Treatment of Small Cell Lung Cancer patients with brain metastases shows promise with the combination therapy of Cardonilumab and Anlotinib

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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 cardonilumab plus anlotinib using RECIST 1.1 and 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. Results The study included 46 individuals diagnosed with brain metastases (BMs) at the beginning. According to RANO-BM criteria, the intracranial lesions showed an objective response rate (ORR) of 80.4%.Additionally, the median overall survival (OS) was observed to be 19.3 months (95% CI, 17.4–21.1 months).The analysis of multivariate Cox regression 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.Out of all the patients, 86.9% experienced adverse events associated with the treatment, while 17.4% reported severe TRAEs of grade3-4. Conclusions According to our results, the combination of cardonilumab and anlotinib appears to be a promising treatment option for SCLC patients with brain metastases. Small cell lung cancer Cardonilumab Anlotinib Brain metastases Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The occurrence of SCLC in Those newly diagnosed with lung cancer is approximately 15%, and it is associated with high rates of recurrence and mortality[ 1 ].Furthermore, individuals afflicted by this fatal illness are at a higher risk of developing brain metastases (BMs) and have limited treatment alternatives, leading to an exceptionally poor survival rate.The median overall survival (OS) of SCLC patients ranged from 3.2 to 8.5 months with nearly half developing BMs during 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 ].Due 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 do more harm than good. Conversely, traditional chemotherapy is not very effective due to the presence of the blood-brain barrier (BBB). Advanced cancer treatment has been revolutionized by utilizing immune checkpoint inhibitors (ICIs), which tap into the potential of the immune system.Additionally, extensive-stage SCLC patients could expect a significantly better prognosis with the use of ICIs.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 the overall survival (OS) compared to conventional chemotherapy (atezolizumab [HR = 0.70, 95%CI 0.54–0.91, P = 0.007], 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 development of novel therapeutic strategies is therefore necessary. AK104, also known as cadonilimab, is an IgG1 antibody that has a tetravalent bispecific structure and includes a single-chain variable fragment (scFv). The Fc-null configuration eradicates antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and cytokine generation. The Fc receptor-mediated effector functions, which eliminate or harm PD-1 and CTLA-4 expressing lymphocytes, may diminish the antitumor efficacy. Cadonilimab exhibits notably reduced toxicities compared to 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 anti-tumor outcomes[ 6 ].According to the researchers, the combination of chemotherapy with anlotinib, a new multitargeted tyrosine kinase inhibitor (TKI), enhanced the progression-free survival and quality of life in SCLC patients with BMs[ 7 ].Preclinical studies investigating the 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. Several studies have shown that Anlotinib combined with ICIs could be effective in treating advanced SCLC patients. However, BM patients were not targeted in these studies. For our study, the combination of Anlotinib with Cadonilimab (AK104) is being evaluated as a potential treatment for advanced SCLC patients with BMs. Methods Patients Between June 2019 and December 2022, The First People's Hospital of Yulin conducted a retrospective evaluation for all patients diagnosed with advanced-stage small cell lung cancer (SCLC) with brain metastases (BMs).The research involved individuals with metastatic small cell lung cancer (SCLC) who were administered AK104 (cadonilimab) and anlotinib concurrently.included the following The inclusion criteria: (1) SCLC diagnosis by pathology or cytology; (2) Magnetic resonance imaging of the brain (MRI) contrasted with baseline BMs; (3) Prior systemic treatment has been received.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.It was May 31, 2023, when the last follow-up visit was made. Endpoints of the study The collection and analysis of data were conducted 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 of 10 mm or greater were considered measurable lesions.The treatment response was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).The ORR, which stands for 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.According to brain lesions, intracranial ORRs and DCRs were calculated.The OS was determined as the duration from the initiation of therapy until the individual's demise or was terminated by the most recent imaging date.Progression-free survival (PFS) refers to the duration from treatment initiation until 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 the treatment (TRAEs) were documented throughout the course of treatment and subsequent monitoring. Statistical analysis Descriptive summaries were utilized to analyze clinical and demographic variables.Generated were the Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS).Censored observations were considered for analyses when patients did not experience disease progression or reach the end of follow-up. Clinical characteristics were compared using a chi-square test. Log-rank tests were utilized to comparethe survival between different groups.We investigated the correlation between survival and clinical factors by utilizing both univariate and multivariate Cox regressions. SPSS17 was used for all analyses.Statistically significant was the consideration for p-values below 