A meta-analysis of the effectiveness and safety of Sintilimab combined with chemotherapy in the trea tment of advanced non-small cell lung cancer

A meta-analysis of the effectiveness and safety of Sintilimab combined with chemotherapy in the trea tment of advanced non-small cell lung cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A meta-analysis of the effectiveness and safety of Sintilimab combined with chemotherapy in the trea tment of advanced non-small cell lung cancer Liling Pan, Qiongqing Chen, Ningsheng Liang, Youjia Guo, Youjia Guo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4587063/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Purpose: Sintilimab, as a domestically produced innovative immune checkpoint inhibitor (ICIs) drug, performs well in the treatment of lung cancer. However, due to the late start of domestically produced ICIs, Sintilimab is currently only available for domestic use, with limited clinical data and facing challenges in post-marketing evaluation. It is planned to use Meta analysis methods to evaluate its safety and effectiveness. Methods: Computerized searches were conducted on various databases from their inception to August 10, 2023. Meta-analysis was carried out using RevMan 5.4 software after two evaluators independently screened the literature, extracted information, and evaluated the risk of bias in the included studies. Results: The results indicated that patients with advanced NSCLC receiving Sintilimab had a 5.14 times higher risk of hypothyroidism compared to the control group. Hematologic toxicity and hepatic impairment were not significantly different from the chemotherapy group, while gastrointestinal and alopecia adverse reactions may be less frequent than in the chemotherapy group. Additionally, the risk of pneumonia, proteinuria, rash, and infusion reaction may be increased. Furthermore, Sintilimab combined with chemotherapy was found to enhance ORR, DCR, and prolong mOS and mPFS in NSCLC patients. Conclusion: Sintilimab in combination with chemotherapy for advanced NSCLC is efficacious, safe and manageable. sintilimab effectiveness safety meta-analysis advanced non-small cell lung cancer Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23 Figure 24 Figure 25 Figure 26 Figure 27 Figure 28 Figure 29 Introduction Lung cancer poses a significant health challenge due to its high incidence and lethality globally and in our country(Global cancer burden sevices.2024;Zheng et al.2024). Non-small-cell lung cancer (NSCLC) accounts for a large portion of lung cancer cases, with most patients diagnosed at advanced stages(Postmus et al. 2017). The introduction of immune checkpoint inhibitors (ICIs), particularly the domestically produced Sintilimab targeting PD-1, has provided a new treatment option for NSCLC. Sintilimab enhances immune surveillance and anti-tumor response by blocking PD-1 interaction with PD-L1/L2(Hoy 2019). Despite its early clinical approval, Sintilimab faces challenges in post-marketing evaluation due to limited data and evaluation. To ensure safety and efficacy, a Meta-analysis following the Technical Guidelines for Comprehensive Clinical Evaluation of Antineoplastic Drugs (2022 Trial Edition) will be conducted to support evidence-based medicine for Sintilimab in combination with chemotherapy for NSCLC and inform clinical application and drug policy decisions (National Heath Commission of the People’s Republic of China.2022). 1. Information and methods 1.1 Inclusion criteria (1) The studies were randomized controlled trials (RCTs) reported in both Chinese and English; (2)The subjects included in the study were clinically diagnosed with intermediate to advanced NSCLC and met the corresponding disease stage and pathological diagnostic criteria; (3)Chemotherapeutic regimens adhered strictly to drug inserts and expert consensus, primarily utilizing Pemetrexed, Gemcitabine, and Paclitaxel combined with Platinum drugs, with dosages following guidelines; (4)Outcome indicators measured included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS), Treatment Emergent Adverse Events (TRAEs) were assessed. Efficacy was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST), while TRAEs were graded and recorded following CTCAE (version 5.0). 1.2 Exclusion criteria (1) duplicate publications; and (2) literature without relevant outcome indicators for this study or without access to the full text. 1.3 Literature search strategy This study conducted a comprehensive search of both domestic and foreign published RCTs on the use of sintilimab in the treatment of NSCLC. The search encompassed foreign journal databases such as PubMed, Embase, Web of Science, and Cochrane Library, as well as Chinese journal databases including CNKI, CBMdisc, cqvip, and Wanfang. The search strategy utilized a combination of subject words and free words, tailored to the specific characteristics of each database. Keywords such as Sintilimab, PD-1/PD-L1, IBI308, Lung Neoplasms, non-small cell lung cancer, and Controlled Clinical Trial were employed. The search period ranged from the inception of each database to August 10, 2023. Additionally, references from the included studies were tracked to supplement relevant literature.As shown in Fig. 1. 1.4 Literature Screening and Data Extraction According to the inclusion and exclusion criteria, two investigators independently screened the literature, extracted the data, and cross-checked them. In cases of disagreement, they consulted a third investigator and attempted to contact the authors for missing information. The inclusion of literature was based on reading the full text, and a standardized data extraction form was used to collect: ① basic information (study name, authors, time, etc.); ② baseline characteristics of the patients (age, sex, stage, type of pathology, and Ecog scores); ③ details of interventions and controls; and ④ endpoint indicators and results. Any disagreements were resolved by a third researcher. 1.5 Literature quality assessment and statistical treatment The quality of literature in the included RCTs was evaluated using the Cochrane Handbook tool (Zeng et al.2012; Higgins et al.2003). Meta-analysis was conducted with Revman 5.4, where OS and PFS were assessed using HR (hazard ratio) and 95% CI, while dichotomous variables like ORR, DCR, and TRAEs were analyzed with RR and 95% CI. A significance level of ( P >0.1, I 2 ≤ 50%) and a random-effects model for heterogeneity ( P ≤ 0.1, I 2 > 50%) to address clinical heterogeneity. Subgroup analyses, sensitivity analyses, or descriptive analyses were employed for significant heterogeneity. Funnel plots will be used for bias assessment if there are more than 10 articles for a specific outcome metric and the results are statistically significant. A symmetrical distribution of scatter points suggests no significant publication bias, while an asymmetrical distribution indicates the presence of publication bias. 2. Results 2.1 Literature screening results and process Based on the search strategy, 1,702 papers were initially obtained. After using EndnoteX9 to filter out irrelevant papers, 1,158 papers remained. Excluding 1,130 non-RCT documents such as reviews, the full text of the remaining 28 documents that met the criteria for analysis was thoroughly reviewed. Seven documents were excluded due to incomplete content or inaccessible outcome indicators, leaving 21 documents for the Meta-analysis. The literature screening process is illustrated in Fig. 2. 2.2 Basic characteristics of the included studies Among the 21 papers finally included, there was 1 master's thesis and 20 journal papers; 4 were in English and 17 in Chinese; the publication years were from 2021 to 2023.A total of 2,487 patients with advanced NSCLC were included in the 21 papers, with 1,312 cases in the experimental group and 1,175 cases in the control group. The detailed baseline characteristics are shown in Table 1. 2.3 Evaluation of the quality of literature All 21 papers were randomized controlled trials. Among them, 5 explicitly mentioned randomized control and allocation method concealment (Zhang et al.2022; Zhou et al, 2021; Lu et al,2023; He et al 2021; Lan et al.2022), such as the randomized envelope method and centralized randomized system method, which were defined as 'low risk'. 16 trials did not explicitly mention allocation method concealment, but only mentioned randomization, which was defined as 'unclear'. 3 trials were double-blind evaluations, defined as 'low risk' (Zhang et al.2022; Zhou et al, 2021; Lu et al,2023), while 18 trials were non-blinded evaluations, defined as 'high risk'. One trial had shedding cases but complete data, defined as 'low risk'. The remaining 20 trials with complete data and no selective reporting were also considered 'low risk' (Yang et al.2022). All studies with complete study objectives and no reporting bias were defined as 'low risk'. Other biases were not described in detail and were defined as 'unclear'. The quality of the literature is shown in Fig. 3a-3b. 2.4 Safety meta-analysis results 2.4.1 TRAEs at any level Two studies were included in the analysis of TRAEs(Zhou et al, 2021; Lu et al,2023). The heterogeneity test revealed no statistically significant difference between the studies ( P =0.94, I²=0%), thus the fixed-effects model was utilized for effect size combination. The pooled results indicated that there may be no significant variance in adverse reaction incidence between the combination group and the control group (RR=1.00, 95%CI: 0.98-1.02, P >0.05). The Meta-analysis results can be observed in Fig.4. Out of the 21 included studies, 15 reported various categories of adverse events. This study will examine adverse reaction categories across all included literature. Arrhythmia and hypoproteinemia were excluded from the analysis due to being reported in only one study, preventing I 2 calculation in Revman. The study findings suggested no significant disparity between the intervention group and the control group in adverse event occurrence related to Platelet count decreased, Neutrophil count decreased, White blood cell count decreased, anemia, and hepatic impairment, with no statistically significant differences ( P > 0.05). The intervention group exhibited slightly lower occurrence rates of gastrointestinal reactions like nausea, vomiting, and hair loss compared to the control group, with no statistically significant differences ( P > 0.05). Conversely, the intervention group may have slightly higher incidence rates than the control group in pneumonia, albuminuria, skin rash, and infusion reaction adverse events, with no statistically significant differences ( P > 0.05). Notably, the intervention group had a significantly higher probability of hypothyroidism compared to the control group (RR = 5.14, 95% CI: 2.36-11.21, P < 0.05). The Meta-analysis results are displayed in Fig.5-16. 