) in the other treatment group, with grade 3–4 pneumonitis occurring in 9 patients (6.6%) versus 11 patients (6.2%), respectively. All in-hospital adverse events were actively managed, and no treatment-related deaths were reported. Detailed information on other adverse events in both groups is provided in Table 3 . Table 3 Treatment-related adverse events of rechallenge cohort and other-treatment cohort. EP/EC ± IO Other Any grade (%) ≥Grade 3 (%) Any grade (%) ≥Grade 3(%) Neutropenia 78(57.4%) 32(23.5%) 96(54.2%) 38(21.5%) Thrombocytopenia 40(29.4%) 20(14.7%) 37(20.9%) 25(14.1%) Lymphopenia 28(20.6%) 10(7.4%) 35(19.8%) 6(3.4%) Anaemia 50(36.8%) 23(16.9%) 41(23.2%) 20(11.3%) Erythrocytopenia 15(11.0%) 8(5.9%) 16(9.0%) 9(5.1%) Pneumonia 25(18.4%) 9(6.6%) 28(15.8%) 11(6.2%) Asthenia 42(30.9%) 5(3.7%) 58(32.8%) 5(2.8%) Gastrointestinal reaction 56(41.2%) 4(2.9%) 49(27.7%) 5(2.8%) Fever 22(16.2%) 4(2.9%) 35(19.8%) 1(0.6%) Allergic reaction/Pruritus 7(5.1%) 0(0.0%) 11(6.2%) 0(0.0%) Hair loss 4(2.9%) 0(0.0%) 1(0.6%) 0(0.0%) Hypothyroidism 2(1.5%) 0(0.0%) 1(0.6%) 0(0.0%) Key Factors and Individualized Model for Rechallenge Therapy To explore the factors influencing the efficacy of rechallenge therapy and improve outcomes, we comprehensively collected and analyzed 44 clinical variables in the rechallenge cohort, including baseline characteristics, details of first-line treatment (e.g., radiotherapy dose), therapeutic efficacy, relapse patterns, metastatic sites, and immunotherapy modalities. The results of the multivariate analysis are presented in Fig. 4 . Among baseline characteristics, a Ki-67 index ≥ 90% (HR = 4.26; 95% CI, 2.08–8.74; P < 0.001), liver metastases (HR = 7.36; 95% CI, 3.55–15.27; P < 0.001), and bone metastases (HR = 3.56; 95% CI, 1.64–7.72; P = 0.001) demonstrated significant prognostic value (Fig. 4 A). Among first-line treatment–related factors, a thoracic radiotherapy dose of 45 Gy/bid (HR = 0.33; 95% CI, 0.13–0.86; P = 0.045), a carboplatin-based regimen (HR = 1.74; 95% CI, 1.01–3.06; P = 0.038), and achieving a first-line partial response (HR = 0.95; 95% CI, 0.5–1.18; P = 0.087) were associated with overall survival (Fig. 4 B). Analysis of relapse patterns and second-line treatment showed that, compared with relapse at original sites, the development of new extrapulmonary metastases (HR = 7.64; 95% CI, 3.07–54.52; P = 0.053), and the concomitant occurrence of both intrapulmonary and extrapulmonary metastases (HR = 7.91; 95% CI, 4.15–54.15; P = 0.042) was associated with a poorer prognosis (Fig. 4 C). In contrast, second-line concurrent immunotherapy (HR = 0.46; 95% CI, 0.24–0.89; P = 0.022) and immunotherapy consolidation (HR = 0.34; 95% CI, 0.14–0.82; P = 0.032) were associated with significant survival benefits. To further identify key prognostic factors, we utilized a Random Forest algorithm to rank variables by importance. We shortlisted variables based on a dual criterion: a minimal depth below the average and a Variable Importance (VIMP) score in the top quartile (≥ 75th percentile, Fig. 4 D). By intersecting these with the significant factors from the multivariate analysis, eight core predictors were ultimately identified: Ki-67 index, baseline liver and bone metastasis, first-line radiotherapy, relapse and metastasis patterns, second-line chemotherapy with concurrent or consolidation immunotherapy. Based on multivariate analysis, we constructed machine learning/regression models for prognostic prediction, including Random Survival Forest (RSF), XGBoost-Cox, and the Cox Proportional Hazards (COXPH) model. Performance evaluation using the Area Under the Curve (AUC) showed that the COXPH model excelled in predicting both short-term (3 and 6 months) and long-term (1–3 years) survival, achieving an average AUC of 0.858 and corresponding AUC values of 0.861, 0.855, and 0.849 for the 1-, 2-, and 3-year survival predictions, respectively (Fig. 4 E). The predictive performance of each algorithm, including the AUC values and C-index are comprehensively summarized in Supplementary Fig. 7. Building on its superior performance, we developed a personalized prognostic calculator. This tool integrates patients' baseline characteristics with first- and second-line treatment metrics to evaluate trends in their short- and long-term OS risk (Figure. 5A-B). It provides a quantitative basis for timely clinical monitoring and treatment adjustments. This free online calculator is accessible at http://43.154.9.125:3838/ . Discussion Through a large-scale, multi-center real-world cohort, this study deeply investigated a clinically controversial population: SCLC patients with a CTFI of 3–6 months following first-line treatment failure. We demonstrated that an EP/EC rechallenge strategy, compared to other second-line therapies, resulted in a higher ORR and superior prognostic benefits (mOS: 15.0 vs. 12.1 months, HR = 0.57, P<0.001; mPFS: 5.1 vs. 3.6 months, HR = 0.68, P = 0.004), with a manageable safety profile. Additionally, we present the first real-world evidence that incorporating ICIs into the rechallenge strategy significantly prolongs patient survival, thereby addressing an evidence gap in this area. Furthermore, by integrating 44 clinical characteristics, we systematically screened for favorable prognostic factors and subgroups deriving benefit from rechallenge. Based on these findings, we constructed highly sensitive prediction models for short- and long-term survival and developed a user-friendly online tool for real-time use by clinicians and patients, advancing the personalized management of rechallenge strategies. Current international guidelines generally recommend prioritizing platinum rechallenge for patients with a CTFI of ≥ 6 months. However, recent studies collectively point to the clinical rationale for advancing the timing of this rechallenge. A Japanese phase III randomized trial showed that among SCLC patients with a CTFI ≥ 3 months, the carboplatin plus etoposide group had significantly superior PFS compared to the topotecan group (mPFS: 4.7 vs. 2.7 months; HR = 0.57, P = 0.00041), although median OS was not significantly extended( 12 ). Garassino et al. reported that in a study of 30 patients with sensitive-relapse SCLC, platinum-based regimens achieved better PFS trends (p = 0.08)( 18 ). An analysis by Korkmaz et al. on 33 platinum-sensitive SCLC patients (CTFI ≥ 3 months) receiving second-line chemotherapy showed that those treated with platinum rechallenge had a higher ORR than patients who did not receive platinum-based therapy( 19 ). The team of Giovenzio Genestreti, despite not having a control group, also proposed that re-treatment with a platinum regimen could be a reasonable option for relapsed SCLC with a CTFI ≥ 3 months( 13 ). Utilizing a large-scale, multicenter real-world data, we focused on a clinically controversial cohort of patients with limited- or extensive-stage SCLC who experienced disease progression with a CTFI of 3–6 months. Our findings indicate that rechallenge with EP/EC (± immunotherapy) yields superior outcomes compared to alternative therapies, with a manageable safety profile. Through detailed subgroup analyses according to clinical characteristics, patterns of disease progression, and prior treatment history, this study further validates the clinical feasibility of early rechallenge of EP/EC regimens in real-world practice. Previous studies were all conducted in the pre-immunotherapy era. Since the IMpower133 and ADRIATIC studies respectively validated the significant benefits of immunotherapy for ES-SCLC and LS-SCLC, this combination has become the standard of care in the first-line setting( 20 , 21 ). In the era of immunotherapy, treatment strategies for relapsed SCLC also should be re-evaluated and optimized. Our data first reveal that even among relapsed patients with a CTFI of 3–6 months, rechallenge with chemoimmunotherapy continues to yield a significant benefit. Furthermore, our study is also the first of its kind to include patients who received chemoimmunotherapy as their first-line treatment, a population where the decision to continue immunotherapy post-relapse is intensely debated( 16 – 19 ). Our data demonstrate that even among these patients who relapsed with a CTFI of 3–6 months, continuing immunotherapy during rechallenge therapy still provides additional benefit (mOS: 18.1 vs. 13.0 months; HR = 0.57, P = 0.033). This indicates that disease progression following first-line chemoimmunotherapy does not signify true acquired resistance to immunotherapy. It is plausible that strategies like switching the immunotherapy agent or harnessing the "immuno-sensitizing" properties of chemotherapy could restore tumor responsiveness( 24 ). This finding provides a new and valuable perspective for selecting strategies after progression on first-line immunotherapy. Additionally, our stratification of benefiting populations provides guidance for precision therapy. We discovered that patients who achieved a CR/PR to first-line therapy derived particularly significant benefits from rechallenge, while patients with SD showed no significant advantage. This was corroborated by analyses correlating first- and second-line treatment efficacy, and by subgroup analyses of OS and PFS. This suggests that the biological basis for the efficacy of rechallenge may rely on targeting tumor clones sensitive to initial therapy. Notably, EP/EC rechallenge was the superior option across all relapse patterns (e.g., local progression from limited-stage, distant progression from limited-stage, and progression from extensive-stage), and combining it with immunotherapy provided additional benefits in these subgroups. This implies that even patients with limited-stage disease at relapse should receive early combination immunotherapy to amplify their therapeutic advantage. Second-line therapy for relapsed SCLC is palliative, and while toxicities are unavoidable, they must be kept within an acceptable range. Regarding the post-relapse chemotherapy regimen of carboplatin plus etoposide evaluated by Goto and colleagues, the reported primary Grade 3–4 adverse events were neutropenia (14%), thrombocytopenia (31%), and anemia (25%), and no treatment-related deaths were observed. Notably, 47 of 81 patients (58%) were able to proceed to third-line chemotherapy after study treatment, due to the absence of prohibitive toxicity. In our cohort, the incidence of all-grade adverse events was comparable between the rechallenge and control groups (92.0% vs. 89.8%), and no significant differences in grade 3–4 toxicities were observed between the two groups. Prior treatment exposure allowed earlier recognition and proactive management