0.05. Results A total of 46 patients with advanced small cell lung cancer (SCLC) and brain metastases (BMs) received treatment with a combination of cardonilumab plus anlotinib. Figure 1 and Table 1 displays the contains a summary of the fundamental clinical and pathological characteristics. The majority of the patients, approximately 65.2%, were below the age of 60 and exhibited 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.Out of the total number of patients, 20 individuals (43.5%) experienced brain lesions with symptoms, while 34 patients (73.9%) had multiple brain lesions. Additionally, a majority of 63.1% of the subjects attained LDH levels surpassing the upper limit of normal (ULN).36.9% of patients achieved higher LDH levels than the ULN. Table 1 Study population baseline and clinical characteristics . Characteristic N (%)(N = 46) 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 1–2 37(80.4%) ≥3 11(23.9%) 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 of all 46 patients was assessed.The overall response rate (ORR) and disease control rate (DCR) for these patients were 47.8% 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 80.4% (1 CR, 18 PR) (Table 2 ). Figure 2 exhibits display typical MRI scans of a complete response in brain lesions prior to and following therapy, The expression of PD1 in SCLC tissues is shown in Fig. 3 , Patients with detectable lesions are depicted in Fig. 4 , illustrating alterations both inside and outside the skull. A median OS and a median PFS of 19.3 (95% CI, 17.4–21.1 months) and 14.2 (95% CI, 12.5–15.9 months) were reported in the all-population study (Fig. 4 ). 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 26(47.8%) DCR 40(86.9%) The intracranial response to cadonilimab plus anlotinib was evaluated among patients with measurable lesions based on the RANO-BM criteria. 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 20(41.3%) DCR 41(91.3%) Survival prognoses In addition, we investigated the impact of various factors on survival by employing univariate and multivariate Cox models. The multivariate analysis encompassed all variables that showed significant correlations and trends (P < 0.05) in the univariate analysis. The multivariate Cox model analysis for overall survival (OS) included smoking, the number of brain metastases (BMs), and the number of metastatic organs. PD1 < 50% (HR = 4.83, P 50% (HR = 4.385, P = 0.001) or metastatic organs ≥ 2 (HR = 0.245, P = 0.04) had a worse outcome (Table 4 ). Subsequently, Kaplan-Meier survival plots were generated based on significant prognostic factors identified in the multivariate Cox model analysis. Compared to individuals who do not have it, patients without metastatic organs ≥ 2 (10.9 vs. 20.7 months, P = 0.001) or PD1 > 50% (13.6 vs. 21.9 months, P = 0.000) experienced notably reduced overall survival, as shown in Fig. 5 A-B.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 C-D). Table 3 OS survival analyses by univariate and multivariate Characteristic Univariate survival analyses of OS Multivariate survival analyses of OS HR 95%CI P Value HR 95%CI P Value Age at diagnosis < 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 The survival analyses for intracranial PFS on a univariate and multivariate basis Characteristic Univariate survival analyses of PFS Multivariate survival analyses of PFS HR 95%CI P Value HR 95%CI P Value Age at diagnosis < 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 with cadonilimab plus anlotinib is shown in Table 5 .Out of a total of 46 patients, 26 individuals (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 for 30.4%.Among 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 ranked third with a occurrence rate of 2.2% (n = 1). Table 5 Treatment-related adverse events Treatment-related adverse event,N (%) All patients (n = 46) ALL grades 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 Regarding SCLC, there has been no comparable investigation conducted to assess the effectiveness of cadonilimab in combination with anlotinib for BMs in the central nervous system.Although intracranial radiotherapy is extensively utilized for treating BMs, it results in adverse effects on healthy tissues, ultimately impacting the patient's intellectual capacity, recollection, and cognitive abilities.It is imperative to find new therapeutic methods as the majority of SCLC patients with BMs, despite receiving systemic and radiotherapy, continue to experience recurrences or develop resistance to treatment.In this retrospective study, a total of 46 patients with small cell lung cancer (SCLC) and brain metastases (BMs) were included. These patients were treated with a combination of cadonilimab and anlotinib.The combination therapy demonstrated strong efficacy in the central nervous system, resulting in a median overall survival of 19.3 months. In recent years, there has been significant advancement in immuno-oncology (IO) treatments, with programmed cell death-1 (PD-1) targeted monoclonal antibodies (mAbs) becoming the established treatment for several cancer forms.Numerous combinations of anti-PD-1 antibodies have been explored in order to enhance the effectiveness of PD-1 monotherapy.Promising research has shown significant improvements in efficacy for difficult-to-treat cancer types through combination therapy involving anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-PD-1 antibodies. However, the utilization of this drug in kidney, gastric, and lung cancers has been restricted due to its toxic effects.AK104 (cadonilimab), a groundbreaking immunotherapy medication, aims to mitigate the adverse effects linked to the concurrent usage of PD-1 and CTLA-4 antibodies.A significant advantage of cadonilimab is its low toxicities in the clinic.Despite its high binding avidity and lack of Fc, cadonilimab may