2.4.2 ≥ 3 TRAEs Four studies analyzed grade ≥3 treatment-related adverse events in advanced NSCLC patients treated with Sintilimab in combination with chemotherapy(Zhou et al, 2021; Lu et al,2023; Song 2021;Cao 2022). A statistically significant heterogeneity was observed among the studies ( P =0.0002, I²=84%), and a random-effects model was used to combine the effect sizes. The results indicated that the intervention group may have a slightly lower incidence of grade ≥3 treatment-related adverse events compared to the control group, but the difference was not statistically significant (RR=0.81, 95% CI: 0.56-1.17, P >0.05). The meta-analysis results are presented in Fig.17. This study focused on analyzing literature concerning grade ≥3 adverse reactions. The findings revealed that, in comparison to the control group, the combination group had a slightly higher incidence of grade ≥3 adverse reactions related to Platelet count decreased, which was not statistically significant ( P >0.05). There were no significant differences between the combination group and the control group in grade ≥3 adverse reactions related to Neutrophil count decreased and anemia ( P >0.05). Additionally, the combination group had a lower incidence of grade ≥3 adverse reactions related to nausea, vomiting, other gastrointestinal(GI) reactions, and hepatic function impairment compared to the control group, with no statistically significant differences ( P >0.05). The results of the meta-analysis can be seen in Fig.18-23. 2.5 Effectiveness Meta-analysis Results 2.5.1 Median overall survival Three studies provided HR values and 95% CIs for mOS (Zhang et al.2022; Zhou et al, 2021; Lu et al,2023). After detecting possible heterogeneity among the studies ( P =0.08, I 2 =60%), a random-effects model was used to combine the effect sizes. Subsequently, a random-effects model was selected for the meta-analysis of the three papers, as depicted in Fig.24a. Further investigation into the sources of heterogeneity revealed no significant heterogeneity ( P =0.62, I 2 =0%), leading to the utilization of a fixed-effects model for meta-analysis. This analysis indicated that the combination group exhibited a longer time to mOS and a 37% reduced risk of death in advanced NSCLC patients compared to the control group, with statistical significance (HR=0.63, 95% CI:0.50-0.79, P < 0.05), as illustrated in Fig.24b. 2.5.2 Median progression-free survival HR values and 95% CIs for mPFS were extracted from two papers for analysis (Zhou et al, 2021; Lu et al,2023). A heterogeneity test indicated potential differences between the studies ( P =0.11, I 2 =61%), prompting the use of a random-effects model for combining effect sizes. The findings revealed that the combination therapy group exhibited a longer time to mPFS and a 38% reduced risk of disease progression in NSCLC patients compared to the control group, with a statistically significant result (HR = 0.62, 95% CI:0.46-0.82, P < 0.05). These results are visually presented in Fig. 25. 2.5.3 Objective response rate Eighteen papers reported ORR data(He et al.2021; Lan et al.2022; Zhang et al.2023; Zhang 2023; Ye 2022; Yang et al.2022; Jin et al.2022; Ma et al.2021; Wu 2022; Wang et al.2022; Song 2021; Shao and Li 2023; Zheng and Li 2022; Hu et al.2022; Hong 2023; Chen et al.2022; Cao 2022; Liang and Wei 2021). A heterogeneity test indicated no statistical heterogeneity among the studies ( P =0.81, I 2 =0%), therefore, effect sizes were combined using a fixed-effects model. The results demonstrated a significant improvement in ORR for NSCLC patients in the combination group compared to the control group, with a statistically significant difference (RR=1.74, 95% CI: 1.55-1.94, P <0.05). The results of the meta-analysis can be seen in Fig.26. 2.5.4 Disease control rate Nineteen papers reported data on DCR(Zhou et al.2021;He et al.2021; Lan et al.2022; Zhang et al.2023; Zhang 2023; Ye 2022; Yang et al.2022; Jin et al.2022; Ma et al.2021; Wu 2022; Wang et al.2022; Song 2021; Shao and Li 2023; Zheng and Li 2022; Hu et al.2022; Hong 2023; Chen et al.2022; Cao 2022; Liang and Wei 2021), and the heterogeneity test indicated no statistical heterogeneity among the studies ( P =0.45, I 2 =1%). The effect sizes were combined using a fixed-effects model. The findings revealed that the combination group significantly improved the DCR of NSCLC patients compared to the control group, with a statistically significant difference (RR=1.26, 95% CI: 1.19-1.34, P <0.05). The results of the meta-analysis can be seen in Fig.27. 2.6 Publication bias The number of meta-analysis documents for 2 indicators (ORR and DCR) exceeds 10, with statistically significant results. A funnel plot was utilized to assess distribution shape and detect publication bias. The findings revealed a convergence towards the tip and symmetrical distribution in both plots, falling within the 95% CI, suggesting minimal publication bias (Fig. 28-29) 3. Discussion In 2021, the National Health Commission released the 'Notice on Standardizing the Comprehensive Clinical Evaluation of Drugs' along with the 'Guidelines for the Management of Comprehensive Clinical Evaluation of Drugs (2021 Trial Version)' to advance the clinical assessment of drugs(China National Health Development Research Center.2022). Responding to this initiative, as clinical pharmacy professionals, we selected Sintilimab, a novel domestic anti-tumor medication with independent intellectual property rights, for evaluation due to the significant prevalence and fatality rates associated with lung cancer. Given its limited clinical usage history and unique status in China as a medical insurance drug, our plan is to conduct a preliminary assessment of the efficacy and safety of Sintilimab in combination with chemotherapy for treating advanced non-small cell lung cancer using Meta-analysis. This study adheres to the 'Technical Guidelines for Comprehensive Clinical Evaluation of Anti-Tumor Drugs (2022 Trial Version)'. Initially, the evidence will be scrutinized through a systematic literature review, with a recommendation to include additional clinical empirical evidence if deemed insufficient. Prior to the initiation of this study, numerous clinical trials investigating the efficacy of Sintilimab in treating NSCLC were already underway, with a multitude of RCTs results having been reported. Initial searches revealed existing studies on the use of Sintilimab either as a standalone treatment or in combination with other therapies. A meta-analysis was subsequently conducted to evaluate the drug's effectiveness and safety. Systematic reviews and meta-analyses that had been previously published were synthesized for comparative purposes, with detailed findings presented in Table 2. The outcomes of the Meta-analysis were inconclusive, warranting further investigation in this medical research area. It is crucial to continuously update Meta-analyses as new evidence or literature emerges. In cases where research findings differ significantly or are contradictory, prompt adjustments to existing conclusions are necessary. This ongoing study aims to provide updated results and explore the most recent evidence supporting the use of Sintilimab in combination with chemotherapy for NSCLC treatment. The evaluation of a drug or treatment plan typically involves analyzing qualitative and quantitative data related to safety, effectiveness, and economics. With the evolving needs of social development and national policy formulation, this evaluation now includes assessing aspects like innovation, suitability, and accessibility to ensure a more comprehensive evaluation. Safety remains a top priority throughout the evaluation process. Notably, anti-tumor drugs, including traditional chemotherapy drugs, targeted drugs, and ICIs, tend to have higher toxicity levels compared to other drug types like anti-hypertensive, anti-hyperlipidemic, anti-bacterial, and digestive system drugs. Therefore, special attention must be given to the safety of anti-tumor drugs due to their high potential for side effects. Regarding safety, 15 out of the 21 papers included in the study reported TRAEs, with 2 of them specifically mentioning various grades of immune-related adverse reactions, including grade ≥3 reactions. The control group consisted of a placebo in combination with chemotherapy. However, it was not specified whether the placebo was an ICIs, therefore a meta-analysis on immune-related adverse reactions could not be conducted. It is unlikely that immune-related adverse reactions occurred in the pure chemotherapy control group, hence the Chinese literature analyzed did not mention Sintilimab. Furthermore, immune-related adverse events(irAEs) were attributed to antibiotics. Upon thorough