of toxicities, supporting the overall feasibility and manageable safety profile of EP/EC rechallenge. To advance personalized application of the rechallenge strategy, we developed a high-precision prognostic model by integrating 44 clinical variables selected through a multi-model evaluation. This model not only validated established negative prognostic factors (e.g., high Ki-67, baseline metastases) but also uncovered novel insights, such as the association between 45Gy/bid thoracic radiotherapy and improved OS, potentially indicating a superior radio-chemo-immuno synergistic effect. Incorporating core predictors, such as post-first-line progression patterns (primary tumor progression, intrathoracic progression, extrathoracic progression, and multiple metastases), we developed an online prediction tool. This tool is designed to translate the complex model into a user-friendly clinical decision-support instrument. By forecasting short- and long-term survival probabilities, it aids in screening for patients most likely to benefit from rechallenge, identifying critical points in survival post-treatment that warrant close monitoring (via imaging and molecular biopsies), and guiding timely therapeutic adjustments. The ultimate goal is to maximize the therapeutic benefit of re-induction therapy and advance individualized management. Our study has some limitations. First, the selection bias inherent in its retrospective design could not be entirely avoided; we aimed to mitigate this through multi-center data and rigorous statistical adjustments. Second, this study could not completely exclude the potential impact of subsequent treatments beyond the second line on patient prognosis. Notwithstanding these limitations, we believe that this study offers valuable evidence for assessing the clinical outcomes of this strategy. The development of a convenient online tool further assists clinicians and patients in collaborative, personalized treatment decision-making. In conclusion, EP/EC rechallenge with or without immunotherapy offers a promising treatment option for relapsed SCLC patients with a CTFI of 3 to 6 months. Furthermore, given the advantages of lower cost, high clinical accessibility, and favorable tolerability upon re-administration, this regimen holds the potential to confer clinical benefits across a broad patient population. We plan to conduct prospective randomized controlled trials and explore biomarkers predictive of treatment response to further optimize EP/EC-based rechallenge strategies. Ultimately, these efforts aim to improve patients' quality of life and survival rates while advancing the development of personalized and precision treatment approaches. Abbreviations SCLC: Small cell lung cancer; LS-SCLC: Limited-stage small cell lung cancer; ES-SCLC: Extensive-stage small cell lung cancer; CTFI: Chemotherapy-free interval; EP: Etoposide plus cisplatin; EC: Etoposide plus carboplatin; EP/EC: Etoposide plus cisplatin or carboplatin; IO: Immunotherapy; ICI: Immune checkpoint inhibitor; ICIs: Immune checkpoint inhibitors; OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate; DCR: Disease control rate; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; HR: Hazard ratio; CI: Confidence interval; RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1; ECOG PS: Eastern Cooperative Oncology Group performance status; PCI: Prophylactic cranial irradiation; RSF: Random survival forest; XGB: Extreme gradient boosting; CoxPH: Cox proportional hazards model; AUC: Area under the receiver operating characteristic curve; ROC: Receiver operating characteristic; C-index: Concordance index; Met: Metastasis; ETM: Extrathoracic metastasis; ITM: Intrathoracic metastasis; VIMP: Variable importance. Declarations Competing interests The authors declare that they have no competing interests. Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committees of Shandong Cancer Hospital and Institute, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Qilu Hospital of Shandong University (Ethics approval number: 20250919). Due to the retrospective design, no separate informed consent was obtained. Consent for publication Not applicable due to the retrospective nature of this study. Appendices Supplementary material associated with this article is provided in Supplementary_Material.docx Funding The study was funded by the National Natural Science Foundation of China (82272845), Natural Science Foundation of Shandong (ZR2023LZL001), Collaborative Academic Innovation Project of Shandong Cancer Hospital (ZF003), Foundation of Shandong Provincial Medical Association (YXH2024ZS007) and Beijing Science And Technology Innovation Medical Development Foundation (KC2023-JX-0288-PM97). Author Contribution: CRediT XJM and CY: conceptualization, supervision, funding acquisition, writing—review and editing. ZHW, YL and ZQH: data curation, software, formal analysis, writing—original draft preparation. XYL and GYL: methodology, visualization, investigation. XLL, MHY and WXC: investigation, resources. All authors read and approved the final manuscript. Acknowledgements We thank all the enrolled patients and their families for supporting our work. And we are grateful to all the participating medical centers. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Megyesfalvi Z, Gay CM, Popper H, Pirker R, Ostoros G, Heeke S et al. Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions. CA: A Cancer Journal for Clinicians. 2023;73(6):620–52. Zhai X, Zhang Z, Chen Y, Wu Y, Zhen C, Liu Y, et al. Current and future therapies for small cell lung carcinoma. J Hematol Oncol. 2025;18(1):37. Chen J, Pan X, Na F, Chen X, Chen C. Epigenetic reprogramming in small cell lung cancer. Cancer Biol Med. 2022;19(8):1111–6. Yang F, Zhao H. Progress in radiotherapy for small-cell lung cancer. Precis Radiat Oncol 2023 July 31;7(3):207–17. Krpina K, Vranić S, Tomić K, Samaržija M, Batičić L. Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives. Biomedicines. 2023 July;13(7):1982. Bernabé-Caro R, Chen Y, Dowlati A, Eason P. Current and Emerging Treatment Options for Patients With Relapsed Small-cell Lung Carcinoma: A Systematic Literature Review. Clin Lung Cancer. 2023;24(3):185–208. Gong J, Salgia R. Managing Patients With Relapsed Small-Cell Lung Cancer. J Oncol Pract. 2018 June;14(6):359–66. Subbiah V, Paz-Ares L, Besse B, Moreno V, Peters S, Sala MA, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for rechallenge with the first-line treatment. Lung Cancer. 2020;150:90–6. Rittberg R, Leung B, Al-Hashami Z, Ho C. Real World Patient Eligibility for Second Line Lurbinectedin Based Treatment in Small Cell Lung Cancer: Understanding Epidemiology and Estimating Health Care Utilization. Curr Oncol. 2022;29(12):9744–52. Postmus PE, Berendsen HH, van Zandwijk N, Splinter TA, Burghouts JT, Bakker W. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol. 1987 Sept;23(9):1409–11. Chiang CL, Liao YT, Sun RL, Huang HC, Shen CI, Tseng YH, et al. Treatment patterns and survival outcomes in patients with small-cell lung cancer following failure of first-line platinum-based chemotherapy. Clin Transl Oncol. 2025 Sept;27(9):3664–71. Baize N, Monnet I, Greillier L, Geier M, Lena H, Janicot H et al. Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial. The Lancet Oncology. 2020 Sept 1;21(9):1224–33. Genestreti G, Tiseo M, Kenmotsu H, Kazushige W, Di Battista M, Cavallo G, et al. Outcomes of Platinum-Sensitive Small-Cell Lung Cancer Patients Treated With Platinum/Etoposide Rechallenge: A Multi-Institutional Retrospective Analysis. Clin Lung Cancer. 2015;16(6):e223–228. Ishwaran H, Kogalur UB, Blackstone EH, Lauer MS. Random survival forests. Annals Appl Stat. 2008 Sept;2(3):841–60. Ma B, Yan G, Chai B, Hou X. XGBLC: an improved survival prediction model based on XGBoost. Bioinformatics. 2022;38(2):410–8. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36. Harrell FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361–87. Garassino MC, Torri V, Michetti G, Lo Dico M, La Verde N, Aglione S, et al. Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: a multi-institutional retrospective analysis. Lung Cancer. 2011 June;72(3):378–83. Korkmaz T, Seber S, Kefeli U, Sari E, Canhoroz M, Oven B, et al. Comparison of second-line treatment outcomes between sensitive and refractory small cell lung cancer patients: a retrospective analysis. Clin Transl Oncol. 2013 July;15(7):535–40. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220–9. Cheng Y, Spigel DR, Cho BC, Laktionov KK, Fang J, Chen Y, et al. Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. N Engl J Med. 2024;391(14):1313–27. Desai P, Thomas A. Small Cell Lung Cancer: New Hope, New Challenges. JCO Oncology Advances [Internet]. 2024 Sept [cited 2025 Nov 3]; Available from: https://ascopubs.org/doi/10.1200/OA.0000000000000001 Zhang B, Bao H, Li Z, Chen J, Yu H, Li M, et al. Continuing immune checkpoint inhibitors after progression: Real-world patterns of care and outcomes in second-line treatment for extensive-stage small-cell lung cancer. Lung Cancer. 2025;199:108021. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44(2):343–54. