Efficacy and safety of Cadonilimab plus anlotinib in small cell lung cancer with brain metastases

Efficacy and safety of Cadonilimab plus anlotinib in small cell lung cancer with brain metastases | 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 Efficacy and safety of Cadonilimab plus anlotinib in small cell lung cancer with brain metastases Jin-Jing Chen, Wei Lv, Hai-Zhen Yi, Zhan Lin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5939578/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: This study aimed to evaluate the efficiency and safety of Cadonilimab and Anlotinib pairing in individuals diagnosed with small cell lung cancer (SCLC) and brain metastases (BMs). Methods: A review was performed on individuals who were diagnosed with small cell lung cancer (SCLC) and had central nervous system (CNS) metastases confirmed via magnetic resonance imaging (MRI) of the brain.We assessed the treatment response of Cadonilimab plus Anlotinib using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response assessment in neuro-oncology brain metastases (RANO-BM) for evaluating solid tumors and neuro-oncology brain metastases, respectively.The patients' prognosis was determined using Kaplan-Meier analysis and Cox regression analysis. Findings: The study initially included 46 patients diagnosed with SCLC who presented with brain metastases (BMs). According to the RANO-BM criteria, intracranial lesions showed an objective response rate (ORR) of 41.3%. The median overall survival (OS) was observed to be 19.3 months (95% CI, 17.4-21.1 months). Multivariate Cox regression analysis showed that having a PD1 level below 50% (HR=4.83, P <0.001) or having two or more metastatic organs (HR = 2.71, P = 0.036) were independent factors that positively predicted overall survival of all the patients, 86.9% experienced treatment-related adverse events (TRAEs) associated with the treatment, while 17.4% reported severe TRAEs of grade3-4. Implications: According to our results, the combination of Cadonilimab and Anlotinib appears to be a promising treatment option for SCLC patients with brain metastases. Small cell lung cancer Cadonilimab Anlotinib Brain metastases PD-1 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Approximately 15% of patients newly diagnosed with lung cancer have small cell lung cancer (SCLC), which is associated with high rates of recurrence and mortality[ 1 ]. Furthermore, individuals afflicted with this fatal illness are at a higher risk of developing brain metastases (BMs) and have limited treatment alternatives, leading to an abnormal survival rate. The median overall survival (OS) of patients with small cell lung cancer (SCLC) typically spans from 3.2 to 8.5 months, with nearly half of these patients developing brain metastases (BMs) during their treatment [ 2 ]. It is currently recommended that radiotherapy take the form of stereotactic radiation (SRS) or whole-brain radiation (WBRT) in combination with systemic therapy for the treatment of metastatic SCLC patients with BMs[ 3 ]. Owing to the cognitive decline that often accompanies treatment, along with the high relapse rate, patients with asymptomatic and stable BMs should exercise caution when considering brain radiotherapy, as it may cause more harm than good. Conversely, traditional chemotherapy is not very effective because of the presence of the blood-brain barrier (BBB). The utilization of immune checkpoint inhibitors (ICIs), which tap into the potential of the immune system, has revolutionized advanced cancer treatment. Additionally, extensive-stage SCLC patients could expect a significantly better prognosis with ICIs. P rior research has demonstrated that the inclusion of PD-L1 inhibitor (atezolizumab) and PD-1 inhibitor (pembrolizumab) in chemotherapy can significantly extend OS compared to conventional chemotherapy (atezolizumab [HR = 0.70, 95%CI 0.54–0.91, P = 0.007] and pembrolizumab [HR = 0.80, 95%CI 0.64–0.98, P = 0.0164]) [ 4 , 5 ]. However, subgroup analyses of these randomized trials (KEYNOTE-604, HR = 1.07, 95%CI 0.60–1.91; IMpower133, HR = 0.96, 95% CI 0.46–2.01) did not show that ICIs combined with chemotherapy have any benefit for BMs SCLC patients. The introduction of immune checkpoint inhibitors (ICIs), particularly PD-1/CTLA-4-targeted agents, has transformed the therapeutic landscape of advanced malignancies by enhancing antitumor immunity through blockade of inhibitory T-cell signaling pathways. Additionally, extensive-stage SCLC patients could expect a significantly better prognosis with ICIs.Liu, and Liu SV and Rudin CM have demonstrated that the inclusion of PD-L1 inhibitor (atezolizumab) and PD-1 inhibitor (pembrolizumab) in chemotherapy can significantly extend overall survival (OS) compared to conventional chemotherapy (atezolizumab [HR = 0.70, 95%CI 0.54–0.91, P = 0.007] and pembrolizumab [HR = 0.80, 95%CI 0.64–0.98, P = 0.0164]) [ 4 , 5 ]. However, subgroup analyses of these randomized trials (KEYNOTE-604, HR = 1.07, 95%CI 0.60–1.91; IMpower133, HR = 0.96, 95% CI 0.46–2.01) did not show that ICIs combined with chemotherapy have any benefit for BMs SCLC patients. Therefore , the development of novel therapeutic strategies is necessary. Cadonilimab is an IgG1 antibody with a tetravalent bispecific structure and includes a single-chain variable fragment (scFv). The Fc-null configuration eliminates antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and cytokine generation. Fc receptor-mediated effector functions, which eliminate or harm PD-1 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) expressing lymphocytes, may diminish antitumor efficacy. Cadonilimab exhibits notably reduced toxicities compared with alternative medications in clinical settings. Within a tumor-like environment, the strong affinity of Cadonilimab and its Fc-null structure might enhance drug retention and safety, ultimately leading to effective antitumor outcomes [ 6 , 7 ]. According to researchers, the combination of chemotherapy with anlotinib, a new multitargeted tyrosine kinase inhibitor (TKI), enhances progression-free survival and quality of life in SCLC patients with BMs [ 7 , 8 ]. Numerous studies have demonstrated the synergistic effects of immunotherapy and antiangiogenic therapy in advanced solid tumors. Clinical studies of anti-PD-1/PD-L1 antibodies in combination with anti-angiogenic drugs have shown promising efficacy and manageable safety in treating SCLC. Preclinical studies investigating synergies with ICIs suggest that anlotinib has the potential to modify the microenvironment of tumor immunity by suppressing the expression of PD-L1 on endothelial cells in the vascular system and facilitating the infiltration of cells from the innate immune system. Anlotinib, a new orally administered tyrosine kinase inhibitor that targets vascular endothelial, fibroblast, and platelet-derived growth factor receptors, has been approved as a third-line therapy for advanced SCLC in China, However, these studies did not targeted in these studies. In our study, the combination of Anlotinib with Cadonilimab was evaluated as a potential treatment for advanced SCLC patients with BMs. PATIENTS AND METHODS Study Design Therefore, this study retrospectively screened advanced-stage small cell lung cancer (SCLC) patients with brain metastases (BMs). who received anlotinib plus cadonilimab in clinical practice from June 2019 to December 2022 at The First People's Hospital of Yulin. included the following inclusion criteria: (1) SCLC diagnosis by pathology or cytology, with extensive-stage SCLC (ES‐SCLC); (2) age ≥ 18 years; (3) Magnetic resonance imaging of the brain ( magnetic resonance imaging, MRI) contrasted with baseline BMs; (4) patients who had previously undergone systemic therapy but had not been treated with the combination of ICIs and Anlotinib, nor with ICIs or Anlotinib as standalone therapies;not receive Prior intracranial RT = 0; (5) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 score; (6) measurable target lesions according to RECISTv1.1 criteria to assess the therapeutic response. The exclusion criteria were as follows: (1) diagnosis of one more tumor or a serious disease that might compromise their life; (2) patients receiving systemic treatment other than anlotinib combined with cadonilimab; (3) efficacy assessment data were not available;(4) patients who had received combination therapy before developing BMs or did not have baseline imaging and at least one follow-up scan were not included in the study. The study complied with the Declaration of Helsinki and the International Good Clinical Practice Guidelines. The Institutional Review Board approved the waiver of written informed consent[ 9 – 11 ]. Endpoints of the study The data were collected and analyzed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response Assessment in Neurooncology Brain Metastases (RANO-BM). Tumors with a diameter ≥ 10 mm were considered measurable lesions, which were classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). the objective response rate (ORR), which represents the ratio of systemic objective responses, was determined by calculating the percentage of extracranial lesions showing complete or partial response. The DCR or disease control rate was calculated by considering complete response, partial response, and stable disease. Intracranial ORRs and DCRs were calculated according to brain lesions. The Overall survival (OS) period was defined as the period from the start of treatment to the date of death or the date of last imaging. Progression-free survival (PFS) refers to the duration from treatment initiation to the occurrence of intracranial or extracranial progression, death, or censoring at the time of the most recent imaging. Progression-free survival (PFS) of the brain tumor was determined from From the onset of treatment until the end, mortality, or censoring at the final imaging assessment.Patients who experienced extracranial progression first were not included in the calculation of intracranial PFS. Adverse events associated with treatment TRAEs ( treatment-related adverse events) were documented throughout the course of the treatment and subsequent monitoring. Statistical analysis Descriptive summaries were used to analyze clinical and demographic variables, and Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) were generated. Censored observations were considered for analyses when patients did not experience disease progression or when they reached the end of follow-up. Clinical characteristics were compared using the chi-square d test. Log-rank tests were used to compare survival between different groups, and we investigated the correlation between survival and clinical factors using both univariate and Multivariable Cox regressions. SPSS18 was used for all analyses, was the consideration for P < 0.05. Results The study profile is illustrated in Fig. 1 , A total of 46 patients with advanced small cell lung cancer (SCLC) and brain metastases (BMs) received treatment with a combination of Cadonilimab plus Anlotinib. Table 1 summarizes the fundamental clinical and pathological characteristics of these patients. The majority of the patients (approximately 65.2%) were below the age of 60 and exhibited an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, which accounted for 87% of the total.32.6% of patients had metastatic disease affecting more than two organs. Of the total number of patients, 20 (43.5%) experienced brain lesions with symptoms, while 34 patients (73.9%) had multiple brain lesions. Additionally, 63.1% of the subjects attained lactate dehydrogenase levels(LDH) surpassing the upper limit of normal (ULN).36.9% of patients achieved higher LDH levels than the ULN. Table 1 Baseline characteristics of the study population. Characteristic N (%) Age < 65 30(65.2%) ≥ 65 16(34.8%) Sex Male 38(82.6%) Female 8(17.4%) ECOG-PS 0–1 40(87%) 2 6(13%) Smoking history Never 28(60.8%) Smoked 18(39.2%) metastatic organs 2 31(67.4%) ≥ 2 15(32.6%) Number of BMs Single 12(26.1%) Multiple 34(73.9%) Symptomatic BMs No 26(56.5%) Yes 20(43.5%) Prior lines of systemic therapy 2 11(23.9%) ≥3 37(80.4%) Prior intracranial RT No 46 Yes 0 Prior ICIs treatment No 46 Yes 0 Concurrent intracranial RT No 46 Yes 0 LDH 50% 21 < 50% 25 Evaluating effectiveness The systemic response s of all 46 patients were assessed. The overall response rate (ORR) and disease control rate (DCR) for these patients were 45.7% and 86.9%, respectively( Table 2 ). It contains a summary of the treatment response to Cadonilimab plus Anlotinib, evaluated using RECIST 1.1 criteria.RANO-BM criteria were also used to assess intracranial response, which was 41.3% (1 CR, 18 PR) (Table 2 ). Figure 2 shows typical MRI scans of a complete response in brain lesions before and after therapy; patients with detectable lesions are depicted in Fig. 3 , illustrating alterations both inside and outside