analysis of the research findings, it was observed that the risk of hypothyroidism was significantly higher in the intervention group compared to the control group, with a risk ratio of 5.14. This notable disparity is statistically significant and provides robust data to enhance our understanding of the disease's pathogenesis and refine treatment strategies. The mechanism by which Sintilimab induces hypothyroidism is thought to be linked to its inhibition of PD-1 receptors and the proliferation of T cells, potentially including self-reactive T cells that possess potent immune effects and target the thyroid, resulting in thyroid damage(Weinmann and Pisetsky 2019). Additionally, post-immunotherapy autoimmunity in patients is also considered a contributing factor(Orlov et al. 2015). The incidence of thyroid function impairment due to PD-1 inhibitors ranges from 5% to 10%, primarily manifesting as hypothyroidism and thyrotoxicosis. Hypothyroidism, being more prevalent, disproportionately affects female patients, particularly younger individuals (Expert consensus on immune-related adverse reactions of the endocrine system caused by immune checkpoint inhibitors (2020)). Common symptoms of hypothyroidism include fatigue, weakness, reduced appetite, bradycardia, constipation, and weight gain(Zhang et al.2024). About half of patients with thyroid function impairment experience permanent damage, underscoring the importance of prompt diagnosis and appropriate intervention. The findings of this study suggest that when treating NSCLC patients with Sintilimab, it is crucial to enhance the comprehension of associated TRAEs, particularly the potential occurrence of irAES, and to intensify monitoring. This preparation is essential for effectively managing immune-related adverse reactions through prevention, observation, and timely treatment. Before drugs are approved for clinical use, they must undergo extensive testing to ensure safety and efficacy. This involves selecting subjects using scientific methods, designing and executing rigorous trial protocols with professional physicians. Despite passing these tests, there remains uncertainty regarding the drug's real-world effectiveness due to the limited number of participants in clinical trials. Typically, phase III trials involve around 250-1,000 individuals, with even fewer in phase I and II trials (usually under 100). Once a drug is on the market, it may be used by hundreds of thousands of patients, treated by doctors of varying expertise. Some drugs have been removed from the market due to safety concerns or lack of efficacy in practical use (Madhusoodanan 2023; FDA 2010; Tian et al. 2014). Therefore, continuous monitoring and evaluation of a drug's safety and effectiveness in diverse real-world settings are essential post-market approval. In comparison with published meta-analyses, the results indicate that the combination of chemotherapy and Sintilimab in NSCLC patients led to significantly higher OS and PFS times, as well as increased ORR and DCR when compared to the chemotherapy/Sintilimab single-agent control group. Refer to Table 2 (cont.) for more detailed information. The studies included in this analysis reported a limited number of long-term efficacy indicators such as OS and PFS, which could be attributed to challenges in obtaining survival data and the complexity of statistical analysis(Chen et al.2013). Consequently, the variability in the improvement of survival duration with the combination therapy cannot be further elucidated. Nevertheless, the available research findings suggest that combining Sintilimab with chemotherapy can notably enhance the ORR and DCR in NSCLC patients. Overall, the current evidence supports the clear efficacy of combining Sintilimab with chemotherapy in the treatment of advanced NSCLC. This study is subject to several limitations. Firstly, the nature and ethical considerations of cancer clinical trials make it challenging to blind both patients and doctors. Out of the 21 documents analyzed, only 3 utilized blinding, potentially introducing implementation bias. Secondly, the combined analysis of various outcome indicators revealed high heterogeneity among study outcomes. This heterogeneity could be attributed to several factors: 1) Variations in chemotherapy regimens used in the clinical trials, such as Paclitaxel, Pemetrexed, Gemcitabine, or Etoposide in combination with platinum, which may interact with immune checkpoint inhibitors to produce synergistic effects(Lan et al.2022; Ye 2022; Zheng and Li 2022; Wang et al.2018; Xu et al.2022; Lee et al.2020); 2) Limited availability of data for certain outcome indicators like OS and PFS, hindering a comprehensive meta-analysis to explore sources of heterogeneity; 3) Inadequate reporting of patient status scores in some studies, potentially impacting the efficacy of the intervention; 4) Lack of information on pretreatment before immunotherapy in the intervention group, which could influence adverse reactions and outcomes. Additionally, the study only included literature in Chinese and English, potentially introducing language bias. Finally, specific subgroups such as those with liver or kidney dysfunction, elderly individuals, etc., were not specifically analyzed, highlighting the need for further real-world research on these populations. Declarations Funding This work was supported by the 2022-2023 Guangxi Zhuang Autonomous Region Health Commission Comprehensive Clinical Evaluation of Drugs Subject Funding Project, Project contract number: YPPJ005. Data Availability Not applicable. Declarations Competing interests The authors declare no competing interests. Conflict of interest The authors have no relevant financial or non-financial interests to disclose. Consent to participate Not applicable. Consent to publish Not applicable. Ethics approval Not applicable References Cao J (2022) Effect of Sintilimab on the efficacy and immune function of patients with advanced lung squamous cell carcinoma. 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Lung Cancer 171:56–60 Zhang SF, Wang Y, Sun T et al (2024) Case analysis and pharmacological supervision of a case of immune-related hypothyroidism caused by Sintilimab. China Prescription Drugs 22(01):80–83 (Chinese) Zhang YL (2023) Analysis of the effect of Sintilimab combined with chemotherapy on immune function and tumor marker levels in patients with advanced non-small cell lung cancer. Mod Diagnosis Treat 34(04):553–555 (Chinese) Zhang ZL, Tong Z, Xu JF (2023) Observation on the efficacy of Sintilimab injection combined with chemotherapy in the treatment of patients with recurrent or metastatic NSCLC. J Clin Experimental Med 22(13):1374–1378 (Chinese) Zheng YJ, Li ZR (2022) Effect of Sintilimab combined with PC chemotherapy regimen on disease control rate and serum tumor marker levels in patients with advanced lung adenocarcinoma. Henan Med Res 31(17):3194–3196 (Chinese) Zhou CC, Wu L, Fan Y et al (2021) Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or metastatic squamous NSCLC: results from a randomized, double-blind, phase 3 trial (ORIENT-12). J Thorac Oncol 16(9):1501–1511 Tables Table 1 Table of basic characteristics of the 21 studies First author/s, year Patients T/C(n) Intervention measures(test/control) Outcome index He SY et al. 2021 Patients with advanced NSCLC 35/35 Sin + Ap AP ①②⑤ Zhang ZL et al. 2023 Patients with advanced non-squamous NSCLC lung cancer 30/30 Sin + Paclitaxel Paclitaxel ①②③④⑤ Zhang YL 2023 Patients with advanced NSCLC 26/26 Sin + GP GP ①②⑤ Ye ZG 2022 Patients with advanced squamous NSCLC 42/42 Sin + GP GP ①②⑤ Yang MW et al. 2022 Patients with advanced NSCLC 38/38 Sin + TP TP ①②⑤ Jin X et al. 2022 Patients with advanced NSCLC 39/39 non-squamous :Sin + PC Squamous:Sin + TP non-squamous :PC squamous:TP ①② Ma FQ et al. 2021 Patients with advanced NSCLC 28/27 Sin + EP EP ①②⑤ Wu QB 2022 Patients with advanced NSCLC 30/30 Sin + TP TP ①②⑤ Wang KS et al. 2022 Patients with advanced NSCLC 40/40 Sin + PC PC ①② Song MX 2022 Patients with Unresectable and Radical Synchronized Radiotherapy for Advanced Squamous NSCLC 30/30 Sin + GP GP ①②④⑤ Table 1 (cont.) First author/s, year Patients T/C(n) Intervention measures(test/control) Outcome index Shao JP et al. 2023 Patients with advanced NSCLC 35/35 Sin + GP GP ①②⑤ Zheng YJ et al. 2022 Patients with advanced non-squamous NSCLC 35/35 Sin + PC PC ①②⑤ Lan WB et al. 2022 Patients with advanced NSCLC without driver mutations 34/34 Sin + TP TP ①②⑤ Hu YM et al. 2022 Unresectable Stage III ~ IV NSCLC 43/43 Sin + GP GP ①②⑤ Hong YD 2023 Patients with advanced NSCLC 34/32 Sin + TP TP ①② Chen LX et al. 2022 Patients with advanced NSCLC 90/90 Sin + GP GP ①② Cao J 2022 Patients with advanced squamous NSCLC lung cancer 40/40 Sin + EP EP ①②⑤ LuS 2023 Advanced EGFR-mutated non-squamous NSCLC 158/160 Sin + PC placebo-controlled substance + PC ①④⑤ LiangXY2021 Patients with advanced NSCLC 60/60 Sin + GP GP ①② ZhouCC2021 Untreated advanced squamous NSCLC 179/178 Sin + GP placebo-controlled substance + GP ②④⑤ ZhangL2022 Patients with untreated locally advanced or metastatic non-squamous NSCLC 266/131 Sin + PC placebo-controlled substance + PC ③ Notes: T为treatment group;༣༚control group༛sin༚Sintilimab༛PC༚Pemetrexed + platinum༛GP:Gemcitabine + platinum༛TP༚Paclitaxel + Platinum༛EP༚Etoposide + Platinum༛AP༚Albumin paclitaxel ①ORR, Objective Response Rate; ②DCR, Disease Control Rate; ③mOS, median-overall survival; ④mPFS, median-progressionfree survival; ⑤TRAEs, treatment-related adverse events. Table 2 Basic information of SR/ meta-analysis published First author and year of publication Literature search deadline Patient type Number of relevant studies Sources of data for inclusion in the literature Intervention vs. control Outcome Measures for Meta-Analysis Xie J 2022 October 2021 advanced stage