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 14 Apr, 2026 Editor assigned by journal 06 Apr, 2026 Submission checks completed at journal 06 Apr, 2026 First submitted to journal 01 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9293073","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":623021163,"identity":"ea398c6a-dcfa-4b0a-a21d-49390674a9e2","order_by":0,"name":"Zhonghui Wei","email":"","orcid":"","institution":"Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Zhonghui","middleName":"","lastName":"Wei","suffix":""},{"id":623021165,"identity":"8c16601f-6684-4029-b979-0735403a6213","order_by":1,"name":"Yang Liu","email":"","orcid":"","institution":"Shandong Tumor Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Liu","suffix":""},{"id":623021166,"identity":"459448df-ed9e-4747-9c67-e5fada8eb0b9","order_by":2,"name":"Zhaoqin Huang","email":"","orcid":"","institution":"Shandong Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhaoqin","middleName":"","lastName":"Huang","suffix":""},{"id":623021170,"identity":"c3e4d3bb-7e5b-4c44-9433-a2e945f16346","order_by":3,"name":"Xiaoyu Luo","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyu","middleName":"","lastName":"Luo","suffix":""},{"id":623021171,"identity":"918dcf52-7d61-4901-bce7-78dbf1e6c3c1","order_by":4,"name":"Guoyu Li","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Guoyu","middleName":"","lastName":"Li","suffix":""},{"id":623021173,"identity":"d69edfad-fa89-43c9-8665-9e1a0791443c","order_by":5,"name":"Xiaoli Liu","email":"","orcid":"","institution":"Shandong Tumor Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaoli","middleName":"","lastName":"Liu","suffix":""},{"id":623021175,"identity":"8641d675-fa32-462b-94dd-b822168ac8f7","order_by":6,"name":"Wenxing Cui","email":"","orcid":"","institution":"Shandong Tumor Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenxing","middleName":"","lastName":"Cui","suffix":""},{"id":623021176,"identity":"cff602af-242e-405c-974c-7eb9843c69a7","order_by":7,"name":"Minghao Yu","email":"","orcid":"","institution":"Shandong Tumor Hospital","correspondingAuthor":false,"prefix":"","firstName":"Minghao","middleName":"","lastName":"Yu","suffix":""},{"id":623021177,"identity":"6cd459d0-fd7e-49e7-a6cd-221d2ee936c1","order_by":8,"name":"Yu Chen","email":"","orcid":"","institution":"Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Chen","suffix":""},{"id":623021178,"identity":"e997fef3-8429-4b3d-a756-551dfdb2d4f5","order_by":9,"name":"Xiangjiao Meng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYNACHhsGhgMkakkjWQvDYRK06Lb3Hn7NI3Penu8A88PPBTU2+Qzsh49uwKfF7My5NMsZPLcTZx5gM5aecSzNsoEnLe0GXi03cswMPvDcTjC4/4ZBmrfhsAGDBI8Zfi3335gZJPCcszc4wMP8m7fhPxFabvAYP/jAc4BxwwEeNqAtB4jQcibHjHEGTzLIL2bWPMeSDdgI+uX4GePPvD12oBB7fJunxs6An/3wMbxagIBNgrEHmUtAOQgwf2D4QYSyUTAKRsEoGLkAAJAWRvkMbIxoAAAAAElFTkSuQmCC","orcid":"","institution":"Shandong University","correspondingAuthor":true,"prefix":"","firstName":"Xiangjiao","middleName":"","lastName":"Meng","suffix":""}],"badges":[],"createdAt":"2026-04-01 14:12:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9293073/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9293073/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107705669,"identity":"0cd983d0-218f-451c-85a4-592d6214f6ca","added_by":"auto","created_at":"2026-04-24 09:14:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":397669,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient enrollment. First-line relapse: rechallenge cohort and other cohort.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9293073/v1/af1fcce07752c187cfb3b0cd.png"},{"id":107705338,"identity":"858b39e5-8443-4873-8423-8bf0244a4d7b","added_by":"auto","created_at":"2026-04-24 09:11:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":308967,"visible":true,"origin":"","legend":"\u003cp\u003eBest tumor responses to first-line and post-relapse treatment strategies and their inter-relationships. (A) Best responses during initial EP/EC±IO and subsequent salvage therapies. (B) Sankey diagram depicting response transitions from first- to second-line treatment.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9293073/v1/ac3033860200a39a249841dd.png"},{"id":107705834,"identity":"5c421878-9a76-4072-bd82-48a5f43222aa","added_by":"auto","created_at":"2026-04-24 09:15:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":507269,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier analysis of OS and PFS. (A, B) Post-relapse outcomes by treatment: EP/EC±IO rechallenge versus alternative salvage regimens. (C, D) Post-relapse outcomes according to rechallenge therapy with or without immunotherapy.(E, F) Post-relapse outcomes by treatment in patients treated with first-line chemo-immunotherapy.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9293073/v1/192bae5565a5811baf232b2e.png"},{"id":107500500,"identity":"6d44bca0-8219-4efd-9572-312b1d84d861","added_by":"auto","created_at":"2026-04-22 05:48:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":376395,"visible":true,"origin":"","legend":"\u003cp\u003eMulti-model screening to identify key prognostic factors for OS in rechallenge therapy. (A-C) Cox regression was performed to assess the OS impact of variables related to baseline characteristics (A), first-line treatment (B), relapse and post-relapse treatment (C). (D) A Random Forest machine learning model ranked key variables by their predictive importance (VIMP score). (E) Performance evaluation of three models for short- and long-term survival prediction. ICI, immune checkpoint inhibitor; 1/2L, first-line/second-line therapy; Met, metastasis; ETM, Extrathoracic metastasis; ITM, Intrathoracic metastasis; RSF, random survival forest; CoxPH, Cox proportional hazards model; XGB, extreme gradient boosting.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9293073/v1/51134e6c33eee4d0243c9066.png"},{"id":107706041,"identity":"3482ce11-b3a4-4e46-9aee-9104a860d90a","added_by":"auto","created_at":"2026-04-24 09:17:13","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":252722,"visible":true,"origin":"","legend":"\u003cp\u003eAn online web-based tool for individualized prediction in rechallenged patients. (A) User interface illustrating data input and real-time generation of individualized prediction results. (B) Tool overview page describing the variables incorporated.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9293073/v1/8834e74ff50988dcab0a050b.png"},{"id":108006084,"identity":"101cc4c5-240e-4f9e-8c8f-c0c9ceccc8e3","added_by":"auto","created_at":"2026-04-28 12:53:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2203768,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9293073/v1/9be5b6bd-a7a6-4af7-97a8-167a3c00c131.pdf"},{"id":107500495,"identity":"e9f97597-7605-4c08-be71-7cac3f0a7662","added_by":"auto","created_at":"2026-04-22 05:48:02","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2701158,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-9293073/v1/f9bf6f17aba182e061f1c017.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Etoposide–Platinum Rechallenge in Small Cell Lung Cancer Worth More Application: A Multicenter Study and Web-Based Predictive Model","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSmall cell lung cancer accounts for roughly 15% of newly diagnosed lung cancers(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). This malignancy is defined by its high-grade aggressive biology and a profound tendency for early systemic dissemination, which leads to poor prognosis for patients(\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). While first-line treatment with platinum-based chemotherapy typically elicits a high initial response rate, this therapeutic benefit is often transient. Unfortunately, most patients relapse in 6 months or less(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Numerous clinical studies have shown that the CTFI after first-line therapy substantially influences both the selection and the efficacy of second-line treatments in SCLC(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOwing to the lower cost, high accessibility, and favorable tolerability upon re-administration, etoposide-platinum rechallenge regimens are widely utilized after first-line recurrence and have demonstrated favorable clinical efficacy(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Although current guidelines recommend etoposide-platinum rechallenge for SCLC patients with a CTFI of \u0026ge;\u0026thinsp;6 months, a recent prospective Japanese study including patients with a CTFI\u0026thinsp;\u0026gt;\u0026thinsp;3 months demonstrated that carboplatin plus etoposide was significantly superior in PFS and non-inferior to topotecan in OS (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Another study based on data from 2007\u0026ndash;2011 indicated that platinum rechallenge achieved a mOS of 7.9 months in platinum-sensitive relapsed SCLC, though lacking control-arm validation(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These findings indicate the potential of earlier rechallenge of etoposide\u0026ndash;platinum therapy; however, conclusive evidence comparing different treatment regimens in relapsed or metastatic SCLC patients with a CTFI of 3\u0026ndash;6 months after first-line therapy is currently lacking.\u003c/p\u003e \u003cp\u003eAdditionally, given the widespread use of immunotherapy in the first-line treatment of SCLC today, it is essential to re-evaluate the value of etoposide cisplatin/carboplatin (EP/EC) rechallenge regimens in the immunotherapy era, with particular attention to whether rechallenge with concurrent or consolidation immunotherapy can translate into significant survival benefits. Our study is the first real-world study focusing specifically on relapsed patients with a CTFI of 3\u0026ndash;6 months following first-line platinum-based therapy, comparing outcomes based on the receipt of etoposide-platinum rechallenge (with or without immunotherapy). As the first study of its kind to include patients who received immunotherapy during the first-line or rechallenge phases, it closely reflects current clinical practice. We systematically evaluated differences in objective response rate (ORR), progression-free survival (PFS), overall survival (OS) among different post-relapse treatments, aiming to identify populations likely to benefit and predictive factors for EP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;immunotherapy efficacy, thus providing evidence to guide subsequent management.\u003c/p\u003e \u003cp\u003eIn summary, we conducted the largest multi-center real-world study to date evaluating EP/EC rechallenge (\u0026plusmn;\u0026thinsp;immune checkpoint inhibitors, ICIs) in the clinically contentious patients relapsing with a CTFI of 3\u0026ndash;6 months. This study further addresses the evidence gap by comparing the efficacy of rechallenge combined with immunotherapy against other chemo-immunotherapy regimens. We also investigated pressing clinical questions in the management of relapsed SCLC, such as the influence of varying relapse/progression patterns on outcomes and treatment selection after first-line immunotherapy failure. To further refine the rechallenge strategy, we identified the optimal subgroup for rechallenge and developed a highly accurate prognostic model evaluating machine learning algorithms with over 40 variables. We aim to provide evidence-based support to guide the clinical application of EP/EC rechallenge, both as a standalone therapy or in combination with immunotherapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study enrolled patients with limited- or extensive-stage SCLC who experienced disease progression with a CTFI of 3\u0026ndash;6 months after first-line EP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;immunotherapy at 3 medical centers between August 2018 and May 2025. Patients who received\u0026thinsp;\u0026le;\u0026thinsp;2 cycles of chemotherapy or who were lost to follow-up immediately after first-line relapse were excluded. Collected variables included demographics, performance status, details of first-line therapy and response, subsequent treatments, and outcomes. Tumor response was evaluated per RECIST v1.1. Follow-up assessments were performed regularly to record recurrence and survival. The study was conducted in accordance with the Declaration of Helsinki and received approval from the institutional review boards/independent ethics committees of the participating centers.