the skull. In the overall study, In the overall study population, the median overall survival (OS) was found to be 19.3 months(95% CI, 17.4–21.1 months), and the median progression-free survival (PFS) was 14.2 months(95% CI, 12.5–15.9 months) (Fig. 4 ,A,B). Table 2 Efficacy of Cadonilimab plus Anlotinib Characteristic N (%)(N = 46) Response to Cadonilimab plus Anlotinib treatment, measured using the RECIST 1.1 criteria. CR 1 PR 20 SD 19 PD 6 ORR 21(45.6%) DCR 40(86.9%) The intracranial efficacy of Cadonilimab plus Anlotinib was evaluated in patients with measurable lesions per RANO-BM. Reduction of steroid treatment No 10 Yes 36 Neurological symptoms Stable or improved 44 Worse 2 T2/FLAIR signal Stable or decreased 42 Increased 4 Intracranial response CR 1 PR 18 SD 23 PD 4 ORR 19(41.3%) DCR 42(91.3%) FLAIR Fluid attenuated inversion recovery; CR Complete response; PR Partial response; SD Stable disease; PD Progression disease; ORR Objective response rate; DCR Disease control rate Prognosis In addition, we investigated the impact of various factors on survival using univariate and multivariate Cox models. The multivariate analysis encompassed all variables that showed significant correlations and trends ( P < 0.05) in the univariate analysis. Multivariable Cox model analysis for overall survival (OS) included smoking, number of brain metastases (BMs), and number of metastatic organs. PD1 < 50% (HR = 4.83, P 50% ( hazard ratio [HR] = 4.385 , P = 0.001) or metastatic organs ≥ 2 (HR = 0.245, P = 0.04) had worse outcome s ( Table 4 ). Subsequently, Kaplan-Meier survival plots were generated based on the significant prognostic factors identified in the multivariate Cox model analysis. Patients with more than two metastatic organs (10.9 vs. 20.7 months, P = 0.001) or PD1 expression less than 50% (13.6 vs. 21.9 months, P = 0.000) exhibited significantly shorter overall survival compared to their counterparts, as depicted in Fig. 5 A-D. Furthermore, the presence of two or more metastatic organs (7.3 vs. 15.2 months, P = 0.000) or a PD1 level exceeding 50% (9.0 vs. 16.6 months, P = 0.000) exhibited a significant correlation with reduced intracranial PFS, as depicted in Fig. 5 A-D). Table 3 Univariate and multivariable Cox regression analysis for OS Characteristic Univariate survival analyses of OS Multivariable survival analyses of OS HR 95%CI P Value HR 95%CI P Value Age < 60 ≥ 60 0.595 0.273–1.297 0.192 Sex Male Female 0.965 0.855–10.277 0.087 ECOG 0–1 2 1.643 0.556–4.850 0.920 Smoking history Never Smoked 0.725 0.355–1.481 0.378 metastatic organs < 2 ≥ 2 0.053 0.014–0.201 0.000 0.101 0.034–0.302 0.000 Number of BMs Single Multiple 0.885 0.288–2.720 0.831 Symptomatic BMs No Yes 0.683 0.354–1.316 0.254 LDH 50% < 50% 0.939 17.428–21.109 0.000 3.313 1.398–7.853 0.007 Table 4 Univariate and multivariable Cox regression analysis for PFS Characteristic Univariate survival analyses of PFS Multivariable survival analyses of PFS HR 95%CI P Value HR 95%CI P Value Age < 60 ≥ 60 0.901 0.410–1.978 0.794 Sex Male Female 1.922 0.615–6.008 0.261 ECOG-PS 0–1 2 1.437 0.494–4.181 0.506 Smoking history Never Smoked 1.032 0.485–2.196 0.935 metastatic organs <2 ≥2 0.182 0.059–0.563 0.003 0.245 0.094–0.635 0.04 Number of BMs Single Multiple 0.853 0.290–2.511 0.773 Symptomatic BMs No Yes 0.960 0.505–1.824 0.901 LDH 50% < 50% 0.818 11.318–14.525 0.006 4.385 1.829–10.515 0.001 Safety An analysis of TRAEs associated with cadonilimab plus anlotinib is shown in Table 5 . Of the 46 patients, 26 (56.5%, n = 26) experienced grade 1–2 treatment-related adverse events (TRAEs), while 6 patients (13%) encountered grade 3–4 TRAEs.As a whole, hypertension accounted for 52%, hypertension accounted for 50%, and leukemia accounted for 30.4%. Among the grade 3–4 TRAEs, Hypertension accounted for the highest occurrence rate (6.5%, n = 3), followed by thyroid dysfunction (4.3%, n = 2). Leukopenia, Hepatic dysfunction, and positive urinary protein were ranked third, with an occurrence rate of 2.2% (n = 1). Table 5 Treatment-related adverse events Adverse event,N (%) patients (n = 46) ALL Grade 1–2 Grade 3–4 Any adverse event 32(69.6%) 26(56.5%) 6(13.0%) Thyroid dysfunction 24(52.2%) 22(47.8%) 2(4.3%) Hypertension 23(50%) 20(58.7%) 3(6.5%) Leukopenia 17(30.4%) 16(34.8%) 1(2.2%) Hepatic dysfunction 9(19.6%) 8(17.4%) 1(2.2%) Thrombocytopenia 3(6.5%) 3(6.5%) 0 Hand-foot skin reaction 6(13.0%) 6(13.0%) 0 Gastrointestinal response 3(6.5%) 3(6.5%) 0 Positive urinary protein 2(4.3%) 1(2.2%) 1(2.2%) Dental ulcer 1(2.2%) 1(2.2%) 0 Cough 1(2.2%) 1(2.2%) 0 Fatigue 2(4.3%) 2(4.3%) 0 Rash 2(4.3%) 2(4.3%) 0 Pneumonitis 1(2.2%) 1(2.2%) 0 Diarrhea 1(2.2%) 1(2.2%) 0 Discussion In the realm of small-cell lung cancer (SCLC), no parallel research has been conducted to evaluate the efficacy of Cadonilimab combined with anlotinib for brain metastases (BMs) in the central nervous system. While intracranial radiotherapy is widely employed for brain metastases (BMs) treatment, it has detrimental effects on the surrounding healthy tissues, which can impair the patient’s cognitive function, memory, and intellectual capacity. The search for novel therapeutic approaches is crucial, as the majority of SCLC patients with BMs, even after undergoing systemic radiotherapy, continue to face recurrence or develop resistance to treatment. To the best of our knowledge, this study is the first to report the use of Cadonilimab combined with anlotinib for the treatment of extensive SCLC with brain metastases (BMs) in real-world clinical practice. The use of Cadonilimab combined with anlotinib regimens provided a 19.3 months of Overall survival (OS) and 14.2 months of Progression-free survival (PFS). This regimen showed significant efficacy within the central nervous system. We found that a metastatic organs ≥ 2 and PD1 > 50% concentration were independent predictive factors associated with shorter OS in the studied patients. Thyroid dysfunction and Hypertension accounted for most of the treatment-related AEs in this study; these AEs were manageable, and no treatment-related deaths occurred. In recent years, there has been significant advancement in immuno-oncology (IO) treatments, with monoclonal antibodies (mAbs) targeting programmed cell death-1 (PD-1) now recognized as the standard treatment for various types of cancer. Numerous combinations of anti-PD-1 antibodies have been explored to enhance the efficacy of PD-1 monotherapy. Promising research has shown significant improvements in the efficacy of combination therapy involving anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-PD-1 antibodies for difficult-to-treat cancer types. However , its use in kidney, gastric, and lung cancers has been restricted because of its toxic effects. Cadonilimab represents a humanized IgG1 bispecific antibody, engineered for enhanced functionality via the Akeso Tetrabody platform. Yet, it lacks the conventional Fc effector functions such as antibody-dependent cellular cytotoxicity, phagocytosis, and complement-mediated cytotoxicity. This dual-targeting agent simultaneously engages PD-1 and CTLA-4, thereby inhibiting the PD-1/PD-L1, PD-1/PD-L2, CTLA-4/B7.1, and CTLA-4/B7.2 interactions. Preliminary investigative findings in preclinical research suggest that cadonilimab’s selective accumulation within tumor tissues, in contrast to standard anti-PD-1 and anti-CTLA-4 antibodies, may contribute to an enhanced safety profile. Initial results from the phase 1 trial of cadonilimab imply that it might confer superior tolerance compared to the concurrent administration of PD-1 and CTLA-4 inhibitors. Moreover, in June 2022, cadonilimab received marketing authorization in China for the treatment of patients with relapsed or metastatic cervical cancer following progression on platinum-based chemotherapy, based on the encouraging outcomes of a pivotal phase II clinical trial. Just a few years ago, the oncology community firmly dismissed the idea of using immunotherapy to treat brain metastases. Immune checkpoint-targeting monoclonal antibodies have demonstrated significant efficacy against various types of tumors; however, individuals with brain disorders are consistently ineligible for participation in clinical trials. Treatment options for patients with brain metastases include surgical removal, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and their combinations[ 12 ]. Chemotherapy is rarely utilized because of its limited ability to effectively cross the blood-brain barrier[ 13 ]. Historically, individuals with brain metastases (BMs) , as well as their unfavorable prognosis, have typically been ineligible for chemotherapeutic trials. This identical situation has similarly been extended to immunotherapy involving immune checkpoint inhibitors (ICIs) in recent times[ 14 ]. In the past few years , scientists have examined the connections between the immune system and the tumor microenvironment (TME) in brain metastases, leading to the recognition of the central nervous system (CNS) as a separate immunological area rather than an isolated one [ 15 ]. The majority of individuals with brain metastases possess an inflamed tumor microenvironment (TME) that is invaded by tumor-infiltrating lymphocytes (TIL). These lymphocytes frequently exhibit immunosuppressive elements such as programmed death-1 (PD-1) ligand (PD-L1) [ 16 ]. Recently, anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies have emerged, which further endorse their application in immunotherapy. Moreover, these antibodies are utilized in patients with brain metastases and CNS tumors that develop in the brain. Patients diagnosed with non-small cell lung cancer and currently experiencing brain metastases were not included in the clinical trials involving ICI treatment. However, a limited number of retrospective studies have been conducted to compare the effectiveness of ICI therapy with that of alternative treatments in this specific patient population. During a phase II study, pembrolizumab demonstrated a 29.4% intracranial objective response rate (ORR) in 10 of 34 patients with PD-L1 + status. No objective response was observed in the patients without PD-L1 expression. The median overall survival for all patients was 8.9 months, with a 31% survival rate at 2 years [ 18 ]. The role of nivolumab in patients with non-small cell lung cancer (NSCLC) who had asymptomatic brain metastases, either previously treated or untreated, was analyzed by combining the findings from the CheckMate 063 (phase II), 017 (phase III), and 057 (phase III) trials [ 19 ]. During the assessment of patients with previously treated brain metastases at the point of overall disease progression (PD) or the latest tumor evaluation, 33% exhibited no indications of central nervous system (CNS) advancement, whereas 52% did. Nivolumab therapy demonstrated a longer median overall survival (8.4 months) in comparison to docetaxel chemotherapy. According to the Italian expanded access program, nivolumab has proven successful in the treatment of NSCLC patients with brain metastases who are either asymptomatic or have received prior treatment for brain metastases. The program reported an overall response rate (ORR) of 17% and a disease control rate (DCR) of 40% [ 20 ]. Moreover, an exploratory subgroup analysis was conducted on the OAK study [ 21 ], Considering patients who have or have not previously had asymptomatic, treated brain metastases, anti-PD-L1 atezolizumab showed a favorable safety profile, and ezolizumab compared to docetaxel showed a trend in favor of a longer Overall survival (OS) (16 versus 11.9 months). In contrast to docetaxel, atezolizumab delay s the radiological identification of new symptomatic brain metastases[ 22 ]. The effectiveness of ICIs in improving survival in SCLC patients with BMs is uncertain, but ICIs have shown promise in treating other types of tumors, such as NSCLC and melanoma. The study revealed that atezolizumab did not show any survival advantage when compared to chemotherapy alone in IMpower133, which included 35 patients with SCLC and BMs. Similarly, durvalumab, another PD-L1 inhibitor, did not demonstrate any survival benefit. Nevertheless , individuals who receive serplulimab, a PD-1 inhibitor, could potentially experience advantages from ASTRUM-005 (HR, 0.61, 0.33–1.13) [ 23 ], The mPFS and mOS data of this study are much better than those of previous studies were related to cadonilimab plus anlotinib regimen, and also related to the physical condition of enrolled patients and the underlying factors of metastatic tumor. Clinical studies of anti-PD-1/PD-L1 antibodies in combination with antiangiogenic drugs have shown good efficacy and manageable safety in the treatment of various solid tumors, recent studies[ 11 ] showed the superiority of immunization with anlotinib, specifically cadonilimab (PD-1/CTLA-4 bispeci-c antibody) plus anlotinib, in lung cancer. In a previous study , anlotinib was