NSCLC 6 ORINET-11、RCTs for hospitals sin + CT/anlotinib vs.CT/anlotinib PFS、OS、ORR、DCR、TRAEs Li J 2023 April 2022 advanced stage NSCLC 8 ORINET-11、ORIENT-12、RCTs for hospitals sin ± CT/anlotinib/apatinib/bevacizumab biosimilarvs.CT/anlotinib/apatinib/sorafenib PFS、OS、ORR、DCR、TRAEs this study August 10, 2023 advanced stage NSCLC 21 ORINET-11、ORIENT-12、ORIENT-31、RCTs for hospitals sin + CT vs. CT PFS、OS、ORR、DCR、TRAEs Notes: SR:systematic reviews;sin:Sintilimab༛CT:Chemotherapy、Chemotherapy regimens include: Gemcitabine + Platinum,Pemetrexed + Platinum,Paclitaxel + Platinum,Etoposide + Platinum;PFS:Progression-free survival༛OS:Overall survival;ORR༚Objective response rate;DCR:disease control rate Table 2 (cont.) First author and year of publication Number of cases Efficacy results Safety results Xie J 2022 1162 OS and PFS times, ORR and DCR were significantly higher in NSCLC patients in the intervention group compared with the control group Three studies showed no significant TRAEs difference in advanced NSCLC patients between intervention and control groups. However, this study also observed that hypothyroidism risk was significantly higher (RR: 5.14) in the intervention group. Potential risks of pneumonia, proteinuria, skin rash, and infusion reaction were observed, though not statistically significant. Gastrointestinal issues and hair loss decreased in the intervention group, but not significantly. Safety and chemotherapy groups showed no significant differences in adverse events like hematological toxicity and liver damage. Li J 2023 1553 This study 2487 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 08 Jul, 2024 Reviews received at journal 04 Jul, 2024 Reviewers agreed at journal 04 Jul, 2024 Reviewers invited by journal 04 Jul, 2024 Editor assigned by journal 17 Jun, 2024 Submission checks completed at journal 17 Jun, 2024 First submitted to journal 15 Jun, 2024 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. 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27","display":"","copyAsset":false,"role":"figure","size":15070,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of DCR\u003c/p\u003e","description":"","filename":"image27.png","url":"https://assets-eu.researchsquare.com/files/rs-4587063/v1/8a8a3378fff0a0fd4a7beda0.png"},{"id":60017846,"identity":"75008fe2-881b-41ef-9193-93e7ff35e0b9","added_by":"auto","created_at":"2024-07-10 15:07:56","extension":"png","order_by":28,"title":"Figure 28","display":"","copyAsset":false,"role":"figure","size":3847085,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot of ORR\u003c/p\u003e","description":"","filename":"image28.png","url":"https://assets-eu.researchsquare.com/files/rs-4587063/v1/c1415f91bb291c4c1eae463c.png"},{"id":60019337,"identity":"23dcea32-edea-411c-9e82-edb6a9caac4a","added_by":"auto","created_at":"2024-07-10 15:23:56","extension":"png","order_by":29,"title":"Figure 29","display":"","copyAsset":false,"role":"figure","size":3847085,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot of DCR\u003c/p\u003e","description":"","filename":"image29.png","url":"https://assets-eu.researchsquare.com/files/rs-4587063/v1/80b35ae9d279416e14af80dc.png"},{"id":60020237,"identity":"543746bf-0d26-4ce6-aff8-33c67c868377","added_by":"auto","created_at":"2024-07-10 15:40:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1580584,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4587063/v1/71ce2f51-617a-4639-8ad0-ad417c4b7905.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A meta-analysis of the effectiveness and safety of Sintilimab combined with chemotherapy in the trea tment of advanced non-small cell lung cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer poses a significant health challenge due to its high incidence and lethality globally and in our country(Global cancer burden sevices.2024;Zheng et al.2024). Non-small-cell lung cancer (NSCLC) accounts for a large portion of lung cancer cases, with most patients diagnosed at advanced stages(Postmus et al. 2017). The introduction of immune checkpoint inhibitors (ICIs), particularly the domestically produced Sintilimab targeting PD-1, has provided a new treatment option for NSCLC. Sintilimab enhances immune surveillance and anti-tumor response by blocking PD-1 interaction with PD-L1/L2(Hoy 2019). Despite its early clinical approval, Sintilimab faces challenges in post-marketing evaluation due to limited data and evaluation. To ensure safety and efficacy, a Meta-analysis following the Technical Guidelines for Comprehensive Clinical Evaluation of Antineoplastic Drugs (2022 Trial Edition) will be conducted to support evidence-based medicine for Sintilimab in combination with chemotherapy for NSCLC and inform clinical application and drug policy decisions (National Heath Commission of the People\u0026rsquo;s Republic of China.2022).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"1. Information and methods","content":"\u003cp\u003e1.1 Inclusion criteria\u003c/p\u003e\n\u003cp\u003e(1) The studies were randomized controlled trials (RCTs) reported in both Chinese and English; (2)The subjects included in the study were clinically diagnosed with intermediate to advanced NSCLC and met the corresponding disease stage and pathological diagnostic criteria; (3)Chemotherapeutic regimens adhered strictly to drug inserts and expert consensus, primarily utilizing Pemetrexed, Gemcitabine, and Paclitaxel combined with Platinum drugs, with dosages following guidelines; (4)Outcome indicators measured included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS), Treatment Emergent Adverse Events (TRAEs) were assessed.\u003c/p\u003e\n\u003cp\u003eEfficacy was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST), while TRAEs were graded and recorded following CTCAE (version 5.0).\u003c/p\u003e\n\u003cp\u003e1.2 Exclusion criteria\u003c/p\u003e\n\u003cp\u003e(1) duplicate publications; and (2) literature without relevant outcome indicators for this study or without access to the full text.\u003c/p\u003e\n\u003cp\u003e1.3 Literature search strategy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study conducted a comprehensive search of both domestic and foreign published RCTs on the use of sintilimab in the treatment of NSCLC. The search encompassed foreign journal databases such as PubMed, Embase, Web of Science, and Cochrane Library, as well as Chinese journal databases including CNKI, CBMdisc, cqvip, and Wanfang. The search strategy utilized a combination of subject words and free words, tailored to the specific characteristics of each database. Keywords such as Sintilimab, PD-1/PD-L1, IBI308, Lung Neoplasms, non-small cell lung cancer, and Controlled Clinical Trial were employed. The search period ranged from the inception of each database to August 10, 2023. Additionally, references from the included studies were tracked to supplement relevant literature.As shown in Fig. 1.\u003c/p\u003e\n\u003cp\u003e1.4 Literature Screening and Data Extraction\u003c/p\u003e\n\u003cp\u003eAccording to the inclusion and exclusion criteria, two investigators independently screened the literature, extracted the data, and cross-checked them. In cases of disagreement, they consulted a third investigator and attempted to contact the authors for missing information. The inclusion of literature was based on reading the full text, and a standardized data extraction form was used to collect:\u0026nbsp;①\u0026nbsp;basic information (study name, authors, time, etc.);\u0026nbsp;②\u0026nbsp;baseline characteristics of the patients (age, sex, stage, type of pathology, and Ecog scores);\u0026nbsp;③\u0026nbsp;details of interventions and controls; and\u0026nbsp;④\u0026nbsp;endpoint indicators and results. Any disagreements were resolved by a third researcher.\u003c/p\u003e\n\u003cp\u003e1.5 Literature quality assessment and statistical treatment\u003c/p\u003e\n\u003cp\u003eThe quality of literature in the included RCTs was evaluated using the Cochrane Handbook tool\u0026nbsp;(Zeng et al.2012; Higgins et al.2003). Meta-analysis was conducted with Revman 5.4, where OS and PFS were assessed using HR (hazard ratio) and 95% CI, while dichotomous variables like ORR, DCR, and TRAEs were analyzed with RR and 95% CI. A significance level of (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.1, I\u003csup\u003e2\u003c/sup\u003e \u0026le;\u0026nbsp;50%) and a random-effects model for heterogeneity (\u003cem\u003eP\u003c/em\u003e \u0026le;\u0026nbsp;0.1, I\u003csup\u003e2\u003c/sup\u003e \u0026gt; 50%) to address clinical heterogeneity. Subgroup analyses, sensitivity analyses, or descriptive analyses were employed for significant heterogeneity. Funnel plots will be used for bias assessment if there are more than 10 articles for a specific outcome metric and the results are statistically significant. A symmetrical distribution of scatter points suggests no significant publication bias, while an asymmetrical distribution indicates the presence of publication bias.\u003c/p\u003e"},{"header":"2. Results","content":"\u003cp\u003e2.1 Literature screening results and process\u003c/p\u003e\n\u003cp\u003eBased on the search strategy, 1,702 papers were initially obtained. After using EndnoteX9 to filter out irrelevant papers, 1,158 papers remained. Excluding 1,130 non-RCT documents such as reviews, the full text of the remaining 28 documents that met the criteria for analysis was thoroughly reviewed. Seven documents were excluded due to incomplete content or inaccessible outcome indicators, leaving 21 documents for the Meta-analysis. The literature screening process is illustrated in Fig. 2.