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary endpoints of this analysis were overall survival (OS) and progression-free survival (PFS). In this study, PFS was defined from the initiation of second-line therapy to disease progression, death or last follow-up, while OS was defined from the initiation of second-line therapy to death or last follow-up. One-, two-, and three-year survival rates were also estimated. Efficacy and safety served as important comparative endpoints in this study. Radiographic assessment of treatment response was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). To identify subpopulations potentially benefiting from rechallenge therapy, exploratory subgroup analyses were performed based on multiple covariates. Univariate and multivariate Cox proportional-hazards models were applied to assess prognostic factors in relapsed SCLC patients after first-line therapy and to further identify determinants associated with benefit from rechallenge regimens.\u003c/p\u003e \u003cp\u003eTo predict the prognosis of the rechallenge cohort and facilitate personalized management, a multivariate prognostic prediction model was constructed. By evaluating Random Survival Forest (RSF)(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), XGBoost-Cox(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), and the Cox Proportional Hazards (COXPH) model, key prognostic variables were identified, leading to the development of an interactive prediction tool. The performance of each model was robustly evaluated on the training dataset using a repeated 5-fold cross-validation scheme (10 repetitions). The models' predictive accuracy was assessed based on their discrimination and calibration. Discrimination was quantified using metrics such as the Area Under the Receiver Operating Characteristic (ROC) curve (AUC)(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and the Concordance Index (C-index)(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Developed using the Shiny R platform and deployed on a public web server, this tool is conveniently accessible to both clinicians and patients.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eCategorical variables were compared using the χ\u0026sup2; test or Fisher\u0026rsquo;s exact test, as appropriate. Continuous variables were compared using the Wilcoxon rank-sum test, and correlations between continuous variables were assessed with Pearson\u0026rsquo;s correlation coefficient. Overall OS and PFS were estimated by the Kaplan\u0026ndash;Meier method and compared using the log-rank test. Exploratory subgroup analyses were performed with unstratified Cox proportional-hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs); results are presented as forest plots. Univariate and multivariate Cox proportional-hazards models were used to identify prognostic factors. Two-sided p values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. All analyses were conducted using R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria) and SPSS version 23.0 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eBetween August 2018 and May 2025, a total of 991 patients with limited-stage or extensive-stage SCLC experienced disease progression after first-line EP/EC and were subsequently followed up. This study focused on the 313 patients with CTFI of 3\u0026ndash;6 months to evaluate the feasibility of EP/EC rechallenge (with or without immunotherapy). The study flowchart is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In the overall cohort, patients were predominantly male (74.4%), most had an ECOG performance status of 0\u0026ndash;1 (92.7%), 55.6% were younger than 65 years, and 68.7% presented with extensive-stage disease. A best overall response of complete or partial response to first-line therapy was achieved in 213 patients (68.1%). Baseline clinical characteristics were balanced between the rechallenge and non-rechallenge groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Second-line treatments were further classified as EP/EC\u0026thinsp;+\u0026thinsp;IO, EP/EC, other chemo-IO combinations, and other chemotherapy; baseline remained well balanced across these cohorts (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eTreatment regimens\u003c/h2\u003e \u003cp\u003eIn this cohort, 136 patients (43.5%) received EP/EC rechallenge with or without immunotherapy as second-line treatment. The non-rechallenge control group (n\u0026thinsp;=\u0026thinsp;177, 56.5%) received more heterogeneous chemotherapy regimens, most commonly nab-paclitaxel plus platinum agent (n\u0026thinsp;=\u0026thinsp;77, 43.5%), irinotecan monotherapy (n\u0026thinsp;=\u0026thinsp;36, 20.3%), and temozolomide (n\u0026thinsp;=\u0026thinsp;31, 17.5%). Temozolomide was predominantly used for patients who subsequently developed brain metastases, reflecting its role in CNS-directed therapy. A total of 127 patients (40.6%) received ICIs in the second-line setting; of these, 61 (48.0%) received ICIs combined with EP/EC rechallenge.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline and therapeutic characteristics of patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;IO cohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther cohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;136 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;177 (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.645\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33(24.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47(26.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e103(75.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e130(73.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.216\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e81(59.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e93(52.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55(40.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e84(47.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG PS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e126(92.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e164(92.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.998\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10(7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13(7.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.134\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53(39.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e84(47.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e83(61.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e93(52.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eProgression patterns\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTo limited-stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47(34.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51(28.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.277\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTo extensive-stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e89(65.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e126(71.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFirst-line chemotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68(50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e82(46.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.519\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68(50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e95(53.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFirst-line radiotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34(25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51(28.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.452\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e102(75.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e126(71.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePCI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e84(61.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e103(58.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.523\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52(38.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e74(41.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFirst-line immunotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e51(37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54(30.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.194\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e85(62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e123(69.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFirst-line efficacy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.352\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40(29.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60(33.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e83(61.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e107(60.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(9.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10(5.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBrain metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53(39.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70(39.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.917\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29(21.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37(20.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.928\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBone metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20(14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32(18.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.427\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eECOG PS Eastern Cooperative Oncology Group performance status, CR complete response, PR partial response, CTFI chemotherapy-free interval, PCI prophylactic cranial irradiation\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical efficacy: tumor response\u003c/h3\u003e\n\u003cp\u003eWe collected the best tumor responses to first- and post-relapse therapy between the two cohorts. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA shows best responses during initial EP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;immunotherapy and following relapse with various salvage regimens. No significant difference in ORR was observed between groups during first-line treatment (P\u0026thinsp;=\u0026thinsp;0.35). In the second-line setting, patients who received rechallenge had a higher ORR than the non-rechallenge cohort (46.3% vs. 35.6%) and a higher disease control rate (DCR: 81.6% vs. 74.0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB presents a Sankey diagram illustrating the relationship between first- and second-line responses, enhancing visualization of these associations. Patients who achieved CR or PR to first-line therapy and subsequently received rechallenge therapy had a second-line ORR of 54.2%, which was significantly greater than the non-rechallenge group (34.0%). Based on these findings, EP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;immunotherapy rechallenge may be considered in the second-line setting, particularly for patients who attained CR or PR after first-line treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eSurvival analyses\u003c/h3\u003e\n\u003cp\u003eThe median follow-up was 26.3 months (95% CI, 22.5\u0026ndash;33.7). The median PFS was 5.1 months (95% CI, 4.4\u0026ndash;6.7) in the rechallenge cohort versus 3.6 months (95% CI, 2.9\u0026ndash;4.8) in the cohort receiving other therapies (HR\u0026thinsp;=\u0026thinsp;0.68; 95% CI, 0.52\u0026ndash;0.89; P\u0026thinsp;=\u0026thinsp;0.004; Fig.\u0026nbsp;3A). To account for treatment and biological heterogeneity, we calculated the PFS2/PFS1 ratio using each patient as their own control. PFS1 and PFS2 were defined as the PFS following the initiation of first-line and relapse therapies, respectively. In this study, the PFS2/PFS1 ratio was significantly correlated with survival outcomes (Pearson correlation coefficient\u0026thinsp;=\u0026thinsp;0.4, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Supplementary Fig.\u0026nbsp;2). The proportion of patients with PFS2/PFS1\u0026thinsp;\u0026gt;\u0026thinsp;1 was 55.6% in the rechallenge cohort and 45.3% in the other-treatment cohort, with median values of 1.36 and 1.10 respectively, suggesting a greater probability of prolonged disease control, with a potential impact on overall survival.\u003c/p\u003e \u003cp\u003eThe median OS was 15.0 months (95% CI, 13.2\u0026ndash;20.3) in the rechallenge cohort versus 12.1 months (95% CI, 10.0\u0026ndash;13.4) in the non-rechallenge cohort (HR\u0026thinsp;=\u0026thinsp;0.57; 95% CI, 0.44\u0026ndash;0.76; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;3B). One- and two-year OS rates were 64.8% (95% CI, 57.0\u0026ndash;73.7%) and 36.4% (95% CI, 28.2\u0026ndash;46.9%) in the rechallenge group versus 50.5% (95% CI, 43.3\u0026ndash;58.9%) and 17.6% (95% CI, 12.0\u0026ndash;25.8%) in the other group. In summary, rechallenge with EP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;immunotherapy was associated with superior short- and long-term survival rate, demonstrating improvements in both OS and PFS.\u003c/p\u003e \u003cp\u003eSubgroup analyses were conducted to investigate the impact of rechallenge versus other regimens on OS and PFS across patients with varying characteristics (Supplementary Fig.\u0026nbsp;3\u0026ndash;4). Rechallenge therapy demonstrated a trend toward clinical benefit in the majority of subgroups, supporting its recommendation as a superior therapeutic strategy (Supplementary Fig.\u0026nbsp;3). When stratifying by disease progression patterns, rechallenge of EP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;immunotherapy showed significant survival benefits across all patients, including those progressing from initial limited-stage disease (to either limited-stage, HR\u0026thinsp;=\u0026thinsp;0.57, 95% CI 0.33\u0026ndash;0.97, P\u0026thinsp;=\u0026thinsp;0.040; or to extensive-stage disease, HR\u0026thinsp;=\u0026thinsp;0.64, 95% CI 0.42\u0026ndash;0.97, P\u0026thinsp;=\u0026thinsp;0.034) as well as those progressing from initial extensive-stage disease (HR\u0026thinsp;=\u0026thinsp;0.52, 95% CI 0.31\u0026ndash;0.87, P\u0026thinsp;=\u0026thinsp;0.013). It is noteworthy that the benefit from rechallenge was particularly significant for patients who had achieved CR (HR\u0026thinsp;=\u0026thinsp;0.28, 95% CI 0.09\u0026ndash;0.84, P\u0026thinsp;=\u0026thinsp;0.024) or PR (HR\u0026thinsp;=\u0026thinsp;0.64, 95% CI 0.45\u0026ndash;0.90, P\u0026thinsp;=\u0026thinsp;0.011) to first-line therapy, while the benefit remained uncertain for those with SD. Additionally, patients with brain metastases at entry experienced a more pronounced benefit from rechallenge after first-line relapse (HR\u0026thinsp;=\u0026thinsp;0.47, 95% CI 0.30\u0026ndash;0.72, P\u0026lt; 0.001), a significant difference not observed in patients with other sites of metastasis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor relapsed SCLC, EP/EC\u0026thinsp;+\u0026thinsp;IO rechallenge provided greater survival benefit than other chemo-IO regimens (Supplementary Fig.\u0026nbsp;3). Given the increasing interest in immunotherapy for SCLC, we conducted a survival analysis comparing EP/EC\u0026thinsp;+\u0026thinsp;IO rechallenge, other chemo-IO, and EP/EC monotherapy in relapsed patients (Fig.\u0026nbsp;3C-D). The EP/EC\u0026thinsp;+\u0026thinsp;IO rechallenge group demonstrated a significantly longer median OS of 18.1 months (95% CI: 14.4\u0026ndash;50.5, P\u0026thinsp;=\u0026thinsp;0.033), compared to 14.6 months for other chemo-IO (95% CI: 13.2\u0026ndash;20.7) and 13.0 months for EP/EC rechallenge monotherapy (95% CI: 11.2\u0026ndash;17.3). A trend towards improved PFS was observed in the EP/EC\u0026thinsp;+\u0026thinsp;IO rechallenge group versus the other chemo-IO group (median PFS: 5.5 months [95% CI: 4.6\u0026ndash;8.2] vs. 4.2 months [95% CI: 3.2\u0026ndash;7.0]; P\u0026thinsp;=\u0026thinsp;0.14). These results indicate that re-challenging with EP/EC plus immunotherapy provides a more substantial survival advantage for SCLC patients after first-line treatment relapse.\u003c/p\u003e \u003cp\u003eFigure 3 Kaplan\u0026ndash;Meier analysis of OS and PFS. (A, B) Post-relapse outcomes by treatment: EP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;IO rechallenge versus alternative salvage regimens. (C, D) Post-relapse outcomes according to rechallenge therapy with or without immunotherapy.(E, F) Post-relapse outcomes by treatment in patients treated with first-line chemo-immunotherapy.\u003c/p\u003e \u003cp\u003eTo facilitate individualized application of rechallenge therapy, we conducted subgroup analysis to explore OS benefits from EP/EC rechallenge vs. EP/EC plus immunotherapy rechallenge across different patient characteristics (Supplementary Fig.\u0026nbsp;5\u0026ndash;6). In addition to patients with extensive-stage disease at relapse, those who remained classified as limited-stage after progression also appeared to derive an overall survival benefit from EP/EC plus immunotherapy rechallenge (HR\u0026thinsp;=\u0026thinsp;0.44, 95% CI 0.19\u0026ndash;1.01, P\u0026thinsp;=\u0026thinsp;0.050). In terms of progression-free survival, the analysis also indicated a supportive trend (HR\u0026thinsp;=\u0026thinsp;0.57, 95% CI 0.29\u0026ndash;1.12, P\u0026thinsp;=\u0026thinsp;0.102). This finding is particularly relevant to the hot topics about immunotherapy strategies in LS-SCLC, suggesting that timely IO combination is advantageous. Critically, we also found that patients exposed to first-line immunotherapy still derived a significant survival advantage from a second-line EP/EC\u0026thinsp;+\u0026thinsp;IO rechallenge. The median OS was longer in the EP/EC\u0026thinsp;+\u0026thinsp;IO rechallenge group than in the EP/EC rechallenge group (14.6 months, 95% CI, 13.03\u0026ndash;NR vs. 11.3 months, 95% CI, 8.5\u0026ndash;NR; P\u0026thinsp;=\u0026thinsp;0.024, Fig.\u0026nbsp;3E-F). These results demonstrate the feasibility of immunotherapy-based rechallenge in patients who have developed resistance to first-line immunotherapy, and continued exposure to immunotherapy can still provide additional clinical benefit.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePrognostic analysis of OS and PFS\u003c/h2\u003e \u003cp\u003eUnivariate and multivariate Cox regression analyses identified several significant prognostic factors for OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the multivariable analysis, first-line radiotherapy (HR\u0026thinsp;=\u0026thinsp;0.7, 95% CI 0.49\u0026ndash;0.98, P\u0026thinsp;=\u0026thinsp;0.047) and achieving a CR to first-line treatment (HR 0.45, 95% CI 0.24\u0026ndash;0.84, P\u0026thinsp;=\u0026thinsp;0.013) were significantly associated with improved OS. Regarding post-relapse treatment, second-line rechallenge therapy (HR 0.57, 95% CI 0.42\u0026ndash;0.75, P\u0026lt; 0.001) and immunotherapy consolidation (HR 0.56, 95% CI 0.35\u0026ndash;0.90, P\u0026thinsp;=\u0026thinsp;0.017) were also identified as significant prognostic factors. The presence of extrapulmonary metastases was significantly associated with a poorer OS prognosis, including liver metastases (HR\u0026thinsp;=\u0026thinsp;2.38, 95% CI 1.66\u0026ndash;3.42, P\u0026lt; 0.001) and bone metastases (HR\u0026thinsp;=\u0026thinsp;1.75, 95% CI 1.15\u0026ndash;2.59, P\u0026thinsp;=\u0026thinsp;0.005). Additionally, those who were initially diagnosed with limited-stage disease exhibited longer PFS, regardless of whether they progressed to limited-stage disease (HR\u0026thinsp;=\u0026thinsp;0.69, 95% CI 0.49\u0026ndash;0.98, P\u0026thinsp;=\u0026thinsp;0.037) or extensive-stage disease (HR\u0026thinsp;=\u0026thinsp;0.72, 95% CI 0.52\u0026ndash;1.01, P\u0026thinsp;=\u0026thinsp;0.057; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariable and multivariable analyses of OS and PFS.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariable (OS)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eMultivariable (OS)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnivariable (PFS)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eMultivariable (PFS)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.46 (1-2.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.17 (0.86\u0026ndash;1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.312\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.808\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.708\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG PS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.71 (0.99\u0026ndash;2.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.19 (0.86\u0026ndash;1.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.519\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eProgression patterns\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eES to ES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLS to ES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.03 (0.69\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.72 (0.52\u0026ndash;1.