be more effective against tumors in a tumor-like setting because of its high safety and efficacy.Just a few years ago, the oncology community firmly dismissed the idea of using immunotherapy to treat brain metastases.As a result, 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 due to its limited ability to effectively cross the blood-brain barrier[ 13 ].Historically, individuals with brain metastases have typically been ineligible for chemotherapeutic trials because of this concept, as well as their unfavorable prognosis. This identical situation has similarly been extended to immunotherapy involving immune checkpoint inhibitors (ICIs) in recent times[ 14 ].In the past few years, though, Scientists have examined the connections between the immune system and tumor microenvironment (TME) in brain metastases, leading to the recognition of the 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 like programmed death-1 (PD-1) ligand (PD-L1) [ 16 ].Recently, there has been an emergence of anti-CTLA-4 antibodies, anti-PD-1 antibodies, and anti-PD-L1 antibodies, which further endorse their application in immunotherapy. Moreover, these antibodies are utilized in patients with brain metastases and CNS tumors that have developed in the brain.Patients diagnosed with non-small cell lung cancer and currently experiencing brain metastases were not included in the significant clinical trials involving ICI treatment. However, a limited number of retrospective studies have been conducted to compare the effectiveness of ICI therapy with alternative treatments in this specific patient population.During a phase II study, pembrolizumab demonstrated a 29.4% intracranial objective response rate (ORR) in 10 out of 34 patients with PD-L1 + status. There were no objective responses observed in 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 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 to be 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, the anti-PD-L1 atezolizumab shows a favorable safety profile, Aezolizumab compared to docetaxel showed a trend in favor of a longer OS (16 versus 11.9 months).In contrast to docetaxel, atezolizumab delayed the radiological identification of new symptomatic brain metastases.[ 22 ] The effectiveness of ICIs in improving survival for SCLC patients with BMs is uncertain, but they have shown promise in treating other types of tumors like NSCLC and melanoma.The study revealed that atezolizumab did not show any survival advantage when compared to chemotherapy alone in IMpower133, which involved 35 patients with SCLC and BMs. Similarly, durvalumab, another PD-L1 inhibitor, also did not demonstrate any benefit in terms of survival.Nevertheless, it seems that individuals who receive serplulimab, a PD-1 inhibitor, could potentially experience advantages from ASTRUM-005 (HR, 0.61, 0.33–1.13) [ 23 ].In a previous study, anlotinib proved to be successful in treating SCLC patients with BMs. It significantly enhanced PFS (3.8 vs 0.8 months, P = 0.001) and OS (6.1 vs 2.6 months, P = 0.006) when used as a third-line or subsequent treatment, surpassing the effectiveness of placebo[ 7 ].The clinical potential of using anlotinib in combination with ICIs for treating patients with BM is promising.According to our research, approximately half (50%) of patients with detectable CNS lesions exhibited a positive response within the brain, and the average overall survival (OS) was 19.3 months, surpassing the effectiveness of each individual treatment.Based on a case report, the combination of anlotinib and durvalumab, a PD-L1 inhibitor, resulted in almost complete disappearance of SCLC brain lesions. This aligns with our discovery that remarkable effectiveness in the brain can be attained by using ICIs along with anlotinib[ 24 ].The combination of treatments can have a synergistic impact because Anlotinib may enhance the infiltration of innate immune cells and promote vessel normalization, thereby altering the immunosuppressive tumor microenvironment and enhancing the effectiveness of immune checkpoint inhibitors. 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 [ 25 , 26 ].As we found in our study, high disease burden and PD1 > 50% are independent negative predictors of both OS and PFS.Moreover, prior research has indicated that increased levels of LDH can have a detrimental impact on the effectiveness of immunotherapy when it induces T-cell immunosuppression in cancer [ 27 ].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 had a more unfavorable prognosis compared to those with only one BM[ 29 , 30 ]. Nevertheless, 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 a small sample size, may explain this. There were no unexpected adverse events associated with AK104 (cadonilimab) combined with anlotinib.Based on prior research, the overall occurrence of treatment-related adverse events (TRAEs) in any level was 69.6%, with a 13.0% incidence of grade 3–4 TRAEs [ 31 , 32 ].On the other hand, there was a higher occurrence of grade 3–4 hypertension (6.5%) and thyroid dysfunction (4.3%), possibly due to cachexia and locally advanced cancer in the majority of patients. Several limitations were found in our study.Firstly, as a retrospective study, this study has inherent limitations associated with retrospective studies.Additionally, the study's potential power could be limited because of its small size and absence of a control group.Furthermore, this study employed a relatively brief six-month follow-up period, and the OS data were not fully developed, indicating the need for additional research. Conclusions In heavily treated patients with SCLC, the combination of AK104 (cadonilimab) and anlotinib showed encouraging efficacy in the central nervous system for the treatment of BMs, as indicated by this study.Additional prospective studies are