\u003c/p\u003e\n\u003cp\u003e2.2 Basic characteristics of the included studies\u003c/p\u003e\n\u003cp\u003eAmong the 21 papers finally included, there was 1 master\u0026apos;s thesis and 20 journal papers; 4 were in English and 17 in Chinese; the publication years were from 2021 to 2023.A total of 2,487 patients with advanced NSCLC were included in the 21 papers, with 1,312 cases in the experimental group and 1,175 cases in the control group. The detailed baseline characteristics are shown in Table 1.\u003c/p\u003e\n\u003cp\u003e2.3 Evaluation of the quality of literature\u003c/p\u003e\n\u003cp\u003eAll 21 papers were randomized controlled trials. Among them, 5 explicitly mentioned randomized control and allocation method concealment\u0026nbsp;(Zhang et al.2022; Zhou et al, 2021; Lu et al,2023; He et al 2021; Lan et al.2022), such as the randomized envelope method and centralized randomized system method, which were defined as \u0026apos;low risk\u0026apos;. 16 trials did not explicitly mention allocation method concealment, but only mentioned randomization, which was defined as \u0026apos;unclear\u0026apos;. 3 trials were double-blind evaluations, defined as \u0026apos;low risk\u0026apos;\u0026nbsp;(Zhang et al.2022; Zhou et al, 2021; Lu et al,2023), while 18 trials were non-blinded evaluations, defined as \u0026apos;high risk\u0026apos;. One trial had shedding cases but complete data, defined as \u0026apos;low risk\u0026apos;. The remaining 20 trials with complete data and no selective reporting were also considered \u0026apos;low risk\u0026apos;\u0026nbsp;(Yang et al.2022). All studies with complete study objectives and no reporting bias were defined as \u0026apos;low risk\u0026apos;. Other biases were not described in detail and were defined as \u0026apos;unclear\u0026apos;. The quality of the literature is shown in Fig. 3a-3b.\u003c/p\u003e\n\u003cp\u003e2.4 Safety meta-analysis results\u003c/p\u003e\n\u003cp\u003e2.4.1 TRAEs at any level\u003c/p\u003e\n\u003cp\u003eTwo studies were included in the analysis of TRAEs(Zhou et al, 2021; Lu et al,2023). The heterogeneity test revealed no statistically significant difference between the studies (\u003cem\u003eP\u003c/em\u003e=0.94, I\u0026sup2;=0%), thus the fixed-effects model was utilized for effect size combination. The pooled results indicated that there may be no significant variance in adverse reaction incidence between the combination group and the control group (RR=1.00, 95%CI: 0.98-1.02, \u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). The Meta-analysis results can be observed in Fig.4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOut of the 21 included studies, 15 reported various categories of adverse events. This study will examine adverse reaction categories across all included literature. Arrhythmia and hypoproteinemia were excluded from the analysis due to being reported in only one study, preventing I\u003csup\u003e2\u003c/sup\u003e calculation in Revman.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study findings suggested no significant disparity between the intervention group and the control group in adverse event occurrence related to Platelet count decreased, Neutrophil count decreased, White blood cell count decreased, anemia, and hepatic impairment, with no statistically significant differences (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05). The intervention group exhibited slightly lower occurrence rates of gastrointestinal reactions like nausea, vomiting, and hair loss compared to the control group, with no statistically significant differences (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05). Conversely, the intervention group may have slightly higher incidence rates than the control group in pneumonia, albuminuria, skin rash, and infusion reaction adverse events, with no statistically significant differences (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05). Notably, the intervention group had a significantly higher probability of hypothyroidism compared to the control group (RR = 5.14, 95% CI: 2.36-11.21, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). The Meta-analysis results are displayed in Fig.5-16.\u003c/p\u003e\n\u003cp\u003e2.4.2\u0026nbsp;\u0026ge;\u0026nbsp;3 TRAEs\u003c/p\u003e\n\u003cp\u003eFour studies analyzed grade\u0026nbsp;\u0026ge;3 treatment-related adverse events in advanced NSCLC patients treated with Sintilimab in combination with chemotherapy(Zhou et al, 2021; Lu et al,2023;\u0026nbsp;Song 2021;Cao 2022). A statistically significant heterogeneity was observed among the studies (\u003cem\u003eP\u003c/em\u003e=0.0002, I\u0026sup2;=84%), and a random-effects model was used to combine the effect sizes. The results indicated that the intervention group may have a slightly lower incidence of grade\u0026nbsp;\u0026ge;3 treatment-related adverse events compared to the control group, but the difference was not statistically significant (RR=0.81, 95% CI: 0.56-1.17, \u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). The meta-analysis results are presented in Fig.17. This study focused on analyzing literature concerning grade\u0026nbsp;\u0026ge;3 adverse reactions. The findings revealed that, in comparison to the control group, the combination group had a slightly higher incidence of grade\u0026nbsp;\u0026ge;3 adverse reactions related to Platelet count decreased, which was not statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). There were no significant differences between the combination group and the control group in grade\u0026nbsp;\u0026ge;3 adverse reactions related to Neutrophil count decreased and anemia (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). Additionally, the combination group had a lower incidence of grade\u0026nbsp;\u0026ge;3 adverse reactions related to nausea, vomiting, other gastrointestinal(GI) reactions, and hepatic function impairment compared to the control group, with no statistically significant differences (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). The results of the meta-analysis can be seen in Fig.18-23.\u003c/p\u003e\n\u003cp\u003e2.5 Effectiveness Meta-analysis Results\u003c/p\u003e\n\u003cp\u003e2.5.1 Median overall survival\u003c/p\u003e\n\u003cp\u003eThree studies provided HR values and 95% CIs for mOS\u0026nbsp;(Zhang et al.2022; Zhou et al, 2021; Lu et al,2023). After detecting possible heterogeneity among the studies (\u003cem\u003eP\u003c/em\u003e=0.08, I\u003csup\u003e2\u003c/sup\u003e=60%), a random-effects model was used to combine the effect sizes. Subsequently, a random-effects model was selected for the meta-analysis of the three papers, as depicted in Fig.24a.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurther investigation into the sources of heterogeneity revealed no significant heterogeneity (\u003cem\u003eP\u003c/em\u003e=0.62, I\u003csup\u003e2\u003c/sup\u003e=0%), leading to the utilization of a fixed-effects model for meta-analysis. This analysis indicated that the combination group exhibited a longer time to mOS and a 37% reduced risk of death in advanced NSCLC patients compared to the control group, with statistical significance (HR=0.63, 95% CI:0.50-0.79, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05), as illustrated in Fig.24b.\u003c/p\u003e\n\u003cp\u003e2.5.2 Median progression-free survival\u003c/p\u003e\n\u003cp\u003eHR values and 95% CIs for mPFS were extracted from two papers for analysis\u0026nbsp;(Zhou et al, 2021; Lu et al,2023). A heterogeneity test indicated potential differences between the studies (\u003cem\u003eP\u003c/em\u003e=0.11, I\u003csup\u003e2\u003c/sup\u003e=61%), prompting the use of a random-effects model for combining effect sizes. The findings revealed that the combination therapy group exhibited a longer time to mPFS and a 38% reduced risk of disease progression in NSCLC patients compared to the control group, with a statistically significant result (HR = 0.62, 95% CI:0.46-0.82, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). These results are visually presented in Fig. 25.\u003c/p\u003e\n\u003cp\u003e2.5.3 Objective response rate\u003c/p\u003e\n\u003cp\u003eEighteen papers reported ORR data(He et al.2021; Lan et al.2022; Zhang et al.2023; Zhang 2023; Ye 2022; Yang et al.2022; Jin et al.2022; Ma et al.2021; Wu 2022; Wang et al.2022; Song 2021; Shao and Li 2023; Zheng and Li 2022; Hu et al.2022; Hong 2023; Chen et al.2022; Cao 2022; Liang and Wei 2021). A heterogeneity test indicated no statistical heterogeneity among the studies (\u003cem\u003eP\u003c/em\u003e=0.81, I\u003csup\u003e2\u003c/sup\u003e=0%), therefore, effect sizes were combined using a fixed-effects model. The results demonstrated a significant improvement in ORR for NSCLC patients in the combination group compared to the control group, with a statistically significant difference (RR=1.74, 95% CI: 1.55-1.94, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). The results of the meta-analysis can be seen in Fig.26.\u003c/p\u003e\n\u003cp\u003e2.5.4 Disease control rate\u003c/p\u003e\n\u003cp\u003eNineteen papers reported data on DCR(Zhou et al.2021;He et al.2021; Lan et al.2022; Zhang et al.2023; Zhang 2023; Ye 2022; Yang et al.2022; Jin et al.2022; Ma et al.2021; Wu 2022; Wang et al.2022; Song 2021; Shao and Li 2023; Zheng and Li 2022; Hu et al.2022; Hong 2023; Chen et al.2022; Cao 2022; Liang and Wei 2021), and the heterogeneity test indicated no statistical heterogeneity among the studies (\u003cem\u003eP\u003c/em\u003e=0.45, I\u003csup\u003e2\u003c/sup\u003e=1%). The effect sizes were combined using a fixed-effects model. The findings revealed that the combination group significantly improved the DCR of NSCLC patients compared to the control group, with a statistically significant difference (RR=1.26, 95% CI: 1.19-1.34, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). The results of the meta-analysis can be seen in Fig.27.