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLS to LS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.86 (0.52\u0026ndash;1.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.578\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.69 (0.49\u0026ndash;0.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFirst-line chemotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.693\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFirst-line radiotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.7 (0.49\u0026ndash;0.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.347\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePCI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.958\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFirst-line immunotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.958\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFirst-line efficacy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.442\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.13 (0.84\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.902\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.08 (0.81\u0026ndash;1.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.591\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.45 (0.24\u0026ndash;0.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.75 (0.44\u0026ndash;1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.292\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBrain metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.15 (0.83\u0026ndash;1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.392\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.820\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.38 (1.66\u0026ndash;3.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.53 (1.07\u0026ndash;2.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBone metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.75 (1.19\u0026ndash;2.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSecond-line rechallenge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.57 (0.42\u0026ndash;0.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.68 (0.52\u0026ndash;0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eConcurrent immunotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.85 (0.58\u0026ndash;1.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.408\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (0.72\u0026ndash;1.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.978\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImmunotherapy consolidation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.56 (0.35\u0026ndash;0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.48 (0.31\u0026ndash;0.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eECOG PS Eastern Cooperative Oncology Group performance status, CR complete response, PR partial response, CTFI chemotherapy-free interval, PCI prophylactic cranial irradiation\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eA total of 284 patients (90.7%) experienced at least one treatment-related adverse event during post-relapse therapy. In the rechallenge cohort, 125 patients (92.0%) developed adverse events, compared with 89.8% in the other treatment group. The most common events were hematologic toxicities, with neutropenia being the most frequent treatment-related serious adverse event. Specifically, neutropenia occurred in 78 patients (57.4%) in the rechallenge cohort and in 96 patients (54.2%) in the other treatment group, with grade 3\u0026ndash;4 events reported in 32 cases (23.5%) versus 38 cases (21.5%), respectively. We also evaluated treatment-related pneumonitis, which was observed in 25 patients (18.4%) in the rechallenge group and in 28 patients (15.8%) in the other treatment group, with grade 3\u0026ndash;4 pneumonitis occurring in 9 patients (6.6%) versus 11 patients (6.2%), respectively. All in-hospital adverse events were actively managed, and no treatment-related deaths were reported. Detailed information on other adverse events in both groups is provided in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment-related adverse events of rechallenge cohort and other-treatment cohort.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eEP/EC\u0026thinsp;\u0026plusmn;\u0026thinsp;IO\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny grade (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ge;Grade 3 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAny grade (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ge;Grade 3(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeutropenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e78(57.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32(23.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e96(54.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e38(21.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThrombocytopenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40(29.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20(14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e37(20.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e25(14.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymphopenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28(20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10(7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35(19.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6(3.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnaemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50(36.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23(16.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e41(23.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20(11.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eErythrocytopenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(11.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8(5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16(9.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9(5.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePneumonia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25(18.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9(6.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e28(15.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11(6.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAsthenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42(30.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5(3.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e58(32.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5(2.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGastrointestinal reaction\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e56(41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(2.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e49(27.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5(2.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFever\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22(16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(2.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35(19.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1(0.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAllergic reaction/Pruritus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7(5.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11(6.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHair loss\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(2.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypothyroidism\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2(1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eKey Factors and Individualized Model for Rechallenge Therapy\u003c/h2\u003e \u003cp\u003eTo explore the factors influencing the efficacy of rechallenge therapy and improve outcomes, we comprehensively collected and analyzed 44 clinical variables in the rechallenge cohort, including baseline characteristics, details of first-line treatment (e.g., radiotherapy dose), therapeutic efficacy, relapse patterns, metastatic sites, and immunotherapy modalities. The results of the multivariate analysis are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Among baseline characteristics, a Ki-67 index\u0026thinsp;\u0026ge;\u0026thinsp;90% (HR\u0026thinsp;=\u0026thinsp;4.26; 95% CI, 2.08\u0026ndash;8.74; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), liver metastases (HR\u0026thinsp;=\u0026thinsp;7.36; 95% CI, 3.55\u0026ndash;15.27; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and bone metastases (HR\u0026thinsp;=\u0026thinsp;3.56; 95% CI, 1.64\u0026ndash;7.72; P\u0026thinsp;=\u0026thinsp;0.001) demonstrated significant prognostic value (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Among first-line treatment\u0026ndash;related factors, a thoracic radiotherapy dose of 45 Gy/bid (HR\u0026thinsp;=\u0026thinsp;0.33; 95% CI, 0.13\u0026ndash;0.86; P\u0026thinsp;=\u0026thinsp;0.045), a carboplatin-based regimen (HR\u0026thinsp;=\u0026thinsp;1.74; 95% CI, 1.01\u0026ndash;3.06; P\u0026thinsp;=\u0026thinsp;0.038), and achieving a first-line partial response (HR\u0026thinsp;=\u0026thinsp;0.95; 95% CI, 0.5\u0026ndash;1.18; P\u0026thinsp;=\u0026thinsp;0.087) were associated with overall survival (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). Analysis of relapse patterns and second-line treatment showed that, compared with relapse at original sites, the development of new extrapulmonary metastases (HR\u0026thinsp;=\u0026thinsp;7.64; 95% CI, 3.07\u0026ndash;54.52; P\u0026thinsp;=\u0026thinsp;0.053), and the concomitant occurrence of both intrapulmonary and extrapulmonary metastases (HR\u0026thinsp;=\u0026thinsp;7.91; 95% CI, 4.15\u0026ndash;54.15; P\u0026thinsp;=\u0026thinsp;0.042) was associated with a poorer prognosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). In contrast, second-line concurrent immunotherapy (HR\u0026thinsp;=\u0026thinsp;0.46; 95% CI, 0.24\u0026ndash;0.89; P\u0026thinsp;=\u0026thinsp;0.022) and immunotherapy consolidation (HR\u0026thinsp;=\u0026thinsp;0.34; 95% CI, 0.14\u0026ndash;0.82; P\u0026thinsp;=\u0026thinsp;0.032) were associated with significant survival benefits.