needed to confirm these findings . Declarations Author contributions The article was conceived and edited by Haizhen Yi and Zhan Lin. Jinjin Chen and Wei Lv collected and analyzed the data. Zhan Lin and Haizhen Yi drafted it . Funding No public, commercial, or non-profit agency funded the research . Data availability Throughout the ongoing investigation, several datasets were produced and/or examined, yet they are not accessible to the public. However, the corresponding author is able to grant access to these datasets upon inquiry. Declarations A conflict of interest has not been reported by the authors. Ethical approval First People's Hospital of Yulin, Sixth Affiliated Hospital of Guangxi Medical University, has approved this retrospective study, which complies with the Declaration of Helsinki. Consent to participate Not required. Consent for publication Not required. 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. 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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. 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. 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-3893558","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":269152164,"identity":"46e78e3c-2638-4c26-8129-9ab0387f1f6c","order_by":0,"name":"Hai-Zhen Yi","email":"","orcid":"","institution":"The First People's Hospital of Yulin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hai-Zhen","middleName":"","lastName":"Yi","suffix":""},{"id":269152165,"identity":"d8e80df8-91b4-48c6-8e21-8173daa0a1ce","order_by":1,"name":"Jin-Jing Chen","email":"","orcid":"","institution":"The First People's Hospital of Yulin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jin-Jing","middleName":"","lastName":"Chen","suffix":""},{"id":269152166,"identity":"c93c4320-2bd3-457b-b0c7-a0a3aa6169eb","order_by":2,"name":"Wei Lv","email":"","orcid":"","institution":"The First People's Hospital of Yulin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Lv","suffix":""},{"id":269152167,"identity":"11836c3f-b1d3-4ca2-a35d-14ffcd8d7521","order_by":3,"name":"Zhan Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYDACduaDDz5USNTzMzMffkCcFma2ZMMZZywSJNvZ0gyI1MJjJs3bVpFgcJ5HQYIoHfLNDAaSM85I5Bkf5mEwYKixiSaohbGZIcEA6Jdis8O8Bx4wHEvLbSDoLmaGA4lAWxi3HeZLMGBsOExYCxszUBlvmwTj5mYeAwmitPAwMzM2A7UkbmAmVosEM9AeoMOMJQ4DAzmBGL/It/d///Ghok6Ov//w4QcfamwIa0EFCaQpHwWjYBSMglGACwAAO3w7hcvWuMMAAAAASUVORK5CYII=","orcid":"","institution":"The First People's Hospital of Yulin","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Zhan","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2024-01-24 09:08:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3893558/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3893558/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50327693,"identity":"dc157efd-7169-42ab-8a82-15016844de7a","added_by":"auto","created_at":"2024-01-29 20:42:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34234,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study design.SCLC = small cell lung cancer.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3893558/v1/0d663ab34e67bfca813bc4af.png"},{"id":50327697,"identity":"55f49742-19cf-4b06-b37d-659e480afcce","added_by":"auto","created_at":"2024-01-29 20:42:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":269868,"visible":true,"origin":"","legend":"\u003cp\u003e(A)Pre- and (B)post-treatment of the intracranial lesion in weighted magnetic resonance images.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-3893558/v1/ff08bd23a64fe0613699ca2a.png"},{"id":50327698,"identity":"8eebda2c-edd1-43b4-b25c-623be0e8f465","added_by":"auto","created_at":"2024-01-29 20:42:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":440310,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemically, the tumor cells were positive for PD1.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-3893558/v1/2e3daa7478c9ff7d2854484a.png"},{"id":50327696,"identity":"4797f4d7-b80c-42ad-a64d-c67105c8176f","added_by":"auto","created_at":"2024-01-29 20:42:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":17371,"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":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-3893558/v1/d646182e482cac3f1827de15.png"},{"id":50327694,"identity":"6b83fbd8-b78d-4426-86ff-9c0e220054b1","added_by":"auto","created_at":"2024-01-29 20:42:33","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":51080,"visible":true,"origin":"","legend":"\u003cp\u003eOS and PFS based on Kaplan-Meier survival analysis. A: OS; B: PFS.\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-3893558/v1/6506fe2378b53f7167b56588.png"},{"id":50328411,"identity":"4160b135-2f83-4397-8b40-36c9b94b6a0f","added_by":"auto","created_at":"2024-01-29 20:50:33","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":34786,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier survival analysis for overall survival (OS) and progression-free survival (PFS) based on significant predictors. OS analysis: A metastatic organs ≥2 vs. without metastatic organs ≥2. C PD1\u0026gt;50% vs. PD1\u0026lt;50%. \u0026nbsp;PFS: B metastatic organs ≥2 vs. without metastatic organs ≥2. D PD1\u0026gt;50% vs. PD1\u0026lt;50%.