\u003c/p\u003e\n\u003cp\u003e2.6 Publication bias\u003c/p\u003e\n\u003cp\u003eThe number of meta-analysis documents for 2 indicators (ORR and DCR) exceeds 10, with statistically significant results. A funnel plot was utilized to assess distribution shape and detect publication bias. The findings revealed a convergence towards the tip and symmetrical distribution in both plots, falling within the 95% CI, suggesting minimal publication bias (Fig. 28-29)\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eIn 2021, the National Health Commission released the \u0026apos;Notice on Standardizing the Comprehensive Clinical Evaluation of Drugs\u0026apos; along with the \u0026apos;Guidelines for the Management of Comprehensive Clinical Evaluation of Drugs (2021 Trial Version)\u0026apos; to advance the clinical assessment of drugs(China National Health Development Research Center.2022). Responding to this initiative, as clinical pharmacy professionals, we selected Sintilimab, a novel domestic anti-tumor medication with independent intellectual property rights, for evaluation due to the significant prevalence and fatality rates associated with lung cancer. Given its limited clinical usage history and unique status in China as a medical insurance drug, our plan is to conduct a preliminary assessment of the efficacy and safety of Sintilimab in combination with chemotherapy for treating advanced non-small cell lung cancer using Meta-analysis. This study adheres to the \u0026apos;Technical Guidelines for Comprehensive Clinical Evaluation of Anti-Tumor Drugs (2022 Trial Version)\u0026apos;. Initially, the evidence will be scrutinized through a systematic literature review, with a recommendation to include additional clinical empirical evidence if deemed insufficient.\u003c/p\u003e\n\u003cp\u003ePrior to the initiation of this study, numerous clinical trials investigating the efficacy of Sintilimab in treating NSCLC were already underway, with a multitude of RCTs results having been reported. Initial searches revealed existing studies on the use of Sintilimab either as a standalone treatment or in combination with other therapies. A meta-analysis was subsequently conducted to evaluate the drug\u0026apos;s effectiveness and safety. Systematic reviews and meta-analyses that had been previously published were synthesized for comparative purposes, with detailed findings presented in Table 2. The outcomes of the Meta-analysis were inconclusive, warranting further investigation in this medical research area. It is crucial to continuously update Meta-analyses as new evidence or literature emerges. In cases where research findings differ significantly or are contradictory, prompt adjustments to existing conclusions are necessary. This ongoing study aims to provide updated results and explore the most recent evidence supporting the use of Sintilimab in combination with chemotherapy for NSCLC treatment.\u003c/p\u003e\n\u003cp\u003eThe evaluation of a drug or treatment plan typically involves analyzing qualitative and quantitative data related to safety, effectiveness, and economics. With the evolving needs of social development and national policy formulation, this evaluation now includes assessing aspects like innovation, suitability, and accessibility to ensure a more comprehensive evaluation. Safety remains a top priority throughout the evaluation process. Notably, anti-tumor drugs, including traditional chemotherapy drugs, targeted drugs, and ICIs, tend to have higher toxicity levels compared to other drug types like anti-hypertensive, anti-hyperlipidemic, anti-bacterial, and digestive system drugs. Therefore, special attention must be given to the safety of anti-tumor drugs due to their high potential for side effects.\u003c/p\u003e\n\u003cp\u003eRegarding safety, 15 out of the 21 papers included in the study reported TRAEs, with 2 of them specifically mentioning various grades of immune-related adverse reactions, including grade\u0026nbsp;\u0026ge;3 reactions. The control group consisted of a placebo in combination with chemotherapy. However, it was not specified whether the placebo was an ICIs, therefore a meta-analysis on immune-related adverse reactions could not be conducted. It is unlikely that immune-related adverse reactions occurred in the pure chemotherapy control group, hence the Chinese literature analyzed did not mention Sintilimab. Furthermore, immune-related adverse events(irAEs) were attributed to antibiotics.\u003c/p\u003e\n\u003cp\u003eUpon thorough analysis of the research findings, it was observed that the risk of hypothyroidism was significantly higher in the intervention group compared to the control group, with a risk ratio of 5.14. This notable disparity is statistically significant and provides robust data to enhance our understanding of the disease\u0026apos;s pathogenesis and refine treatment strategies. The mechanism by which Sintilimab induces hypothyroidism is thought to be linked to its inhibition of PD-1 receptors and the proliferation of T cells, potentially including self-reactive T cells that possess potent immune effects and target the thyroid, resulting in thyroid damage(Weinmann and Pisetsky 2019).\u0026nbsp;Additionally, post-immunotherapy autoimmunity in patients is also considered a contributing factor(Orlov et al. 2015). The incidence of thyroid function impairment due to PD-1 inhibitors ranges from 5% to 10%, primarily manifesting as hypothyroidism and thyrotoxicosis. Hypothyroidism, being more prevalent, disproportionately affects female patients, particularly younger individuals\u0026nbsp;(Expert consensus on immune-related adverse reactions of the endocrine system caused by immune checkpoint inhibitors (2020)). Common symptoms of hypothyroidism include fatigue, weakness, reduced appetite, bradycardia, constipation, and weight gain(Zhang et al.2024). About half of patients with thyroid function impairment experience permanent damage, underscoring the importance of prompt diagnosis and appropriate intervention.\u003c/p\u003e\n\u003cp\u003eThe findings of this study suggest that when treating NSCLC patients with Sintilimab, it is crucial to enhance the comprehension of associated TRAEs, particularly the potential occurrence of irAES, and to intensify monitoring. This preparation is essential for effectively managing immune-related adverse reactions through prevention, observation, and timely treatment.\u003c/p\u003e\n\u003cp\u003eBefore drugs are approved for clinical use, they must undergo extensive testing to ensure safety and efficacy. This involves selecting subjects using scientific methods, designing and executing rigorous trial protocols with professional physicians. Despite passing these tests, there remains uncertainty regarding the drug\u0026apos;s real-world effectiveness due to the limited number of participants in clinical trials. Typically, phase III trials involve around 250-1,000 individuals, with even fewer in phase I and II trials (usually under 100). Once a drug is on the market, it may be used by hundreds of thousands of patients, treated by doctors of varying expertise. Some drugs have been removed from the market due to safety concerns or lack of efficacy in practical use\u0026nbsp;(Madhusoodanan 2023; FDA 2010; Tian et al. 2014). Therefore, continuous monitoring and evaluation of a drug\u0026apos;s safety and effectiveness in diverse real-world settings are essential post-market approval.\u003c/p\u003e\n\u003cp\u003eIn comparison with published meta-analyses, the results indicate that the combination of chemotherapy and Sintilimab in NSCLC patients led to significantly higher OS and PFS times, as well as increased ORR and DCR when compared to the chemotherapy/Sintilimab single-agent control group. Refer to Table 2 (cont.) for more detailed information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe studies included in this analysis reported a limited number of long-term efficacy indicators such as OS and PFS, which could be attributed to challenges in obtaining survival data and the complexity of statistical analysis(Chen et al.2013). Consequently, the variability in the improvement of survival duration with the combination therapy cannot be further elucidated. Nevertheless, the available research findings suggest that combining Sintilimab with chemotherapy can notably enhance the ORR and DCR in NSCLC patients. Overall, the current evidence supports the clear efficacy of combining Sintilimab with chemotherapy in the treatment of advanced NSCLC.\u003c/p\u003e\n\u003cp\u003eThis study is subject to several limitations. Firstly, the nature and ethical considerations of cancer clinical trials make it challenging to blind both patients and doctors. Out of the 21 documents analyzed, only 3 utilized blinding, potentially introducing implementation bias. Secondly, the combined analysis of various outcome indicators revealed high heterogeneity among study outcomes. This heterogeneity could be attributed to several factors: 1) Variations in chemotherapy regimens used in the clinical trials, such as Paclitaxel, Pemetrexed, Gemcitabine, or Etoposide in combination with platinum, which may interact with immune checkpoint inhibitors to produce synergistic effects(Lan et al.2022; Ye 2022; Zheng and Li 2022; Wang et al.2018; Xu et al.2022; Lee et al.2020); 2) Limited availability of data for certain outcome indicators like OS and PFS, hindering a comprehensive meta-analysis to explore sources of heterogeneity; 3) Inadequate reporting of patient status scores in some studies, potentially impacting the efficacy of the intervention; 4) Lack of information on pretreatment before immunotherapy in the intervention group, which could influence adverse reactions and outcomes. Additionally, the study only included literature in Chinese and English, potentially introducing language bias. Finally, specific subgroups such as those with liver or kidney dysfunction, elderly individuals, etc., were not specifically analyzed, highlighting the need for further real-world research on these populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the 2022-2023 Guangxi Zhuang Autonomous Region Health Commission Comprehensive Clinical Evaluation of Drugs Subject Funding Project, Project contract number: YPPJ005.