shown to be successful in treating SCLC patients with BMs. It significantly enhanced Progression-free survival (PFS) (3.8 vs 0.8 months, P = 0.001) and Overall survival (OS) (6.1 vs 2.6 months, P = 0.006) when used as a third-line or subsequent treatment, surpassing the effectiveness of a placebo[ 7 ]. The clinical potential of using Anlotinib in combination with ICIs for treating patients Several clinical factors have a negative impact on the outcomes of patients with BMs who receive ICIs.There was a significant association between poor survival rates and patients with more than two metastatic organs [ 24 – 27 ]. As found in our study, high disease burden and PD1 > 50% were independent negative predictors of both OS and PFS. Moreover, prior research has indicated that increased LDH levels can have a detrimental impact on the effectiveness of immunotherapy when it induces T-cell immunosuppression in cancer [ 28 ]. Ankush et al. discovered that individuals diagnosed with melanoma and experiencing BMs who underwent treatment with ICIs exhibited reduced rates of survival when LDH levels were elevated (HR, 2.45, 1.16–5.16, P = 0.019)[ 28 ]. Additionally, patients with multiple BMs have a more unfavorable prognosis than those with only one brain metastases (BMs) [ 28 – 32 ], likely due to LDH-driven metabolic reprogramming of the tumor microenvironment (TME). However, our study did not yield similar findings. The variation in tumor immunogenicity among different tumor types or the absence of a control group in the study, along with the small sample size, may explain this.The results of our study indicate that the use of Cadonilimab combined with anlotinib regimens as Second or post-line therapy in extensive-stage SCLC is effective and feasible in clinical practice. The combination of Cadonilimab (a bispecific antibody targeting PD-1 and CTLA-4) and Anlotinib (a multi-target tyrosine kinase inhibitor) demonstrated a clinically manageable safety profile in patients with extensive-stage small cell lung cancer (SCLC) and brain metastases (BMs). Treatment-related adverse events (TRAEs) of any grade occurred in 69.6% of patients, with grade 3–4 TRAEs observed in 13.0% of cases, consistent with prior reports on immune checkpoint inhibitor (ICI)-Anlotinib combinations [ 28 – 31 ]. Notably, the incidence of grade 3–4 hypertension (6.5%) and thyroid dysfunction (4.3%) exceeded rates observed in advanced non-small cell lung cancer (NSCLC) cohorts treated with PD-1 inhibitors plus Anlotinib (grade 3–4 TRAEs: ~40%) [ 24 ]. This discrepancy may arise from tumor-specific pathophysiological factors, such as SCLC-associated cachexia and aggressive disease biology, or cumulative toxicities from prior therapies. The retrospective design of this study was necessitated by practical and ethical considerations. Rapid clinical need drove the urgency to evaluate the novel combination of Cadonilimab and Anlotinib in extensive-stage SCLC with brain metastases, limited preliminary data on this specific regimen in SCLC made a retrospective analysis a pragmatic first step to generate hypotheses for future prospective validation and these factors further favored a retrospective approach. Our study had several limitations. as a retrospective study, this study has inherent limitations associated with retrospective studies, selection biases were inevitable owing to the nonrandomized and retrospective design of our study, and physician discretion regarding Cadonilimab combined with Anlotinib discontinuation or rechallenge might also compromise the objective of the results. Additionally, the potential power of the study could be limited because of its small size and the absence of a control group,and the results of our study were still needed to be confirmed in more patients in the future. Furthermore, Although our study’s patients were drawn from single institutions, The ethnic and geographic characteristics of this study’s patients were homogeneous. Although the regimens of the combination treatments were not all the same as immune checkpoint inhibitors plus anlotinib in small cell lung cancer, neither the efficacy nor safety was negatively affected. Based on the results of our study, further clinical studies should focus on the effectiveness and safety of Cadonilimab combined with Anlotinib in extensivestage SCLC patients of Metastatic organs ≥ 2, PD1 > 50%, ethnic groups other than East Asian, and those from different geographic areas. CONCLUSIONS Cadonilimab combined with Anlotinib are feasible for extensive-stage SCLC patients with central nervous system for treating BMs considering their efficacy and safety. Metastatic organs ≥ 2 and PD1 > 50% were associated with unfavorable outcomes, and further therapeutic strategies may be needed for these patients. Declarations Ethics Approval and consent to participate This study was conducted in accordance with the amended Declaration of Helsinki and was approved by the Ethics Committee and Institutional Review Boards of the First People's Hospital of Yulin, Guangxi, China (ylsy-IRB-SR-20240652). All patients were exempt from informed consent due to the retrospective nature of this study. Consent for publication All authors have read and approved the content and agree to submit it for consideration for publication in the journal. Availability of data and materials The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare no potential conflicts of interest. Funding This study is supported by the Guangxi Science and Technology Major Project (GuikeAA22096030) Author contributions Hai-Zhen Yi: Led the title selection process, conducted comprehensive clinical evaluations for patient enrollment, significantly contributed to the study design, and was primarily responsible for drafting the manuscript. Additionally, Yi was involved in the final review of the manuscript for publication and proofreading. Wei Lv: Provided support in selecting the title, acquiring ethics committee approval, and offered writing assistance. Hai-Zhen Yi also contributed to choosing the appropriate scales and questionnaires, intellectually revising the manuscript, and participated in the final review and proofreading for publication. Wei Lv, Zhan lin and Hai-Zhen Yi: Collaboratively worked on the proposal, data collection, analysis, and interpretation. They jointly contributed to the initial draft of the manuscript, its design, and the subsequent editing. Jin-Jing Chen and Wei Lv: Both contributed to the ethics committee approval process, offered writing support, and were involved in the final review and proofreading of the manuscript for publication. Hai-Zhen Yi, Zhan Lin and Jin-Jing Chen: As a clinical oncology expert, Chen played a crucial role in selecting the study topic and conducting the research, alongside Yi. Acknowledgements None. Authors' information Jin-Jing Chen, e-mail: [email protected] . Wei Lv, e-mail: [email protected] . Hai-Zhen Yi, E-mail: [email protected] . Zhan Lin, E-mail: [email protected] . References Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7:3. Rusthoven CG, Yamamoto M, Bernhardt D, et al. Evaluation of first-line radiosurgery vs whole-brain radiotherapy for small cell lung cancer brain metastases. JAMA ONCOL. 2020;6:1028. Rittberg R, Banerji S, Kim JO, Rathod S, Dawe DE. Treatment and prevention of brain metastases in small cell lung cancer. Am J Clin Oncol. 2021;44:629–38. Liu SV, Reck M, Mansfield AS, et al. updated overall sur- vival and pd-l1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39:619–30. Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. 2020;38:2369–79. Friebel J, Moritz E, Witkowski M, et al. Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation. Cells. 2021;10(12):3517. 10.3390/cells10123517 . Published 2021 Dec 13. Cheng Y, Wang Q, Li K, et al. P2.12-26 the impact of anlo- tinib for relapsed sclc patients with brain metastases: a subgroup analysis of ALTER 1202. J Thorac Oncol. 2019;14:S823–4. Liu S, Qin T, Liu Z, et al. Anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vas- cular endothelial cells. CELL DEATH DIS. 2020;11:309. Morse MA, Overman MJ, Hartman L, et al. Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability‐High/Mismatch Repair‐Deficient. Metastatic Colorectal Cancer[J] Oncologist. 2019;24. 10.1634/theoncologist.2019-0129 . Motzer RJ, Rini B, Mcdermott DF et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial[J].The lancet oncology, 2019. 10.1016/S1470-2045(19)30413-9 Chen B, Yao W, Li X, et al. A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer. Br J Cancer. 2024;130(3):450–6. 10.1038/s41416-023-02519-0 . Chamberlain MC, Baik CS, Gadi VK, Bhatia S, Chow LQ. Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma. Neurooncology. 2017;19(1):i1–24. 10.1093/neuonc/now197 . [PMC free article] [PubMed] [CrossRef] [Google Scholar]. Ostrom QT, Wright CH, Barnholtz-Sloan JS. Brain metastases: epidemiology. Handb Clin Neurol. 2018;149:27–42. 10.1016/B978 . [PubMed] [CrossRef] [Google Scholar]. -0-12-811161-1. Kaufman HL, Atkins MB, Subedi P, Wu J, Chambers J, Mattingly TJ, et al. The promise of Immuno-oncology implications for defining the value of cancer treatment. J Immunother Cancer. 2019;7:129. 10.1186/s40425-019-0594-0 . [PMC free article] [PubMed] [CrossRef] [Google Scholar]. Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell. 2017;31(3):326–41. 10.1016/j.ccell.2017.02.009 . [PMC free article] [PubMed] [CrossRef] [Google Scholar]. Berghoff AS, Venur VA, Preusser M, Ahluwalia MS. Immune checkpoint inhibitors in brain metastases: from biology to treatment. Am Soc Clin Oncol Educ Book. 2016;35:e116–22. 1200/EDBK_100005. [PubMed] [CrossRef] [Google Scholar]. Wang X, Guo G, Guan H, Yu Y, Lu J, Yu J. Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma. J Exp Clin Cancer Res. 2019;38(1):87. 10.1186/s13046-019-1085-3 . [PMC free article] [PubMed] [CrossRef] [Google Scholar]. Goldberg SB, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R, et al. Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab. J Clin Oncol. 2018;36(Suppl 15):2009. [CrossRef] [Google Scholar]. Goldman JW, Crinò L, Vokes EE, Holgado E, Reckamp KL, Pluzanski A, et al. Nivolumab in patients with advanced NSCLC and central nervous system metastases. J Clin Oncol. 2016;34(Suppl 15):9038. [CrossRef] [Google Scholar]. Crinò L, Bronte G, Bidoli P, Cravero P, Minenza E, Cortesi E, et al. Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer. 2019;129:35–40. [PubMed] [CrossRef] [Google Scholar]. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–65. [PMC free article] [PubMed] [CrossRef] [Google Scholar]. Gadgeel SM, Lukas RV, Goldschmidt J, Conkling P, Park K, Cortinovis D, et al. Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: exploratory analyses of the phase III OAK study. Lung Cancer. 2019;128:105–12. [PubMed] [CrossRef] [Google Scholar]. Cheng Y, Han L, Wu L, et al. Serplulimab, a novel anti-PD-1 antibody, plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small-cell lung cancer: Aninternational randomized phase 3 study. J Clin Oncol. 2022;40:8505. Dou XJ, Ma RY, Ren DW, Liu Q, Yan P. Effectiveness and Safety of Anlotinib Combined with PD-1 Blockades in Patients with Previously Immunotherapy Treated Advanced Non-Small Cell Lung Cancer: A Retrospective Exploratory Study. Lung Cancer (Auckl). 2024;15:29–40. 10.2147/LCTT.S444884 . Published 2024 Mar 25. Wu Y, Zhang T, Liu Y, Wang J, Bi N. Anlotinib combined with durvalumab in a patient with recurrent multifocal brain metastases of small cell lung cancer after definitive concurrent chemoradiotherapy and palliative radiotherapy of the lung and brain: a case report. Ann Palliat Med. 2021;10:2379–86. Skribek M, Rounis K, Makrakis D et al. (2020) Outcome of patients with NSCLC and brain metastases treated with immune checkpoint inhibitors in a real-life setting. Cancers. Hendriks L, Henon C, Auclin E, et al. Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors. J Thorac Oncol. 2019;14:1244–54. Ding J, Karp JE, Emadi A. Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: interplay between hematologic and solid neoplastic clones and their microenvironments. Cancer Biomark. 2017;19:353–63. Mezquita L, Auclin E, Ferrara R, et al. Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. JAMA Oncol. 2018;4:351–7. Hazuka MB, Burleson WD, Stroud DN, Leonard CE, Lillehei KO, Kinzie JJ. Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy. J CLIN ONCOL. 1993;11:369–73. Shi Y, Ji M, Jiang Y, et al. A cohort study of the efficacy and safety of immune checkpoint inhibitors plus Anlotinib versus immune checkpoint inhibitors alone as the treatment of advanced non-small cell lung cancer in the real world. Transl Lung Cancer Res. 2022;11:1051–68. Feng Y, Tang L, Wang H, et al. Immune checkpoint inhibitors combined with angiogenic inhibitors in the treatment of locally advanced or metastatic lung adenocarcinoma patients. Cancer Immunol Immunother; 2022. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5939578","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":444759177,"identity":"706d23be-efd4-4fb3-8253-8baa67fd083b","order_by":0,"name":"Jin-Jing Chen","email":"","orcid":"","institution":"The First People's Hospital of Yulin","correspondingAuthor":false,"prefix":"","firstName":"Jin-Jing","middleName":"","lastName":"Chen","suffix":""},{"id":444759178,"identity":"6677ebc2-44da-46bc-bffb-092af52a6202","order_by":1,"name":"Wei Lv","email":"","orcid":"","institution":"The First People's Hospital of Yulin","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Lv","suffix":""},{"id":444759179,"identity":"c546663b-3343-4b3b-bfe7-804a79904124","order_by":2,"name":"Hai-Zhen Yi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIie2RMUvDQBTHXykcDtdmkyeR5iu8EAgO+TAXhLhE7OhgayCQLgXXlIKfoaPjyUFc4i7oEBGcM5U6KL2s4tGMDveDg4P3//HeuwOwWP4hgxyARHdDfdrraMI8JWW766kMyjoJxsjix9WyTz+tDEeFiu+RB+qImYPDxUhO3x9m4KzzquEsCZi7bBVw8JxjaRhsLCiunwDfqgtCrnc5fd6o6Rn4q7UwKJwoLiogTEMk1F3gcqNKDoJeDypXWxSk4gLSRnF2ULnpujCUQiuYQh9FAr4k4Ukm9WC8Iv3IaNzFv6tD/6uYg1Oef7rfP9HEW+QfbbuLPMc1KBkwAlC32a8C/hnv8PTXNABzY8BisVgssAelZF+dl8KjLAAAAABJRU5ErkJggg==","orcid":"","institution":"The First People's Hospital of Yulin","correspondingAuthor":true,"prefix":"","firstName":"Hai-Zhen","middleName":"","lastName":"Yi","suffix":""},{"id":444759180,"identity":"063a2b2e-5d6e-4cbf-aa88-2d9faa70f4fb","order_by":3,"name":"Zhan Lin","email":"","orcid":"","institution":"The First People's Hospital of Yulin","correspondingAuthor":false,"prefix":"","firstName":"Zhan","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2025-02-01 03:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5939578/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5939578/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81692140,"identity":"dec71900-f0bc-4163-8c2d-e3faa08e02d1","added_by":"auto","created_at":"2025-04-30 11:39:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":174695,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study design.SCLC = small cell lung cancer. BMs = brain metastases.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5939578/v1/9e76c56f68860cc0fdeaca07.png"},{"id":81689477,"identity":"a41df298-699b-4ad1-9e1c-bad84bef931b","added_by":"auto","created_at":"2025-04-30 11:23:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130293,"visible":true,"origin":"","legend":"\u003cp\u003e(A)Pre-treatment and (B)post-treatment of the intracranial lesion in weighted magnetic resonance images.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5939578/v1/400e1812bc161087c44edf04.png"},{"id":81690916,"identity":"8bd65eb0-209a-45f6-bbc3-63a66f36657a","added_by":"auto","created_at":"2025-04-30 11:31:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":23365,"visible":true,"origin":"","legend":"\u003cp\u003eThe intracranial and extracranial changes in SCLC patients with measurable intracranial lesions are presented in the bar graph.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5939578/v1/ff68c0d4dfda99882be3798f.png"},{"id":81690917,"identity":"0e6696c5-9b63-40df-b145-246d50fd3548","added_by":"auto","created_at":"2025-04-30 11:31:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":50654,"visible":true,"origin":"","legend":"\u003cp\u003eOS and PFS based on Kaplan-Meier survival analysis. A: OS; B: PFS.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5939578/v1/e7bccbd767325c5bf2db0f97.png"},{"id":81689478,"identity":"1d0e634d-8a42-4958-a799-74f19d99d7a3","added_by":"auto","created_at":"2025-04-30 11:23:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":68839,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier survival analysis for overall survival (OS) and progression-free survival (PFS) based on significant predictors. OS: A metastatic organs ≥2 vs. without metastatic organs ≥2; C: PD1\u0026gt;50% vs. PD1\u0026lt;50%. PFS: B metastatic organs ≥2 vs. without metastatic organs ≥2; D PD1\u0026gt;50% vs. PD1\u0026lt;50%.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5939578/v1/4557de52392c487d2000a6e3.png"},{"id":90147012,"identity":"4dcaeb9a-19ba-4bf2-8c10-460edb522c3e","added_by":"auto","created_at":"2025-08-29 06:02:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1437577,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5939578/v1/4a567d49-ad03-4cb4-9c90-954b4e291602.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of Cadonilimab plus anlotinib in small cell lung cancer with brain metastases","fulltext":[{"header":"Introduction","content":"\u003cp\u003eApproximately 15% of patients newly diagnosed with lung cancer have small cell lung cancer (SCLC), which is associated with high rates of recurrence and mortality[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Furthermore, individuals afflicted with this fatal illness are at a higher risk of developing brain metastases (BMs) and have limited treatment alternatives, leading to an abnormal survival rate. The median overall survival (OS) of patients with small cell lung cancer (SCLC) typically spans from 3.2 to 8.5 months, with nearly half of these patients developing brain metastases (BMs) during their treatment [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. It is currently recommended that radiotherapy take the form of stereotactic radiation (SRS) or whole-brain radiation (WBRT) in combination with systemic therapy for the treatment of metastatic SCLC patients with BMs[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Owing to the cognitive decline that often accompanies treatment, along with the high relapse rate, patients with asymptomatic and stable BMs should exercise caution when considering brain radiotherapy, as it may cause more harm than good. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eConversely, traditional chemotherapy is not very effective\u003c/span\u003e because of the presence of the blood-brain barrier (BBB).\u003c/p\u003e \u003cp\u003eThe utilization of immune checkpoint inhibitors (ICIs), which tap into the potential of the immune system, has revolutionized advanced cancer treatment. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eAdditionally, extensive-stage SCLC patients could expect a significantly better prognosis with ICIs.\u003c/span\u003e P\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003erior research has demonstrated that the inclusion of PD-L1 inhibitor (atezolizumab) and PD-1 inhibitor (pembrolizumab) in chemotherapy can significantly extend\u003c/span\u003e OS compared to conventional chemotherapy (atezolizumab [HR\u0026thinsp;=\u0026thinsp;0.70, 95%CI 0.54\u0026ndash;0.91, P\u0026thinsp;=\u0026thinsp;0.007] and pembrolizumab [HR\u0026thinsp;=\u0026thinsp;0.80, 95%CI 0.64\u0026ndash;0.98, P\u0026thinsp;=\u0026thinsp;0.0164]) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, subgroup analyses of these randomized trials (KEYNOTE-604, HR\u0026thinsp;=\u0026thinsp;1.07, 95%CI 0.60\u0026ndash;1.91; IMpower133, HR\u0026thinsp;=\u0026thinsp;0.96, 95% CI 0.46\u0026ndash;2.01) did not show that ICIs combined with chemotherapy have any benefit for BMs SCLC patients. The introduction of immune checkpoint inhibitors (ICIs), particularly PD-1/CTLA-4-targeted agents, has transformed the therapeutic landscape of advanced malignancies by enhancing antitumor immunity through blockade of inhibitory T-cell signaling pathways. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eAdditionally, extensive-stage SCLC patients could expect a significantly better prognosis with ICIs.Liu, and Liu SV and Rudin CM have demonstrated that the inclusion of PD-L1 inhibitor (atezolizumab) and PD-1 inhibitor (pembrolizumab) in chemotherapy can significantly extend\u003c/span\u003e overall survival (OS) compared to conventional chemotherapy (atezolizumab [HR\u0026thinsp;=\u0026thinsp;0.70, 95%CI 0.54\u0026ndash;0.91, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007] and pembrolizumab [HR\u0026thinsp;=\u0026thinsp;0.80, 95%CI 0.64\u0026ndash;0.98, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0164]) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, subgroup analyses of these randomized trials (KEYNOTE-604, HR\u0026thinsp;=\u0026thinsp;1.07, 95%CI 0.60\u0026ndash;1.91; IMpower133, HR\u0026thinsp;=\u0026thinsp;0.96, 95% CI 0.46\u0026ndash;2.01) did not show that ICIs combined with chemotherapy have any benefit for BMs SCLC patients. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eTherefore\u003c/span\u003e, the development of novel therapeutic strategies is necessary.\u003c/p\u003e \u003cp\u003eCadonilimab is an IgG1 antibody with a tetravalent bispecific structure and includes a single-chain variable fragment (scFv). \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eThe Fc-null configuration\u003c/span\u003e eliminates antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and cytokine generation. Fc receptor-mediated effector functions, which eliminate or harm PD-1 and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ecytotoxic T-lymphocyte antigen-4 (CTLA-4) expressing lymphocytes, may diminish antitumor efficacy. Cadonilimab exhibits notably reduced toxicities compared with alternative medications in clinical settings. Within a tumor-like environment, the strong affinity of Cadonilimab and its Fc-null structure might enhance drug retention and safety, ultimately leading to effective antitumor outcomes\u003c/span\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eAccording to researchers, the combination of chemotherapy with anlotinib, a new multitargeted tyrosine kinase inhibitor (TKI), enhances progression-free survival and quality of life in SCLC patients with BMs\u003c/span\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eNumerous studies have demonstrated the synergistic effects of immunotherapy and antiangiogenic therapy in advanced solid tumors. Clinical studies of anti-PD-1/PD-L1 antibodies in combination with anti-angiogenic drugs have shown promising efficacy and manageable safety in treating SCLC. Preclinical studies investigating synergies with ICIs suggest that anlotinib has the potential to modify the microenvironment of tumor immunity by suppressing the expression of PD-L1 on endothelial cells in the vascular system and facilitating the infiltration of cells from the innate immune system. Anlotinib, a new orally administered tyrosine kinase inhibitor that targets vascular endothelial, fibroblast, and platelet-derived growth factor receptors, has been approved as a third-line therapy for advanced SCLC in China, However, these studies did not targeted in these studies. In our study, the combination of Anlotinib with Cadonilimab was evaluated as a potential treatment for advanced SCLC patients with BMs.\u003c/span\u003e\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cp\u003eStudy Design\u003c/p\u003e \u003cp\u003eTherefore, this study retrospectively screened advanced-stage small cell lung cancer (SCLC) patients with brain metastases (BMs). who received anlotinib plus cadonilimab in clinical practice from June 2019 to December 2022 at The First People's Hospital of Yulin. included the following inclusion criteria: (1) SCLC diagnosis by pathology or cytology, with extensive-stage SCLC (ES‐SCLC); (2) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; (3) Magnetic resonance imaging of the brain (\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003emagnetic resonance imaging, MRI) contrasted with baseline BMs; (4) patients who had previously undergone systemic therapy but had not been treated with the combination of ICIs and Anlotinib, nor with ICIs or Anlotinib as standalone therapies;not receive Prior intracranial RT\u0026thinsp;=\u0026thinsp;0; (5) Eastern Cooperative Oncology Group (ECOG) performance status of 0\u0026ndash;2 score; (6) measurable target lesions according to RECISTv1.1 criteria to assess the therapeutic response. The exclusion criteria were as follows: (1) diagnosis of one more tumor or a serious disease that might compromise their life; (2) patients receiving systemic treatment other than anlotinib combined with cadonilimab; (3) efficacy assessment data were not available;(4) patients who had received combination therapy before developing BMs or did not have baseline imaging and at least one follow-up scan were not included in the study.