\u003c/p\u003e","description":"","filename":"Fig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-3893558/v1/9e26613555840dd20577c928.png"},{"id":50329127,"identity":"0146a6cc-ea28-4302-b45b-77bbede9a5cf","added_by":"auto","created_at":"2024-01-29 21:06:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1401398,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3893558/v1/b5098a1f-681c-4906-85d8-80d8f8ce28a6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eTreatment of Small Cell Lung Cancer patients with brain metastases shows promise with the combination therapy of Cardonilumab and Anlotinib\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe occurrence of SCLC in Those newly diagnosed with lung cancer is approximately 15%, and it is associated with high rates of recurrence and mortality[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].Furthermore, individuals afflicted by this fatal illness are at a higher risk of developing brain metastases (BMs) and have limited treatment alternatives, leading to an exceptionally poor survival rate.The median overall survival (OS) of SCLC patients ranged from 3.2 to 8.5 months with nearly half developing BMs during 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].Due 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 do more harm than good. Conversely, traditional chemotherapy is not very effective due to the presence of the blood-brain barrier (BBB).\u003c/p\u003e \u003cp\u003eAdvanced cancer treatment has been revolutionized by utilizing immune checkpoint inhibitors (ICIs), which tap into the potential of the immune system.Additionally, extensive-stage SCLC patients could expect a significantly better prognosis with the use of ICIs.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 the 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], 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. The development of novel therapeutic strategies is therefore necessary.\u003c/p\u003e \u003cp\u003eAK104, also known as cadonilimab, is an IgG1 antibody that has a tetravalent bispecific structure and includes a single-chain variable fragment (scFv). The Fc-null configuration eradicates antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and cytokine generation. The Fc receptor-mediated effector functions, which eliminate or harm PD-1 and CTLA-4 expressing lymphocytes, may diminish the antitumor efficacy. Cadonilimab exhibits notably reduced toxicities compared to 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 anti-tumor outcomes[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].According to the researchers, the combination of chemotherapy with anlotinib, a new multitargeted tyrosine kinase inhibitor (TKI), enhanced the progression-free survival and quality of life in SCLC patients with BMs[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].Preclinical studies investigating the 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. Several studies have shown that Anlotinib combined with ICIs could be effective in treating advanced SCLC patients. However, BM patients were not targeted in these studies. For our study, the combination of Anlotinib with Cadonilimab (AK104) is being evaluated as a potential treatment for advanced SCLC patients with BMs.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003ePatients\u003c/p\u003e \u003cp\u003eBetween June 2019 and December 2022, The First People's Hospital of Yulin conducted a retrospective evaluation for all patients diagnosed with advanced-stage small cell lung cancer (SCLC) with brain metastases (BMs).The research involved individuals with metastatic small cell lung cancer (SCLC) who were administered AK104 (cadonilimab) and anlotinib concurrently.included the following The inclusion criteria: (1) SCLC diagnosis by pathology or cytology; (2) Magnetic resonance imaging of the brain (MRI) contrasted with baseline BMs; (3) Prior systemic treatment has been received.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.It was May 31, 2023, when the last follow-up visit was made.\u003c/p\u003e \u003cp\u003eEndpoints of the study\u003c/p\u003e \u003cp\u003eThe collection and analysis of data were conducted 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 of 10 mm or greater were considered measurable lesions.The treatment response was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).The ORR, which stands for 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.According to brain lesions, intracranial ORRs and DCRs were calculated.The OS was determined as the duration from the initiation of therapy until the individual's demise or was terminated by the most recent imaging date.Progression-free survival (PFS) refers to the duration from treatment initiation until 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 the treatment (TRAEs) were documented throughout the course of treatment and subsequent monitoring.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive summaries were utilized to analyze clinical and demographic variables.Generated were the Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS).Censored observations were considered for analyses when patients did not experience disease progression or reach the end of follow-up. Clinical characteristics were compared using a chi-square test. Log-rank tests were utilized to comparethe survival between different groups.We investigated the correlation between survival and clinical factors by utilizing both univariate and multivariate Cox regressions. SPSS17 was used for all analyses.Statistically significant was the consideration for p-values below 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 46 patients with advanced small cell lung cancer (SCLC) and brain metastases (BMs) received treatment with a combination of cardonilumab plus anlotinib. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e displays the contains a summary of the fundamental clinical and pathological characteristics. The majority of the patients, approximately 65.2%, were below the age of 60 and exhibited 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.Out of the total number of patients, 20 individuals (43.5%) experienced brain lesions with symptoms, while 34 patients (73.9%) had multiple brain lesions. Additionally, a majority of 63.1% of the subjects attained LDH levels 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\u003eStudy population baseline and clinical characteristics .