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCao J (2022) Effect of Sintilimab on the efficacy and immune function of patients with advanced lung squamous cell carcinoma. China Prescription Drugs 20(9):100\u0026ndash;102 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen LX, Sun P, Hu ZZ (2022) Effects of Sintilimab combined with chemotherapy on tumor markers and immune function in advanced non-small cell lung cancer. Lab Med Clin 19(8):1106\u0026ndash;1108 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen X, Xia JL, Jiang ZW (2013) Application of RPSFT method in selective crossover design. China Health Stat 30(02):182\u0026ndash;186\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFDA Pfizer withdraws antitumor drug Mylotarg(2010). J Clin Ration Drug Use 3(13):110.(Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlobal cancer burden growing, amidst mounting need for services(2024). 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Health Care World 2022(24):49\u0026ndash;50 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeinmann SC, Pisetsky DS (2019) Mechanisms of immune- related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology(Oxford) 58(7):59\u0026ndash;67\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang DY, Salem JE, Cohen JV et al (2018) Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 4(12):1721\u0026ndash;1728\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu QB (2022) Clinical effects of Sintilimab combined with TP regimen in the treatment of advanced non-small cell lung cancer. J Clin Ration Drug Use 15(11):70\u0026ndash;73 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu XY, Feng J, Chen H et al (2022) Efficacy and safety analysis of Sintilimab combined with EP regimen in patients with stage IIIa non-small cell lung cancer after radical surgery. Electron J Compr Cancer Therapy 8(03):125\u0026ndash;129 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang MW, Zeng DX, Yang QL et al (2022) Application of Sintilimab in chemotherapy patients with advanced non-small cell lung cancer and its effect on their serum cytokines and immune function. Chin J Clin Pharmacol 38(24):2931\u0026ndash;2935 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYe ZG (2022) Effect of Sintilimab combined with gemcitabine chemotherapy on recent efficacy, serum tumor markers and VEGF levels in patients with squamous lung cancer. China Med Innov 19(34):126\u0026ndash;130 .(Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeng XT, Bao CP, Cao SY et al (2012) Meta-analysis series III: a quality assessment tool for randomized controlled trials. Chin J Evidence-Based Cardiovasc Med 4(03):183\u0026ndash;185 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang L, Wang Z, Fang J et al (2022) Final overall survival data of Sintilimab plus pemetrexed and platinum as First-Line treatment for locally advanced or metastatic nonsquamous NSCLC in the Phase 3 ORIENT-11 study. Lung Cancer 171:56\u0026ndash;60\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang SF, Wang Y, Sun T et al (2024) Case analysis and pharmacological supervision of a case of immune-related hypothyroidism caused by Sintilimab. China Prescription Drugs 22(01):80\u0026ndash;83 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang YL (2023) Analysis of the effect of Sintilimab combined with chemotherapy on immune function and tumor marker levels in patients with advanced non-small cell lung cancer. Mod Diagnosis Treat 34(04):553\u0026ndash;555 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang ZL, Tong Z, Xu JF (2023) Observation on the efficacy of Sintilimab injection combined with chemotherapy in the treatment of patients with recurrent or metastatic NSCLC. J Clin Experimental Med 22(13):1374\u0026ndash;1378 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng YJ, Li ZR (2022) Effect of Sintilimab combined with PC chemotherapy regimen on disease control rate and serum tumor marker levels in patients with advanced lung adenocarcinoma. Henan Med Res 31(17):3194\u0026ndash;3196 (Chinese)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou CC, Wu L, Fan Y et al (2021) Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or metastatic squamous NSCLC: results from a randomized, double-blind, phase 3 trial (ORIENT-12). J Thorac Oncol 16(9):1501\u0026ndash;1511\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cdiv id=\"6\" class=\"btn-xs-small Annotation tooltipped\" data-position=\"top\" data-tooltip=\"\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTable of basic characteristics of the 21 studies\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eFirst author/s, year\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eT/C(n)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eIntervention measures(test/control)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eOutcome index\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eHe SY et al. \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e35/35\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;Ap\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eZhang ZL et al. \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced non-squamous NSCLC lung cancer\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e30/30\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;Paclitaxel\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePaclitaxel\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②③④⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eZhang YL \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e26/26\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eYe ZG \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced squamous NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e42/42\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eYang MW et al. \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e38/38\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;TP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eJin X et al. 2022\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e39/39\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003enon-squamous :Sin\u0026thinsp;+\u0026thinsp;PC\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003eSquamous:Sin\u0026thinsp;+\u0026thinsp;TP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003enon-squamous :PC\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003esquamous:TP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMa FQ et al. \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e28/27\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;EP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eEP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eWu QB \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e30/30\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;TP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eWang KS et al. \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e40/40\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;PC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSong MX 2022\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with Unresectable and Radical Synchronized Radiotherapy for Advanced Squamous NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e30/30\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②④⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e(cont.)\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eFirst author/s, year\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eT/C(n)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eIntervention measures(test/control)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eOutcome index\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eShao JP et al. 2023\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e35/35\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eZheng YJ et al. 2022\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced non-squamous NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e35/35\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;PC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLan WB et al. \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC without driver mutations\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e34/34\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;TP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eHu YM et al. \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnresectable Stage III\u0026thinsp;~\u0026thinsp;IV NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e43/43\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eHong YD \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e34/32\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;TP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChen LX et al. \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e90/90\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eCao J \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced squamous NSCLC lung cancer\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e40/40\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;EP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eEP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLuS 2023\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAdvanced EGFR-mutated non-squamous NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e158/160\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;PC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eplacebo-controlled