\u003c/span\u003e The study complied with the Declaration of Helsinki and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ethe International Good Clinical Practice Guidelines. The Institutional Review Board approved\u003c/span\u003e the waiver of written informed consent[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEndpoints of the study\u003c/p\u003e \u003cp\u003eThe data were collected and analyzed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response Assessment in Neurooncology Brain Metastases (RANO-BM). \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eTumors with a diameter\u003c/span\u003e\u0026thinsp;\u0026ge;\u0026thinsp;10 mm were considered measurable lesions, which were classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). the objective response rate (ORR), \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ewhich represents the ratio of systemic objective responses, was determined by calculating the percentage of extracranial lesions showing complete or partial response. The\u003c/span\u003e DCR or disease control rate was calculated by considering complete response, partial response, and stable disease. Intracranial ORRs and DCRs were calculated \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eaccording to brain lesions.\u003c/span\u003e The Overall survival (OS) period was defined as the period from the start of treatment to the date of death or the date of last imaging. Progression-free survival (PFS) refers to the duration from treatment initiation to the occurrence of intracranial or extracranial progression, death, or censoring at the time of the most recent imaging. Progression-free survival (PFS) of the brain tumor was determined from From the onset of treatment until the end, mortality, or censoring at the final imaging assessment.Patients who experienced extracranial progression first were not included in the calculation of intracranial PFS. Adverse events associated with treatment \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eTRAEs\u003c/span\u003e (\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003etreatment-related adverse events) were documented throughout the\u003c/span\u003e course of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ethe treatment and subsequent monitoring.\u003c/span\u003e\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive summaries were used to analyze clinical and demographic variables, and Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ewere generated. Censored observations were considered for analyses when patients did not experience disease progression or when they reached the end of follow-up.\u003c/span\u003e Clinical characteristics were compared using the chi-square\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed test.\u003c/span\u003e Log-rank tests were used to compare survival between different groups, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eand we investigated the correlation between survival and clinical factors\u003c/span\u003e using both univariate and Multivariable Cox regressions. SPSS18 was used for all analyses, was the consideration for \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe study profile is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, A \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003etotal of 46 patients with advanced small cell lung cancer (SCLC) and brain metastases (BMs) received treatment with a combination of Cadonilimab plus Anlotinib.\u003c/span\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the fundamental clinical and pathological characteristics \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eof these patients. The majority of the patients\u003c/span\u003e (approximately 65.2%) were below the age of 60 and exhibited \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ean Eastern Cooperative Oncology Group (ECOG) performance status of 0\u0026ndash;1, which accounted for 87% of the total.32.6% of patients had metastatic disease affecting more than two organs.\u003c/span\u003e Of the total number of patients, 20 (43.5%) experienced brain lesions with symptoms, while 34 patients (73.9%) had multiple brain lesions. Additionally, 63.1% of the subjects attained lactate dehydrogenase levels(LDH) surpassing the upper limit of normal (ULN).36.9% of patients achieved higher LDH levels than the ULN.\u003c/p\u003e \u003cp\u003e \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 characteristics of the study population.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; 65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30(65.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(34.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e38(82.6%)\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(17.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG-PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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 \u003cp\u003e40(87%)\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(13%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(60.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoked\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18(39.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emetastatic organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e31(67.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(32.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of BMs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12(26.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34(73.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptomatic BMs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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 \u003cp\u003e26(56.5%)\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(43.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior lines of systemic therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(23.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37(80.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior intracranial RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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 \u003cp\u003e46\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior ICIs treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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 \u003cp\u003e46\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcurrent intracranial RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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 \u003cp\u003e46\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; ULN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29(63.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; ULN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(36.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD1/PDL\u0026minus;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\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\u003eEvaluating effectiveness\u003c/p\u003e \u003cp\u003eThe systemic response\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003es of all 46 patients\u003c/span\u003e were assessed. The overall response rate (ORR) and disease control rate (DCR) for these patients were 45.7% and 86.9%, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003erespectively(\u003c/span\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e). It contains a summary of the treatment response to Cadonilimab plus Anlotinib, evaluated using RECIST 1.1 criteria.RANO-BM criteria were also used to assess intracranial response, which was\u003c/span\u003e 41.3% (1 CR, 18 PR) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows typical MRI scans of a complete response in brain lesions before and after therapy; patients with detectable lesions are depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, illustrating alterations both inside and outside the skull. In the overall study, In the overall study population, the median overall survival (OS) was found to be 19.3 months(95% CI, 17.4\u0026ndash;21.1 months), and the median progression-free survival (PFS) was 14.2 months(95% CI, 12.5\u0026ndash;15.9 months) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e,A,B).\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\u003eEfficacy of Cadonilimab plus Anlotinib\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN (%)(N\u0026thinsp;=\u0026thinsp;46)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eResponse to Cadonilimab plus Anlotinib treatment, measured using the RECIST 1.1 criteria.\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(45.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40(86.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eThe intracranial efficacy of Cadonilimab plus Anlotinib was evaluated in patients with measurable lesions per RANO-BM.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduction of steroid treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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 \u003cp\u003e10\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable or improved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2/FLAIR signal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable or decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19(41.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42(91.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eFLAIR Fluid attenuated inversion recovery; CR Complete response; PR Partial response; SD Stable disease; PD Progression disease; ORR Objective response rate; DCR Disease control rate\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePrognosis\u003c/p\u003e \u003cp\u003eIn addition, we investigated the impact of various factors on survival using univariate and multivariate Cox models. The multivariate analysis encompassed all variables that showed significant correlations and trends (\u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in the univariate analysis. Multivariable Cox model analysis for overall survival (OS) included smoking, number of brain metastases (BMs), and number of metastatic organs. PD1\u0026thinsp;\u0026lt;\u0026thinsp;50% (HR\u0026thinsp;=\u0026thinsp;4.83, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) or metastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2 (HR\u0026thinsp;=\u0026thinsp;2.71, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.036) were independent positive predictors of Overall survival (OS) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For Progression-free survival (PFS), patients with PD1\u0026thinsp;\u0026gt;\u0026thinsp;50% (\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ehazard ratio [HR]\u0026thinsp;=\u0026thinsp;4.385\u003c/span\u003e, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.001) or metastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2 (HR\u0026thinsp;=\u0026thinsp;0.245, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.04) had worse outcome\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003es (\u003c/span\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e). Subsequently, Kaplan-Meier survival plots were generated based on the significant prognostic factors identified in the\u003c/span\u003e multivariate Cox model analysis. Patients with more than two metastatic organs (10.9 vs. 20.7 months, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.001) or PD1 expression less than 50% (13.6 vs. 21.9 months, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.000) exhibited significantly shorter overall survival compared to their counterparts, as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA-D. Furthermore, the presence of two or more metastatic organs (7.3 vs. 15.2 months, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.000) or a PD1 level exceeding 50% (9.0 vs. 16.6 months, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.000) exhibited a significant correlation with reduced intracranial PFS, as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA-D).\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\u003eUnivariate and multivariable Cox regression analysis for OS\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=\"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 \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 \u003cdiv align=\"char\" char=\".