\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\" 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\u003e1\u0026ndash;2\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\u003e\u0026ge;3\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\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 of all 46 patients was assessed.The overall response rate (ORR) and disease control rate (DCR) for these patients were 47.8% and 86.9% respectively(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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 80.4% (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 exhibits display typical MRI scans of a complete response in brain lesions prior to and following therapy, The expression of PD1 in SCLC tissues is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Patients with detectable lesions are depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, illustrating alterations both inside and outside the skull. A median OS and a median PFS of 19.3 (95% CI, 17.4\u0026ndash;21.1 months) and 14.2 (95% CI, 12.5\u0026ndash;15.9 months) were reported in the all-population study (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\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\u003e26(47.8%)\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 response to cadonilimab plus anlotinib was evaluated among patients with measurable lesions based on the RANO-BM criteria.\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\u003e20(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\u003e41(91.3%)\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\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSurvival prognoses\u003c/p\u003e \u003cp\u003eIn addition, we investigated the impact of various factors on survival by employing univariate and multivariate Cox models. The multivariate analysis encompassed all variables that showed significant correlations and trends (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in the univariate analysis. The multivariate Cox model analysis for overall survival (OS) included smoking, the number of brain metastases (BMs), and the number of metastatic organs. PD1\u0026thinsp;\u0026lt;\u0026thinsp;50% (HR\u0026thinsp;=\u0026thinsp;4.83, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) or metastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2 (HR\u0026thinsp;=\u0026thinsp;2.71, P\u0026thinsp;=\u0026thinsp;0.036) were independent positive predictors of OS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).For PFS, patients with PD1\u0026thinsp;\u0026gt;\u0026thinsp;50% (HR\u0026thinsp;=\u0026thinsp;4.385, P\u0026thinsp;=\u0026thinsp;0.001) or metastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2 (HR\u0026thinsp;=\u0026thinsp;0.245, P\u0026thinsp;=\u0026thinsp;0.04) had a worse outcome (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Subsequently, Kaplan-Meier survival plots were generated based on significant prognostic factors identified in the multivariate Cox model analysis. Compared to individuals who do not have it, patients without metastatic organs\u0026thinsp;\u0026ge;\u0026thinsp;2 (10.9 vs. 20.7 months, P\u0026thinsp;=\u0026thinsp;0.001) or PD1\u0026thinsp;\u0026gt;\u0026thinsp;50% (13.6 vs. 21.9 months, P\u0026thinsp;=\u0026thinsp;0.000) experienced notably reduced overall survival, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA-B.Furthermore, the presence of two or more metastatic organs (7.3 vs. 15.2 months, P\u0026thinsp;=\u0026thinsp;0.000) or a PD1 level exceeding 50% (9.0 vs. 16.6 months, P\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\u003eC-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\u003eOS survival analyses by univariate and multivariate\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\u003eMultivariate 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\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis\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\u003eThe survival analyses for intracranial PFS on a univariate and multivariate basis\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\u003eMultivariate 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\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis\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\u003e \u003c/p\u003e \u003cp\u003eSafety\u003c/p\u003e \u003cp\u003eAn analysis of TRAEs with cadonilimab plus anlotinib is shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.Out of a total of 46 patients, 26 individuals (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 for 30.4%.Among 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 Positive urinary protein ranked third with a occurrence rate of 2.2% (n\u0026thinsp;=\u0026thinsp;1).\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\u003eTreatment-related adverse event,N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eAll patients (n\u0026thinsp;=\u0026thinsp;46)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALL grades\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\u003eRegarding SCLC, there has been no comparable investigation conducted to assess the effectiveness of cadonilimab in combination with anlotinib for BMs in the central nervous system.Although intracranial radiotherapy is extensively utilized for treating BMs, it results in adverse effects on healthy tissues, ultimately impacting the patient's intellectual capacity, recollection, and cognitive abilities.It is imperative to find new therapeutic methods as the majority of SCLC patients with BMs, despite receiving systemic and radiotherapy, continue to experience recurrences or develop resistance to treatment.In this retrospective study, a total of 46 patients with small cell lung cancer (SCLC) and brain metastases (BMs) were included. These patients were treated with a combination of cadonilimab and anlotinib.The combination therapy demonstrated strong efficacy in the central nervous system, resulting in a median overall survival of 19.3 months.