substance\u0026thinsp;+\u0026thinsp;PC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①④⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLiangXY2021\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with advanced NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e60/60\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e①②\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eZhouCC2021\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUntreated advanced squamous NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e179/178\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eplacebo-controlled substance\u0026thinsp;+\u0026thinsp;GP\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e②④⑤\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eZhangL2022\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients with untreated locally advanced or metastatic non-squamous NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e266/131\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSin\u0026thinsp;+\u0026thinsp;PC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eplacebo-controlled substance\u0026thinsp;+\u0026thinsp;PC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e③\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eNotes: T为treatment group;༣༚control group༛sin༚Sintilimab༛PC༚Pemetrexed\u0026thinsp;+\u0026thinsp;platinum༛GP:Gemcitabine\u0026thinsp;+\u0026thinsp;platinum༛TP༚Paclitaxel\u0026thinsp;+\u0026thinsp;Platinum༛EP༚Etoposide\u0026thinsp;+\u0026thinsp;Platinum༛AP༚Albumin paclitaxel ①ORR, Objective Response Rate; ②DCR, Disease Control Rate; ③mOS, median-overall survival; ④mPFS, median-progressionfree survival; ⑤TRAEs, treatment-related adverse events.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eBasic information of SR/ meta-analysis published\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eFirst author and year of publication\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLiterature search deadline\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatient type\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNumber of relevant studies\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSources of data for inclusion in the literature\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eIntervention vs. control\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eOutcome Measures for Meta-Analysis\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eXie J 2022\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eOctober 2021\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eadvanced stage NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e6\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eORINET-11、RCTs for hospitals\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003esin\u0026thinsp;+\u0026thinsp;CT/anlotinib vs.CT/anlotinib\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePFS、OS、ORR、DCR、TRAEs\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLi J 2023\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eApril 2022\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eadvanced stage NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e8\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eORINET-11、ORIENT-12、RCTs for hospitals\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003esin\u0026thinsp;\u0026plusmn;\u0026thinsp;CT/anlotinib/apatinib/bevacizumab biosimilarvs.CT/anlotinib/apatinib/sorafenib\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePFS、OS、ORR、DCR、TRAEs\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ethis study\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAugust 10, 2023\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eadvanced stage NSCLC\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e21\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eORINET-11、ORIENT-12、ORIENT-31、RCTs for hospitals\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003esin\u0026thinsp;+\u0026thinsp;CT vs. CT\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePFS、OS、ORR、DCR、TRAEs\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eNotes: SR:systematic reviews;sin:Sintilimab༛CT:Chemotherapy、Chemotherapy regimens include: Gemcitabine\u0026thinsp;+\u0026thinsp;Platinum,Pemetrexed\u0026thinsp;+\u0026thinsp;Platinum,Paclitaxel\u0026thinsp;+\u0026thinsp;Platinum,Etoposide\u0026thinsp;+\u0026thinsp;Platinum;PFS:Progression-free survival༛OS:Overall survival;ORR༚Objective response rate;DCR:disease control rate\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e(cont.)\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eFirst author and year of publication\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNumber of cases\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eEfficacy results\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSafety results\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eXie J 2022\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1162\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eOS and PFS times, ORR and DCR were significantly higher in NSCLC patients in the intervention group compared with the control group\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eThree studies showed no significant TRAEs difference in advanced NSCLC patients between intervention and control groups. However, this study also observed that hypothyroidism risk was significantly higher (RR: 5.14) in the intervention group. Potential risks of pneumonia, proteinuria, skin rash, and infusion reaction were observed, though not statistically significant. Gastrointestinal issues and hair loss decreased in the intervention group, but not significantly. Safety and chemotherapy groups showed no significant differences in adverse events like hematological toxicity and liver damage.\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLi J 2023\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1553\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eThis study\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2487\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"naunyn-schmiedebergs-archives-of-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nsap","sideBox":"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)","snPcode":"210","submissionUrl":"https://submission.nature.com/new-submission/210/3","title":"Naunyn-Schmiedeberg's Archives of Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"sintilimab, effectiveness, safety, meta-analysis, advanced non-small cell lung cancer","lastPublishedDoi":"10.21203/rs.3.rs-4587063/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4587063/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eSintilimab, as a domestically produced innovative immune checkpoint inhibitor (ICIs) drug, performs well in the treatment of lung cancer. However, due to the late start of domestically produced ICIs, Sintilimab is currently only available for domestic use, with limited clinical data and facing challenges in post-marketing evaluation. It is planned to use Meta analysis methods to evaluate its safety and effectiveness.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eComputerized searches were conducted on various databases from their inception to August 10, 2023. Meta-analysis was carried out using RevMan 5.4 software after two evaluators independently screened the literature, extracted information, and evaluated the risk of bias in the included studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe results indicated that patients with advanced NSCLC receiving Sintilimab had a 5.14 times higher risk of hypothyroidism compared to the control group. Hematologic toxicity and hepatic impairment were not significantly different from the chemotherapy group, while gastrointestinal and alopecia adverse reactions may be less frequent than in the chemotherapy group. Additionally, the risk of pneumonia, proteinuria, rash, and infusion reaction may be increased. Furthermore, Sintilimab combined with chemotherapy was found to enhance ORR, DCR, and prolong mOS and mPFS in NSCLC patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eSintilimab in combination with chemotherapy for advanced NSCLC is efficacious, safe and manageable.\u003c/p\u003e","manuscriptTitle":"A meta-analysis of the effectiveness and safety of Sintilimab combined with chemotherapy in the trea tment of advanced non-small cell lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-10 15:07:49","doi":"10.21203/rs.3.rs-4587063/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-08T13:05:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-04T09:15:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"84348952890219367717828410992678294877","date":"2024-07-04T09:13:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-04T09:10:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-17T04:37:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-17T04:37:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Naunyn-Schmiedeberg's Archives of Pharmacology","date":"2024-06-15T15:04:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"naunyn-schmiedebergs-archives-of-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nsap","sideBox":"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)","snPcode":"210","submissionUrl":"https://submission.nature.com/new-submission/210/3","title":"Naunyn-Schmiedeberg's Archives of Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"57533d66-f4d5-4429-9c27-6021b5bffd5f","owner":[],"postedDate":"July 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-08-07T06:44:44+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-10 15:07:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4587063","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4587063","identity":"rs-4587063","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}