\" 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\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate survival analyses of OS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariable survival analyses of OS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95%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\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\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;60\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\u0026ge;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.595\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.273\u0026ndash;1.297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.192\u003c/p\u003e \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\u003eSex\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\u003eMale\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.965\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.855\u0026ndash;10.277\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.087\u003c/p\u003e \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\u003eECOG\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\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\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.643\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.556\u0026ndash;4.850\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.920\u003c/p\u003e \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\u003eSmoking history\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\u003eNever\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\u003eSmoked\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.725\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.355\u0026ndash;1.481\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.378\u003c/p\u003e \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\u003emetastatic organs\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;2\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\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.014\u0026ndash;0.201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.034\u0026ndash;0.302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of BMs\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\u003eSingle\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\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.885\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.288\u0026ndash;2.720\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.831\u003c/p\u003e \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\u003eSymptomatic BMs\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\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\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.683\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.354\u0026ndash;1.316\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.254\u003c/p\u003e \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\u003eLDH\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; ULN\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\u0026ge; ULN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.383\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.679\u0026ndash;2.834\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.396\u003c/p\u003e \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\u003ePD1\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\u0026gt;\u0026thinsp;50%\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;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.939\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.428\u0026ndash;21.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.313\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.398\u0026ndash;7.853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.007\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\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariable Cox regression analysis for 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=\"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 \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 \u003cdiv align=\"char\" char=\".\" 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\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate survival analyses of PFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariable survival analyses of PFS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95%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\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\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; 60\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\u0026ge; 60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.410\u0026ndash;1.978\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.794\u003c/p\u003e \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\u003eSex\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\u003eMale\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.922\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.615\u0026ndash;6.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.261\u003c/p\u003e \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\u003eECOG-PS\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\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\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.437\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.494\u0026ndash;4.181\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.506\u003c/p\u003e \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\u003eSmoking history\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\u003eNever\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\u003eSmoked\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.485\u0026ndash;2.196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.935\u003c/p\u003e \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\u003emetastatic organs\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;2\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\u0026ge;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.059\u0026ndash;0.563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.245\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.094\u0026ndash;0.635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of BMs\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\u003eSingle\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\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.290\u0026ndash;2.511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.773\u003c/p\u003e \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\u003eSymptomatic BMs\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\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\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.960\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.505\u0026ndash;1.824\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.901\u003c/p\u003e \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\u003eLDH\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; ULN\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\u0026ge; ULN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.597\u0026ndash;2.423\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.604\u003c/p\u003e \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\u003ePD1\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\u0026gt;\u0026thinsp;50%\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;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.818\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.318\u0026ndash;14.525\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.385\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.829\u0026ndash;10.515\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" 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\u003e \u003c/p\u003e \u003cp\u003eSafety\u003c/p\u003e \u003cp\u003eAn analysis of TRAEs \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eassociated with\u003c/span\u003e cadonilimab plus anlotinib is shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Of the 46 patients, 26 (56.5%, n\u0026thinsp;=\u0026thinsp;26) experienced grade 1\u0026ndash;2 treatment-related adverse events (TRAEs), while 6 patients (13%) encountered grade 3\u0026ndash;4 TRAEs.As a whole, hypertension accounted for 52%, hypertension accounted for 50%, and leukemia \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eaccounted for 30.4%. Among the grade 3\u0026ndash;4 TRAEs, Hypertension accounted for the highest occurrence rate (6.5%, n\u0026thinsp;=\u0026thinsp;3), followed by thyroid dysfunction (4.3%, n\u0026thinsp;=\u0026thinsp;2). Leukopenia, Hepatic dysfunction, and\u003c/span\u003e positive urinary protein \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ewere ranked third, with an occurrence rate of 2.2% (n\u0026thinsp;=\u0026thinsp;1).\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment-related adverse events\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=\"left\" 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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdverse event,N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003epatients (n\u0026thinsp;=\u0026thinsp;46)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 1\u0026ndash;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGrade 3\u0026ndash;4\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny adverse event\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32(69.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26(56.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6(13.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroid dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24(52.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22(47.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(4.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20(58.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(6.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(30.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16(34.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(19.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8(17.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand-foot skin reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(13.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6(13.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive urinary protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDental ulcer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2(4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2(4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the realm of small-cell lung cancer (SCLC), no parallel research has been conducted to evaluate the efficacy of Cadonilimab combined with anlotinib for brain metastases (BMs) in the central nervous system. While intracranial radiotherapy is widely employed for \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ebrain metastases (BMs)\u003c/span\u003e treatment, it has detrimental effects on the surrounding healthy tissues, which can impair the patient\u0026rsquo;s cognitive function, memory, and intellectual capacity. The search for novel therapeutic approaches is crucial, as the majority of SCLC patients with BMs, even after undergoing systemic radiotherapy, continue to face recurrence or develop resistance to treatment. To the best of our knowledge, this study is the first to report the use of Cadonilimab combined with anlotinib for the treatment of extensive SCLC with brain metastases (BMs) in real-world clinical practice. The use of Cadonilimab combined with anlotinib regimens provided a 19.3 months of Overall survival (OS) and 14.2 months of Progression-free survival (PFS). This regimen showed significant efficacy within the central nervous system. We found that a metastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2 and PD1\u0026thinsp;\u0026gt;\u0026thinsp;50% concentration were independent predictive factors associated with shorter OS in the studied patients. Thyroid dysfunction and Hypertension accounted for most of the treatment-related AEs in this study; these AEs were manageable, and no treatment-related deaths occurred.\u003c/p\u003e \u003cp\u003eIn recent years, there has been significant advancement in immuno-oncology (IO) treatments, with monoclonal antibodies (mAbs) targeting programmed cell death-1 (PD-1) now recognized as the standard treatment for various types of cancer. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eNumerous combinations of anti-PD-1 antibodies have been explored to enhance the\u003c/span\u003e efficacy of PD-1 monotherapy. Promising research has shown significant improvements in \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ethe efficacy\u003c/span\u003e of combination therapy involving anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-PD-1 antibodies \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003efor difficult-to-treat cancer types. However\u003c/span\u003e, its use in kidney, gastric, and lung cancers has been restricted because of its toxic effects. Cadonilimab represents a humanized IgG1 bispecific antibody, engineered for enhanced functionality via the Akeso Tetrabody platform. Yet, it lacks the conventional Fc effector functions such as antibody-dependent cellular cytotoxicity, phagocytosis, and complement-mediated cytotoxicity. This dual-targeting agent simultaneously engages PD-1 and CTLA-4, thereby inhibiting the PD-1/PD-L1, PD-1/PD-L2, CTLA-4/B7.1, and CTLA-4/B7.2 interactions. Preliminary investigative findings in preclinical research suggest that cadonilimab\u0026rsquo;s selective accumulation within tumor tissues, in contrast to standard anti-PD-1 and anti-CTLA-4 antibodies, may contribute to an enhanced safety profile. Initial results from the phase 1 trial of cadonilimab imply that it might confer superior tolerance compared to the concurrent administration of PD-1 and CTLA-4 inhibitors. Moreover, in June 2022, cadonilimab received marketing authorization in China for the treatment of patients with relapsed or metastatic cervical cancer following progression on platinum-based chemotherapy, based on the encouraging outcomes of a pivotal phase II clinical trial. Just a few years ago, the oncology community firmly dismissed the idea of using immunotherapy to treat brain metastases. Immune checkpoint-targeting monoclonal antibodies have demonstrated significant efficacy against various types of tumors; however, individuals with brain disorders are consistently ineligible for participation in clinical trials. Treatment options for patients with brain metastases include surgical removal, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and their combinations[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Chemotherapy is rarely utilized because of its limited ability to effectively cross the blood-brain barrier[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Historically, individuals with \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ebrain metastases (BMs)\u003c/span\u003e, as well as their unfavorable prognosis, have typically been ineligible for chemotherapeutic trials. This identical situation has similarly been extended to immunotherapy involving immune checkpoint inhibitors (ICIs) in recent times[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eIn the past few years\u003c/span\u003e, scientists have examined the connections between the immune system and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ethe tumor microenvironment (TME) in brain metastases, leading to the recognition of the central nervous system (CNS) as a separate immunological area rather than an isolated one\u003c/span\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eThe majority of individuals with brain metastases possess an inflamed tumor microenvironment (TME) that is invaded by tumor-infiltrating lymphocytes (TIL). These lymphocytes frequently exhibit immunosuppressive elements such as programmed death-1 (PD-1) ligand (PD-L1)\u003c/span\u003e [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eRecently, anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies have emerged, which further endorse their application in immunotherapy. Moreover, these antibodies are utilized in patients with brain metastases and CNS tumors that develop in the brain. Patients diagnosed with non-small cell lung cancer and currently experiencing brain metastases were not included in the clinical trials involving ICI treatment. However, a limited number of retrospective studies have been conducted to compare the effectiveness of ICI therapy with that of alternative treatments in this specific patient population. During a phase II study, pembrolizumab demonstrated a 29.4% intracranial objective response rate (ORR) in 10 of 34 patients with PD-L1\u0026thinsp;+\u0026thinsp;status.\u003c/span\u003e No objective response \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ewas observed in the patients without PD-L1\u003c/span\u003e expression. The median overall survival for all patients was 8.9 months, with a 31% survival rate at 2 years [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The role of nivolumab in patients with non-small cell lung cancer (NSCLC) who had asymptomatic brain metastases, either previously treated or untreated, was analyzed by combining the findings from \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ethe CheckMate 063 (phase II), 017 (phase III), and 057 (phase III) trials\u003c/span\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eDuring the assessment of patients with previously treated brain metastases at the point of overall disease progression (PD) or the latest tumor evaluation, 33% exhibited no indications of central nervous system (CNS) advancement, whereas 52% did. Nivolumab therapy demonstrated a longer median overall survival (8.4 months) in comparison to docetaxel chemotherapy. According to the Italian expanded access program, nivolumab has proven\u003c/span\u003e successful in the treatment of NSCLC patients with brain metastases who are either asymptomatic or have received prior treatment for brain metastases. The program reported an overall response rate (ORR) of 17% and a disease control rate (DCR) of 40% [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Moreover, an exploratory subgroup analysis was conducted on the OAK study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], Considering patients who have or have not previously had asymptomatic, treated brain metastases, anti-PD-L1 atezolizumab showed a favorable safety profile, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eand\u003c/span\u003e ezolizumab compared to docetaxel showed a trend in favor of a longer Overall survival (OS) (16 versus 11.9 months). \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eIn contrast to docetaxel, atezolizumab delay\u003c/span\u003es the radiological identification of new symptomatic brain metastases[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe effectiveness of ICIs in improving survival in SCLC patients with BMs is uncertain, but ICIs have shown promise in treating other types of tumors, such as NSCLC and melanoma. The study revealed that atezolizumab did not show any survival advantage when compared to chemotherapy alone in IMpower133, which included 35 patients with SCLC and BMs. Similarly, durvalumab, another PD-L1 inhibitor, did not demonstrate any survival \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ebenefit. Nevertheless\u003c/span\u003e, individuals who receive serplulimab, a PD-1 inhibitor, could potentially experience advantages from ASTRUM-005 (HR, 0.61, 0.33\u0026ndash;1.13) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], The mPFS and mOS data of this study are much better than those of previous studies were related to cadonilimab plus anlotinib regimen, and also related to the physical condition of enrolled patients and the underlying factors of metastatic tumor. Clinical studies of anti-PD-1/PD-L1 antibodies in combination with antiangiogenic drugs have shown good efficacy and manageable safety in the treatment of various solid tumors, recent studies[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] showed the superiority of immunization with anlotinib, specifically cadonilimab (PD-1/CTLA-4 bispeci-c antibody) plus anlotinib, in lung cancer. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eIn a previous study\u003c/span\u003e, anlotinib was shown to be successful in treating SCLC patients with BMs. It significantly enhanced Progression-free survival (PFS) (3.8 vs 0.8 months, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.001) and Overall survival (OS) (6.1 vs 2.6 months, \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.006) when used as a third-line or subsequent treatment, surpassing the effectiveness of a placebo[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The clinical potential of using Anlotinib in combination with ICIs for treating patients Several clinical factors have a negative impact on the outcomes of patients with BMs who receive ICIs.There was a significant association between poor survival rates and patients with more than two metastatic organs [\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. As found in our study, high disease burden and PD1\u0026thinsp;\u0026gt;\u0026thinsp;50% were independent negative predictors of both OS and PFS. Moreover, prior research has indicated that increased LDH \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003elevels can have a detrimental impact on the effectiveness of immunotherapy when it induces T-cell immunosuppression in cancer\u003c/span\u003e [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eAnkush et al. discovered that individuals diagnosed with melanoma and experiencing BMs\u003c/span\u003e who underwent treatment with ICIs exhibited reduced rates of survival when LDH levels were elevated (HR, 2.45, 1.16\u0026ndash;5.16, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019)[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Additionally, patients with multiple BMs have a more unfavorable prognosis than those with only one \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ebrain metastases (BMs)\u003c/span\u003e[\u003cspan additionalcitationids=\"CR29 CR30 CR31\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], likely due to LDH-driven metabolic reprogramming of the tumor microenvironment (TME). However, our study did not yield similar findings. The variation in tumor immunogenicity among different tumor types or the absence of a control group in the study, along with the small sample size, may explain this.The results of our study indicate that the use of Cadonilimab combined with anlotinib regimens as Second or post-line therapy in extensive-stage SCLC is effective and feasible in clinical practice.\u003c/p\u003e \u003cp\u003eThe combination of Cadonilimab (a bispecific antibody targeting PD-1 and CTLA-4) and Anlotinib (a multi-target tyrosine kinase inhibitor) demonstrated a clinically manageable safety profile in patients with extensive-stage small cell lung cancer (SCLC) and brain metastases (BMs). Treatment-related adverse events (TRAEs) of any grade occurred in 69.6% of patients, with grade 3\u0026ndash;4 TRAEs observed in 13.0% of cases, consistent with prior reports on immune checkpoint inhibitor (ICI)-Anlotinib combinations [\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Notably, the incidence of grade 3\u0026ndash;4 hypertension (6.5%) and thyroid dysfunction (4.3%) exceeded rates observed in advanced non-small cell lung cancer (NSCLC) cohorts treated with PD-1 inhibitors plus Anlotinib (grade 3\u0026ndash;4 TRAEs: ~40%) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This discrepancy may arise from tumor-specific pathophysiological factors, such as SCLC-associated cachexia and aggressive disease biology, or cumulative toxicities from prior therapies.\u003c/p\u003e \u003cp\u003e The retrospective design of this study was necessitated by practical and ethical considerations. Rapid clinical need drove the urgency to evaluate the novel combination of Cadonilimab and Anlotinib in extensive-stage SCLC with brain metastases, limited preliminary data on this specific regimen in SCLC made a retrospective analysis a pragmatic first step to generate hypotheses for future prospective validation and these factors further favored a retrospective approach. Our study had several limitations. as a retrospective study, this study has inherent limitations associated with retrospective studies, selection biases were inevitable owing to the nonrandomized and retrospective design of our study, and physician discretion regarding Cadonilimab combined with Anlotinib discontinuation or rechallenge might also compromise the objective of the results. Additionally, the potential power of the study could be limited because of its small size and the absence of a control group,and the results of our study were still needed to be confirmed in more patients in the future. Furthermore, Although our study\u0026rsquo;s patients were drawn from single institutions, The ethnic and geographic characteristics of this study\u0026rsquo;s patients were homogeneous. Although the regimens of the combination treatments were not all the same as immune checkpoint inhibitors plus anlotinib in small cell lung cancer, neither the efficacy nor safety was negatively affected. Based on the results of our study, further clinical studies should focus on the effectiveness and safety of Cadonilimab combined with Anlotinib in extensivestage SCLC patients of Metastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2, PD1\u0026thinsp;\u0026gt;\u0026thinsp;50%, ethnic groups other than East Asian, and those from different geographic areas.