\u003c/p\u003e \u003cp\u003eIn recent years, there has been significant advancement in immuno-oncology (IO) treatments, with programmed cell death-1 (PD-1) targeted monoclonal antibodies (mAbs) becoming the established treatment for several cancer forms.Numerous combinations of anti-PD-1 antibodies have been explored in order to enhance the effectiveness of PD-1 monotherapy.Promising research has shown significant improvements in efficacy for difficult-to-treat cancer types through combination therapy involving anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-PD-1 antibodies. However, the utilization of this drug in kidney, gastric, and lung cancers has been restricted due to its toxic effects.AK104 (cadonilimab), a groundbreaking immunotherapy medication, aims to mitigate the adverse effects linked to the concurrent usage of PD-1 and CTLA-4 antibodies.A significant advantage of cadonilimab is its low toxicities in the clinic.Despite its high binding avidity and lack of Fc, cadonilimab may be more effective against tumors in a tumor-like setting because of its high safety and efficacy.Just a few years ago, the oncology community firmly dismissed the idea of using immunotherapy to treat brain metastases.As a result, 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 due to its limited ability to effectively cross the blood-brain barrier[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].Historically, individuals with brain metastases have typically been ineligible for chemotherapeutic trials because of this concept, as well as their unfavorable prognosis. 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].In the past few years, though, Scientists have examined the connections between the immune system and tumor microenvironment (TME) in brain metastases, leading to the recognition of the CNS as a separate immunological area rather than an isolated one[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].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 like programmed death-1 (PD-1) ligand (PD-L1) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].Recently, there has been an emergence of anti-CTLA-4 antibodies, anti-PD-1 antibodies, and anti-PD-L1 antibodies, which further endorse their application in immunotherapy. Moreover, these antibodies are utilized in patients with brain metastases and CNS tumors that have developed in the brain.Patients diagnosed with non-small cell lung cancer and currently experiencing brain metastases were not included in the significant clinical trials involving ICI treatment. However, a limited number of retrospective studies have been conducted to compare the effectiveness of ICI therapy with alternative treatments in this specific patient population.During a phase II study, pembrolizumab demonstrated a 29.4% intracranial objective response rate (ORR) in 10 out of 34 patients with PD-L1\u0026thinsp;+\u0026thinsp;status. There were no objective responses observed in patients without PD-L1 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 CheckMate 063 (phase II), 017 (phase III), and 057 (phase III) trials[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].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 to be 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, the anti-PD-L1 atezolizumab shows a favorable safety profile, Aezolizumab compared to docetaxel showed a trend in favor of a longer OS (16 versus 11.9 months).In contrast to docetaxel, atezolizumab delayed 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 for SCLC patients with BMs is uncertain, but they have shown promise in treating other types of tumors like NSCLC and melanoma.The study revealed that atezolizumab did not show any survival advantage when compared to chemotherapy alone in IMpower133, which involved 35 patients with SCLC and BMs. Similarly, durvalumab, another PD-L1 inhibitor, also did not demonstrate any benefit in terms of survival.Nevertheless, it seems that 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].In a previous study, anlotinib proved to be successful in treating SCLC patients with BMs. It significantly enhanced PFS (3.8 vs 0.8 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and OS (6.1 vs 2.6 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) when used as a third-line or subsequent treatment, surpassing the effectiveness of placebo[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].The clinical potential of using anlotinib in combination with ICIs for treating patients with BM is promising.According to our research, approximately half (50%) of patients with detectable CNS lesions exhibited a positive response within the brain, and the average overall survival (OS) was 19.3 months, surpassing the effectiveness of each individual treatment.Based on a case report, the combination of anlotinib and durvalumab, a PD-L1 inhibitor, resulted in almost complete disappearance of SCLC brain lesions. This aligns with our discovery that remarkable effectiveness in the brain can be attained by using ICIs along with anlotinib[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].The combination of treatments can have a synergistic impact because Anlotinib may enhance the infiltration of innate immune cells and promote vessel normalization, thereby altering the immunosuppressive tumor microenvironment and enhancing the effectiveness of immune checkpoint inhibitors.