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo further identify key prognostic factors, we utilized a Random Forest algorithm to rank variables by importance. We shortlisted variables based on a dual criterion: a minimal depth below the average and a Variable Importance (VIMP) score in the top quartile (\u0026ge;\u0026thinsp;75th percentile, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eD). By intersecting these with the significant factors from the multivariate analysis, eight core predictors were ultimately identified: Ki-67 index, baseline liver and bone metastasis, first-line radiotherapy, relapse and metastasis patterns, second-line chemotherapy with concurrent or consolidation immunotherapy.\u003c/p\u003e \u003cp\u003eBased on multivariate analysis, we constructed machine learning/regression models for prognostic prediction, including Random Survival Forest (RSF), XGBoost-Cox, and the Cox Proportional Hazards (COXPH) model. Performance evaluation using the Area Under the Curve (AUC) showed that the COXPH model excelled in predicting both short-term (3 and 6 months) and long-term (1\u0026ndash;3 years) survival, achieving an average AUC of 0.858 and corresponding AUC values of 0.861, 0.855, and 0.849 for the 1-, 2-, and 3-year survival predictions, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eE). The predictive performance of each algorithm, including the AUC values and C-index are comprehensively summarized in Supplementary Fig.\u0026nbsp;7. Building on its superior performance, we developed a personalized prognostic calculator. This tool integrates patients' baseline characteristics with first- and second-line treatment metrics to evaluate trends in their short- and long-term OS risk (Figure. 5A-B). It provides a quantitative basis for timely clinical monitoring and treatment adjustments. This free online calculator is accessible at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://43.154.9.125:3838/\u003c/span\u003e\u003cspan address=\"http://43.154.9.125:3838/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThrough a large-scale, multi-center real-world cohort, this study deeply investigated a clinically controversial population: SCLC patients with a CTFI of 3\u0026ndash;6 months following first-line treatment failure. We demonstrated that an EP/EC rechallenge strategy, compared to other second-line therapies, resulted in a higher ORR and superior prognostic benefits (mOS: 15.0 vs. 12.1 months, HR\u0026thinsp;=\u0026thinsp;0.57, P\u0026lt;0.001; mPFS: 5.1 vs. 3.6 months, HR\u0026thinsp;=\u0026thinsp;0.68, P\u0026thinsp;=\u0026thinsp;0.004), with a manageable safety profile. Additionally, we present the first real-world evidence that incorporating ICIs into the rechallenge strategy significantly prolongs patient survival, thereby addressing an evidence gap in this area. Furthermore, by integrating 44 clinical characteristics, we systematically screened for favorable prognostic factors and subgroups deriving benefit from rechallenge. Based on these findings, we constructed highly sensitive prediction models for short- and long-term survival and developed a user-friendly online tool for real-time use by clinicians and patients, advancing the personalized management of rechallenge strategies.\u003c/p\u003e \u003cp\u003e Current international guidelines generally recommend prioritizing platinum rechallenge for patients with a CTFI of \u0026ge;\u0026thinsp;6 months. However, recent studies collectively point to the clinical rationale for advancing the timing of this rechallenge. A Japanese phase III randomized trial showed that among SCLC patients with a CTFI\u0026thinsp;\u0026ge;\u0026thinsp;3 months, the carboplatin plus etoposide group had significantly superior PFS compared to the topotecan group (mPFS: 4.7 vs. 2.7 months; HR\u0026thinsp;=\u0026thinsp;0.57, P\u0026thinsp;=\u0026thinsp;0.00041), although median OS was not significantly extended(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Garassino et al. reported that in a study of 30 patients with sensitive-relapse SCLC, platinum-based regimens achieved better PFS trends (p\u0026thinsp;=\u0026thinsp;0.08)(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). An analysis by Korkmaz et al. on 33 platinum-sensitive SCLC patients (CTFI\u0026thinsp;\u0026ge;\u0026thinsp;3 months) receiving second-line chemotherapy showed that those treated with platinum rechallenge had a higher ORR than patients who did not receive platinum-based therapy(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). The team of Giovenzio Genestreti, despite not having a control group, also proposed that re-treatment with a platinum regimen could be a reasonable option for relapsed SCLC with a CTFI\u0026thinsp;\u0026ge;\u0026thinsp;3 months(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Utilizing a large-scale, multicenter real-world data, we focused on a clinically controversial cohort of patients with limited- or extensive-stage SCLC who experienced disease progression with a CTFI of 3\u0026ndash;6 months. Our findings indicate that rechallenge with EP/EC (\u0026plusmn;\u0026thinsp;immunotherapy) yields superior outcomes compared to alternative therapies, with a manageable safety profile. Through detailed subgroup analyses according to clinical characteristics, patterns of disease progression, and prior treatment history, this study further validates the clinical feasibility of early rechallenge of EP/EC regimens in real-world practice.\u003c/p\u003e \u003cp\u003ePrevious studies were all conducted in the pre-immunotherapy era. Since the IMpower133 and ADRIATIC studies respectively validated the significant benefits of immunotherapy for ES-SCLC and LS-SCLC, this combination has become the standard of care in the first-line setting(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In the era of immunotherapy, treatment strategies for relapsed SCLC also should be re-evaluated and optimized. Our data first reveal that even among relapsed patients with a CTFI of 3\u0026ndash;6 months, rechallenge with chemoimmunotherapy continues to yield a significant benefit. Furthermore, our study is also the first of its kind to include patients who received chemoimmunotherapy as their first-line treatment, a population where the decision to continue immunotherapy post-relapse is intensely debated(\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Our data demonstrate that even among these patients who relapsed with a CTFI of 3\u0026ndash;6 months, continuing immunotherapy during rechallenge therapy still provides additional benefit (mOS: 18.1 vs. 13.0 months; HR\u0026thinsp;=\u0026thinsp;0.57, P\u0026thinsp;=\u0026thinsp;0.033). This indicates that disease progression following first-line chemoimmunotherapy does not signify true acquired resistance to immunotherapy. It is plausible that strategies like switching the immunotherapy agent or harnessing the \"immuno-sensitizing\" properties of chemotherapy could restore tumor responsiveness(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). This finding provides a new and valuable perspective for selecting strategies after progression on first-line immunotherapy.\u003c/p\u003e \u003cp\u003eAdditionally, our stratification of benefiting populations provides guidance for precision therapy. We discovered that patients who achieved a CR/PR to first-line therapy derived particularly significant benefits from rechallenge, while patients with SD showed no significant advantage. This was corroborated by analyses correlating first- and second-line treatment efficacy, and by subgroup analyses of OS and PFS. This suggests that the biological basis for the efficacy of rechallenge may rely on targeting tumor clones sensitive to initial therapy. Notably, EP/EC rechallenge was the superior option across all relapse patterns (e.g., local progression from limited-stage, distant progression from limited-stage, and progression from extensive-stage), and combining it with immunotherapy provided additional benefits in these subgroups. This implies that even patients with limited-stage disease at relapse should receive early combination immunotherapy to amplify their therapeutic advantage.\u003c/p\u003e \u003cp\u003eSecond-line therapy for relapsed SCLC is palliative, and while toxicities are unavoidable, they must be kept within an acceptable range. Regarding the post-relapse chemotherapy regimen of carboplatin plus etoposide evaluated by Goto and colleagues, the reported primary Grade 3\u0026ndash;4 adverse events were neutropenia (14%), thrombocytopenia (31%), and anemia (25%), and no treatment-related deaths were observed. Notably, 47 of 81 patients (58%) were able to proceed to third-line chemotherapy after study treatment, due to the absence of prohibitive toxicity. In our cohort, the incidence of all-grade adverse events was comparable between the rechallenge and control groups (92.0% vs. 89.8%), and no significant differences in grade 3\u0026ndash;4 toxicities were observed between the two groups. Prior treatment exposure allowed earlier recognition and proactive management of toxicities, supporting the overall feasibility and manageable safety profile of EP/EC rechallenge.\u003c/p\u003e \u003cp\u003eTo advance personalized application of the rechallenge strategy, we developed a high-precision prognostic model by integrating 44 clinical variables selected through a multi-model evaluation. This model not only validated established negative prognostic factors (e.g., high Ki-67, baseline metastases) but also uncovered novel insights, such as the association between 45Gy/bid thoracic radiotherapy and improved OS, potentially indicating a superior radio-chemo-immuno synergistic effect. Incorporating core predictors, such as post-first-line progression patterns (primary tumor progression, intrathoracic progression, extrathoracic progression, and multiple metastases), we developed an online prediction tool. This tool is designed to translate the complex model into a user-friendly clinical decision-support instrument. By forecasting short- and long-term survival probabilities, it aids in screening for patients most likely to benefit from rechallenge, identifying critical points in survival post-treatment that warrant close monitoring (via imaging and molecular biopsies), and guiding timely therapeutic adjustments. The ultimate goal is to maximize the therapeutic benefit of re-induction therapy and advance individualized management.\u003c/p\u003e \u003cp\u003eOur study has some limitations. First, the selection bias inherent in its retrospective design could not be entirely avoided; we aimed to mitigate this through multi-center data and rigorous statistical adjustments. Second, this study could not completely exclude the potential impact of subsequent treatments beyond the second line on patient prognosis. Notwithstanding these limitations, we believe that this study offers valuable evidence for assessing the clinical outcomes of this strategy. The development of a convenient online tool further assists clinicians and patients in collaborative, personalized treatment decision-making.