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eCadonilimab combined with Anlotinib are feasible for extensive-stage SCLC patients with central nervous system for treating BMs considering their efficacy and safety. Metastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2 and PD1\u0026thinsp;\u0026gt;\u0026thinsp;50% were associated with unfavorable outcomes, and further therapeutic strategies may be needed for these patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the amended Declaration of Helsinki and was approved by the Ethics Committee and Institutional Review Boards of the First People\u0026apos;s Hospital of Yulin, Guangxi, China (ylsy-IRB-SR-20240652). All patients were exempt from informed consent due to the retrospective nature of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the content and agree to submit it for consideration for publication in the journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no potential conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supported by the Guangxi Science and Technology Major Project (GuikeAA22096030)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Hai-Zhen Yi: Led the title selection process, conducted comprehensive clinical evaluations for patient enrollment, significantly contributed to the study design, and was primarily responsible for drafting the manuscript. Additionally, Yi was involved in the final review of the manuscript for publication and proofreading. Wei Lv: Provided support in selecting the title, acquiring ethics committee approval, and offered writing assistance. Hai-Zhen Yi also contributed to choosing the appropriate scales and questionnaires, intellectually revising the manuscript, and participated in the final review and proofreading for publication. Wei Lv, Zhan lin and Hai-Zhen Yi: Collaboratively worked on the proposal, data collection, analysis, and interpretation. They jointly contributed to the initial draft of the manuscript, its design, and the subsequent editing. Jin-Jing Chen and Wei Lv: Both contributed to the ethics committee approval process, offered writing support, and were involved in the final review and proofreading of the manuscript for publication. Hai-Zhen Yi, Zhan Lin and Jin-Jing Chen: As a clinical oncology expert, Chen played a crucial role in selecting the study topic and conducting the research, alongside Yi.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJin-Jing Chen, e-mail: [email protected].\u003c/p\u003e\n\u003cp\u003eWei Lv, e-mail:[email protected].\u003c/p\u003e\n\u003cp\u003eHai-Zhen Yi, E-mail: [email protected].\u003c/p\u003e\n\u003cp\u003eZhan Lin, E-mail: [email protected].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7:3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRusthoven CG, Yamamoto M, Bernhardt D, et al. Evaluation of first-line radiosurgery vs whole-brain radiotherapy for small cell lung cancer brain metastases. JAMA ONCOL. 2020;6:1028.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRittberg R, Banerji S, Kim JO, Rathod S, Dawe DE. Treatment and prevention of brain metastases in small cell lung cancer. Am J Clin Oncol. 2021;44:629\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu SV, Reck M, Mansfield AS, et al. updated overall sur- vival and pd-l1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39:619\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRudin CM, Awad MM, Navarro A, et al. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. 2020;38:2369\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriebel J, Moritz E, Witkowski M, et al. Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation. Cells. 2021;10(12):3517. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cells10123517\u003c/span\u003e\u003cspan address=\"10.3390/cells10123517\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Published 2021 Dec 13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng Y, Wang Q, Li K, et al. P2.12-26 the impact of anlo- tinib for relapsed sclc patients with brain metastases: a subgroup analysis of ALTER 1202. J Thorac Oncol. 2019;14:S823\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu S, Qin T, Liu Z, et al. Anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vas- cular endothelial cells. CELL DEATH DIS. 2020;11:309.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorse MA, Overman MJ, Hartman L, et al. Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability‐High/Mismatch Repair‐Deficient. Metastatic Colorectal Cancer[J] Oncologist. 2019;24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1634/theoncologist.2019-0129\u003c/span\u003e\u003cspan address=\"10.1634/theoncologist.2019-0129\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotzer RJ, Rini B, Mcdermott DF et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial[J].The lancet oncology, 2019.\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1470-2045(19)30413-9\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(19)30413-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen B, Yao W, Li X, et al. A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer. Br J Cancer. 2024;130(3):450\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41416-023-02519-0\u003c/span\u003e\u003cspan address=\"10.1038/s41416-023-02519-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChamberlain MC, Baik CS, Gadi VK, Bhatia S, Chow LQ. Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma. Neurooncology. 2017;19(1):i1\u0026ndash;24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/neuonc/now197\u003c/span\u003e\u003cspan address=\"10.1093/neuonc/now197\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. [PMC free article] [PubMed] [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOstrom QT, Wright CH, Barnholtz-Sloan JS. Brain metastases: epidemiology. Handb Clin Neurol. 2018;149:27\u0026ndash;42. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/B978\u003c/span\u003e\u003cspan address=\"10.1016/B978\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. [PubMed] [CrossRef] [Google Scholar]. -0-12-811161-1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaufman HL, Atkins MB, Subedi P, Wu J, Chambers J, Mattingly TJ, et al. The promise of Immuno-oncology implications for defining the value of cancer treatment. J Immunother Cancer. 2019;7:129. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s40425-019-0594-0\u003c/span\u003e\u003cspan address=\"10.1186/s40425-019-0594-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. [PMC free article] [PubMed] [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell. 2017;31(3):326\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ccell.2017.02.009\u003c/span\u003e\u003cspan address=\"10.1016/j.ccell.2017.02.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. [PMC free article] [PubMed] [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerghoff AS, Venur VA, Preusser M, Ahluwalia MS. Immune checkpoint inhibitors in brain metastases: from biology to treatment. Am Soc Clin Oncol Educ Book. 2016;35:e116\u0026ndash;22. 1200/EDBK_100005. [PubMed] [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Guo G, Guan H, Yu Y, Lu J, Yu J. Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma. J Exp Clin Cancer Res. 2019;38(1):87. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13046-019-1085-3\u003c/span\u003e\u003cspan address=\"10.1186/s13046-019-1085-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. [PMC free article] [PubMed] [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldberg SB, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R, et al. Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab. J Clin Oncol. 2018;36(Suppl 15):2009. [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldman JW, Crin\u0026ograve; L, Vokes EE, Holgado E, Reckamp KL, Pluzanski A, et al. Nivolumab in patients with advanced NSCLC and central nervous system metastases. J Clin Oncol. 2016;34(Suppl 15):9038. [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrin\u0026ograve; L, Bronte G, Bidoli P, Cravero P, Minenza E, Cortesi E, et al. Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer. 2019;129:35\u0026ndash;40. [PubMed] [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255\u0026ndash;65. [PMC free article] [PubMed] [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGadgeel SM, Lukas RV, Goldschmidt J, Conkling P, Park K, Cortinovis D, et al. Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: exploratory analyses of the phase III OAK study. Lung Cancer. 2019;128:105\u0026ndash;12. [PubMed] [CrossRef] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng Y, Han L, Wu L, et al. Serplulimab, a novel anti-PD-1 antibody, plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small-cell lung cancer: Aninternational randomized phase 3 study. J Clin Oncol. 2022;40:8505.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDou XJ, Ma RY, Ren DW, Liu Q, Yan P. Effectiveness and Safety of Anlotinib Combined with PD-1 Blockades in Patients with Previously Immunotherapy Treated Advanced Non-Small Cell Lung Cancer: A Retrospective Exploratory Study. Lung Cancer (Auckl). 2024;15:29\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/LCTT.S444884\u003c/span\u003e\u003cspan address=\"10.2147/LCTT.S444884\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Published 2024 Mar 25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, Zhang T, Liu Y, Wang J, Bi N. Anlotinib combined with durvalumab in a patient with recurrent multifocal brain metastases of small cell lung cancer after definitive concurrent chemoradiotherapy and palliative radiotherapy of the lung and brain: a case report. Ann Palliat Med. 2021;10:2379\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSkribek M, Rounis K, Makrakis D et al. (2020) Outcome of patients with NSCLC and brain metastases treated with immune checkpoint inhibitors in a real-life setting. Cancers.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHendriks L, Henon C, Auclin E, et al. Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors. J Thorac Oncol. 2019;14:1244\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDing J, Karp JE, Emadi A. Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: interplay between hematologic and solid neoplastic clones and their microenvironments. Cancer Biomark. 2017;19:353\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMezquita L, Auclin E, Ferrara R, et al. Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. JAMA Oncol. 2018;4:351\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHazuka MB, Burleson WD, Stroud DN, Leonard CE, Lillehei KO, Kinzie JJ. Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy. J CLIN ONCOL. 1993;11:369\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi Y, Ji M, Jiang Y, et al. A cohort study of the efficacy and safety of immune checkpoint inhibitors plus Anlotinib versus immune checkpoint inhibitors alone as the treatment of advanced non-small cell lung cancer in the real world. Transl Lung Cancer Res. 2022;11:1051\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeng Y, Tang L, Wang H, et al. Immune checkpoint inhibitors combined with angiogenic inhibitors in the treatment of locally advanced or metastatic lung adenocarcinoma patients. Cancer Immunol Immunother; 2022.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Small cell lung cancer, Cadonilimab, Anlotinib, Brain metastases, PD-1","lastPublishedDoi":"10.21203/rs.3.rs-5939578/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5939578/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: This study aimed to evaluate the efficiency and safety of Cadonilimab and Anlotinib pairing in individuals diagnosed with small cell lung cancer (SCLC) and brain metastases (BMs).\u003c/p\u003e\n\u003cp\u003eMethods: A review was performed on individuals who were diagnosed with small cell lung cancer (SCLC) and had central nervous system (CNS) metastases confirmed via magnetic resonance imaging (MRI) of the brain.We assessed the treatment response of Cadonilimab plus Anlotinib using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response assessment in neuro-oncology brain metastases (RANO-BM) for evaluating solid tumors and neuro-oncology brain metastases, respectively.The patients' prognosis was determined using Kaplan-Meier analysis and Cox regression analysis.\u003c/p\u003e\n\u003cp\u003eFindings: The study initially included 46 patients diagnosed with SCLC who presented with brain metastases (BMs). According to the RANO-BM criteria, intracranial lesions showed an objective response rate (ORR) of 41.3%. The median overall survival (OS) was observed to be 19.3 months (95% CI, 17.4-21.1 months). \u0026nbsp;Multivariate Cox regression analysis showed that having a PD1 level below 50% (HR=4.83, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) or having two or more metastatic organs (HR = 2.71, \u003cem\u003eP\u003c/em\u003e = 0.036) were independent factors that positively predicted overall survival of all the patients, 86.9% experienced treatment-related adverse events (TRAEs) associated with the treatment, while 17.4% reported severe TRAEs of grade3-4.\u003c/p\u003e\n\u003cp\u003eImplications: According to our results, the combination of Cadonilimab and Anlotinib appears to be a promising treatment option for SCLC patients with brain metastases.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of Cadonilimab plus anlotinib in small cell lung cancer with brain metastases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-30 11:23:45","doi":"10.21203/rs.3.rs-5939578/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"18b2fe8c-64e6-4b2c-a554-84edc4145746","owner":[],"postedDate":"April 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-29T05:54:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-30 11:23:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5939578","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5939578","identity":"rs-5939578","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}