\u003c/p\u003e \u003cp\u003eSeveral 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 citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].As we found in our study, high disease burden and PD1\u0026thinsp;\u0026gt;\u0026thinsp;50% are independent negative predictors of both OS and PFS.Moreover, prior research has indicated that increased levels of LDH can have a detrimental impact on the effectiveness of immunotherapy when it induces T-cell immunosuppression in cancer [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].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\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 had a more unfavorable prognosis compared to those with only one BM[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Nevertheless, 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 a small sample size, may explain this.\u003c/p\u003e \u003cp\u003eThere were no unexpected adverse events associated with AK104 (cadonilimab) combined with anlotinib.Based on prior research, the overall occurrence of treatment-related adverse events (TRAEs) in any level was 69.6%, with a 13.0% incidence of grade 3\u0026ndash;4 TRAEs [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].On the other hand, there was a higher occurrence of grade 3\u0026ndash;4 hypertension (6.5%) and thyroid dysfunction (4.3%), possibly due to cachexia and locally advanced cancer in the majority of patients.\u003c/p\u003e \u003cp\u003eSeveral limitations were found in our study.Firstly, as a retrospective study, this study has inherent limitations associated with retrospective studies.Additionally, the study's potential power could be limited because of its small size and absence of a control group.Furthermore, this study employed a relatively brief six-month follow-up period, and the OS data were not fully developed, indicating the need for additional research.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn heavily treated patients with SCLC, the combination of AK104 (cadonilimab) and anlotinib showed encouraging efficacy in the central nervous system for the treatment of BMs, as indicated by this study.Additional prospective studies are needed to confirm these findings .\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eThe article was conceived and edited by Haizhen Yi and Zhan Lin. Jinjin Chen and Wei Lv collected and analyzed the data. Zhan Lin and Haizhen Yi drafted it .\u003c/p\u003e\n\u003cp\u003eFunding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo public, commercial, or non-profit agency funded the research .\u003c/p\u003e\n\u003cp\u003eData availability\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThroughout the ongoing investigation, several datasets were produced and/or examined, yet they are not accessible to the public. However, the corresponding author is able to grant access to these datasets upon inquiry.\u003c/p\u003e\n\u003cp\u003eDeclarations\u003c/p\u003e\n\u003cp\u003eA conflict of interest has not been reported by the authors.\u003c/p\u003e\n\u003cp\u003eEthical approval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFirst People\u0026apos;s Hospital of Yulin, Sixth Affiliated Hospital of Guangxi Medical University, has approved this retrospective study, which complies with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eConsent to participate\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not required.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not required.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. 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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, Cardonilumab, Anlotinib, Brain metastases","lastPublishedDoi":"10.21203/rs.3.rs-3893558/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3893558/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe aim of this research was to evaluate the efficiency and security of the pairing of cardonilumab and anlotinib in individuals diagnosed with small cell lung cancer (SCLC) and brain metastases (BMs).\u003c/p\u003e \u003cp\u003eMethods\u003c/p\u003e \u003cp\u003e 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 cardonilumab plus anlotinib using RECIST 1.1 and 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 \u003cp\u003eResults\u003c/p\u003e \u003cp\u003eThe study included 46 individuals diagnosed with brain metastases (BMs) at the beginning. According to RANO-BM criteria, the intracranial lesions showed an objective response rate (ORR) of 80.4%.Additionally, the median overall survival (OS) was observed to be 19.3 months (95% CI, 17.4\u0026ndash;21.1 months).The analysis of multivariate Cox regression showed that having a PD1 level below 50% (HR\u0026thinsp;=\u0026thinsp;4.83, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) or having two or more metastatic organs (HR\u0026thinsp;=\u0026thinsp;2.71, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036) were independent factors that positively predicted overall survival.Out of all the patients, 86.9% experienced adverse events associated with the treatment, while 17.4% reported severe TRAEs of grade3-4.\u003c/p\u003e \u003cp\u003eConclusions\u003c/p\u003e \u003cp\u003eAccording to our results, the combination of cardonilumab and anlotinib appears to be a promising treatment option for SCLC patients with brain metastases.\u003c/p\u003e","manuscriptTitle":"Treatment of Small Cell Lung Cancer patients with brain metastases shows promise with the combination therapy of Cardonilumab and Anlotinib","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-29 20:42:28","doi":"10.21203/rs.3.rs-3893558/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":"662a0eb6-b6d5-4eaa-8f57-1bda66f69150","owner":[],"postedDate":"January 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-01-29T20:42:30+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-29 20:42:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3893558","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3893558","identity":"rs-3893558","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}