\u003c/p\u003e \u003cp\u003eIn conclusion, EP/EC rechallenge with or without immunotherapy offers a promising treatment option for relapsed SCLC patients with a CTFI of 3 to 6 months. Furthermore, given the advantages of lower cost, high clinical accessibility, and favorable tolerability upon re-administration, this regimen holds the potential to confer clinical benefits across a broad patient population. We plan to conduct prospective randomized controlled trials and explore biomarkers predictive of treatment response to further optimize EP/EC-based rechallenge strategies. Ultimately, these efforts aim to improve patients' quality of life and survival rates while advancing the development of personalized and precision treatment approaches.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSCLC: Small cell lung cancer; LS-SCLC: Limited-stage small cell lung cancer; ES-SCLC: Extensive-stage small cell lung cancer; CTFI: Chemotherapy-free interval; EP: Etoposide plus cisplatin; EC: Etoposide plus carboplatin; EP/EC: Etoposide plus cisplatin or carboplatin; IO: Immunotherapy; ICI: Immune checkpoint inhibitor; ICIs: Immune checkpoint inhibitors; OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate; DCR: Disease control rate; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; HR: Hazard ratio; CI: Confidence interval; RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1; ECOG PS: Eastern Cooperative Oncology Group performance status; PCI: Prophylactic cranial irradiation; RSF: Random survival forest; XGB: Extreme gradient boosting; CoxPH: Cox proportional hazards model; AUC: Area under the receiver operating characteristic curve; ROC: Receiver operating characteristic; C-index: Concordance index; Met: Metastasis; ETM: Extrathoracic metastasis; ITM: Intrathoracic metastasis; VIMP: Variable importance.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committees of Shandong Cancer Hospital and Institute, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Qilu Hospital of Shandong University (Ethics approval number: 20250919). Due to the retrospective design, no separate informed consent was obtained.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable due to the retrospective nature of this study.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eAppendices\u003c/h2\u003e \u003cp\u003eSupplementary material associated with this article is provided in Supplementary_Material.docx\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe study was funded by the National Natural Science Foundation of China (82272845), Natural Science Foundation of Shandong (ZR2023LZL001), Collaborative Academic Innovation Project of Shandong Cancer Hospital (ZF003), Foundation of Shandong Provincial Medical Association (YXH2024ZS007) and Beijing Science And Technology Innovation Medical Development Foundation (KC2023-JX-0288-PM97).\u003c/p\u003e\u003ch2\u003eAuthor Contribution: CRediT\u003c/h2\u003e\u003cp\u003eXJM and CY: conceptualization, supervision, funding acquisition, writing\u0026mdash;review and editing. ZHW, YL and ZQH: data curation, software, formal analysis, writing\u0026mdash;original draft preparation. XYL and GYL: methodology, visualization, investigation. XLL, MHY and WXC: investigation, resources. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe thank all the enrolled patients and their families for supporting our work. And we are grateful to all the participating medical centers.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMegyesfalvi Z, Gay CM, Popper H, Pirker R, Ostoros G, Heeke S et al. Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions. 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Bioinformatics. 2022;38(2):410\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarrell FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarassino MC, Torri V, Michetti G, Lo Dico M, La Verde N, Aglione S, et al. Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: a multi-institutional retrospective analysis. Lung Cancer. 2011 June;72(3):378\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKorkmaz T, Seber S, Kefeli U, Sari E, Canhoroz M, Oven B, et al. Comparison of second-line treatment outcomes between sensitive and refractory small cell lung cancer patients: a retrospective analysis. Clin Transl Oncol. 2013 July;15(7):535\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng Y, Spigel DR, Cho BC, Laktionov KK, Fang J, Chen Y, et al. Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. N Engl J Med. 2024;391(14):1313\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesai P, Thomas A. Small Cell Lung Cancer: New Hope, New Challenges. JCO Oncology Advances [Internet]. 2024 Sept [cited 2025 Nov 3]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ascopubs.org/doi/10.1200/OA.0000000000000001\u003c/span\u003e\u003cspan address=\"https://ascopubs.doi/10.1200/OA.0000000000000001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang B, Bao H, Li Z, Chen J, Yu H, Li M, et al. Continuing immune checkpoint inhibitors after progression: Real-world patterns of care and outcomes in second-line treatment for extensive-stage small-cell lung cancer. Lung Cancer. 2025;199:108021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44(2):343\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"respiratory-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rere","sideBox":"Learn more about [Respiratory Research](http://respiratory-research.biomedcentral.com/)","snPcode":"12931","submissionUrl":"https://submission.nature.com/new-submission/12931/3","title":"Respiratory Research","twitterHandle":"@RespiratoryBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Small Cell Lung Cancer, Relapse, Rechallenge, Platinum, Immunotherapy","lastPublishedDoi":"10.21203/rs.3.rs-9293073/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9293073/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003e Guidelines generally recommend platinum rechallenge for patients with small cell lung cancer (SCLC) who progress more than 6 months after first-line platinum-based chemotherapy. However, clinical practice indicates therapeutic benefit in patients with a 3-6-month chemotherapy-free interval (CTFI), warranting re-evaluation particularly in the immunotherapy era. This study aimed to investigate the efficacy and safety of etoposide plus platinum rechallenge\u0026thinsp;\u0026plusmn;\u0026thinsp;immunotherapy in this controversial population to provide evidence to fill this clinical gap, and a user-friendly online tool was constructed to facilitate personalized prognostic management.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis real-world study enrolled SCLC patients from three hospitals (August 2018\u0026ndash;May 2025) who progressed 3\u0026ndash;6 months after first-line etoposide-platinum (\u0026plusmn;\u0026thinsp;immunotherapy) treatment. Patients were stratified based on whether they received etoposide-platinum rechallenge after relapse. We systematically evaluated the efficacy and safety. Based on 44 clinical features, this study assessed three machine learning models to generate survival prediction curves. An interactive online platform was established to facilitate convenient prognostic evaluation.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBetween 2018 and 2025, we enrolled 313 limited- or extensive-stage SCLC patients who experienced disease progression with a CTFI of 3\u0026ndash;6 months; the median follow-up was 26.3 months. Etoposide plus platinum rechallenge (\u0026plusmn;\u0026thinsp;immunotherapy) improved mOS (15.0 vs 12.1 months; HR\u0026thinsp;=\u0026thinsp;0.57; P\u0026lt; 0.001) and mPFS (5.1 vs 3.6 months; HR\u0026thinsp;=\u0026thinsp;0.68; P\u0026thinsp;=\u0026thinsp;0.004). The rechallenge significantly improved ORR compared to other regimens (46.3% vs. 35.6%), especially in patients who achieved a complete or partial response (CR/PR) during first-line (54.2% vs. 34.0%). Notably, survival benefits from the rechallenge regimen were consistently observed across different recurrence patterns (local or distant progression) and disease stages. Regardless of first-line immunotherapy exposure, rechallenge with combination immunotherapy (concurrent/consolidation) conferred significant benefits, with a median OS of 18.1 months. Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events were comparable between cohorts. Finally, a multi-time-point survival prediction model (3 months to 3 years) was developed for the rechallenge cohort (mean AUC\u0026thinsp;=\u0026thinsp;0.858) to facilitate prognostic assessment and enhanced monitoring, with a web-based visualization tool: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://43.154.9.125:3838/\u003c/span\u003e\u003cspan address=\"http://43.154.9.125:3838/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAs an inexpensive and widely accessible regimen with controllable adverse events, the etoposide-platinum rechallenge (\u0026plusmn;\u0026thinsp;immunotherapy) in relapsed SCLC with a CTFI of 3\u0026ndash;6 months after first-line therapy offers significant clinical benefits and a manageable safety profile.\u003c/p\u003e","manuscriptTitle":"Etoposide–Platinum Rechallenge in Small Cell Lung Cancer Worth More Application: A Multicenter Study and Web-Based Predictive Model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-22 05:47:58","doi":"10.21203/rs.3.rs-9293073/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-04-14T11:34:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-06T17:18:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-06T12:02:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"Respiratory Research","date":"2026-04-01T14:01:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"respiratory-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rere","sideBox":"Learn more about [Respiratory Research](http://respiratory-research.biomedcentral.com/)","snPcode":"12931","submissionUrl":"https://submission.nature.com/new-submission/12931/3","title":"Respiratory Research","twitterHandle":"@RespiratoryBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"711e7584-0c39-4f65-9b3d-7a6bdb0808f8","owner":[],"postedDate":"April 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-22T05:47:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-22 05:47:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9293073","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9293073","identity":"rs-9293073","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}