Comparative effectiveness of immune checkpoint inhibitors in squamous vs. non-aquamous cervical carcinoma: a meta-analysis of randomized controlled trials

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This study aimed to evaluate the efficacy of ICI therapy in metastatic cervical SCC versus non-SCC. Methods A literature search was conducted across PubMed/Embase/the Cochrane Library to identify randomized controlled trials (RCTs) assessing the efficacy of ICI treatment in metastatic cervical cancer. Primary endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results Four RCTs were included in the meta-analysis. ICI treatment demonstrated significant improvements in PFS and OS compared to control treatment in both SCC and non-SCC patients. Anti-PD-1 therapy significantly enhanced ORR in SCC patients (P = 0.0001) but not in non-SCC patients (P = 0.23). Subgroup analysis revealed anti-PD-1 and anti-PD-1/CTLA4 therapies prolonged PFS in SCC patients (both P < 0.0001) but not in non-SCC patients (P = 0.13 and P = 0.83, respectively). Conversely, anti-PD-L1 therapy did not improve PFS in SCC patients (P = 0.22) but significantly enhanced PFS in non-SCC patients (P < 0.0001). OS subgroup analysis indicated prolonged OS in SCC patients treated with anti-PD-1, anti-PD-L1, or anti-PD-1/CTLA4. In non-SCC patients, only the anti-PD-1 subgroup exhibited OS benefit (P = 0.006), while no significant differences were observed in the anti-PD-L1 and anti-PD-1/CTLA4 subgroups (P = 0.08 and P = 0.83, respectively). Conclusions ICI treatment improves outcomes in metastatic cervical cancer; however, the efficacy varies significantly between SCC and non-SCC patients. These findings deserve high clinical attention. aquamous cervical carcinoma non-aquamous cervical carcinoma immune checkpoint inhibitors programmed cell death protein 1 (PD-1) programmed death-ligand 1 (PD-L1) cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Cervical cancer represents a prevalent malignancy that significantly impacts women's health, ranking as the second most common gynecological cancer in terms of both incidence and mortality [1]. The implementation of (human papillomavirus) HPV vaccination programs and cervical cancer screening initiatives has contributed to a global decline in cervical cancer incidence and mortality rates over the past decade [2]. Nevertheless, disease recurrence and metastasis remain substantial challenges in clinical management, with patients experiencing these complications demonstrating poor prognostic outcomes, thereby presenting a persistent therapeutic challenge in gynecological oncology [3,4]. Recent advancements in immunotherapy, particularly the development of immune checkpoint inhibitors (ICIs), have demonstrated significant potential in cervical cancer treatment, offering improved long-term survival prospects [5]. ICIs have been shown to potentiate the efficacy of conventional radiotherapy and chemotherapy through immune system modulation [6–8]. Clinical evidence indicates that the combination of ICIs with radiotherapy and chemotherapy yields superior outcomes for locally advanced cervical cancer patients compared to radiotherapy and chemotherapy alone [8]. In the context of recurrent or metastatic cervical cancer, multiple studies have established that first-line treatment incorporating ICIs in combination with chemotherapy, with or without bevacizumab, significantly enhances long-term survival outcomes [5,9]. Consequently, this combination therapy has emerged as a recommended standard therapeutic strategy for recurrent or metastatic cervical cancer [5,9,10]. Despite the widespread recommendation of ICIs for recurrent or metastatic cervical cancer, there remains a paucity of evidence regarding the differential efficacy of ICI strategies across various histological subtypes, particularly between squamous cell carcinoma (SCC) and non-squamous cell carcinoma (non-SCC). To address this knowledge gap, we conducted a comprehensive meta-analysis of randomized controlled trials (RCTs) to evaluate the comparative efficacy of ICI treatments in recurrent or metastatic SCC versus non-SCC, thereby providing more nuanced evidence to inform clinical decision-making in cervical cancer management. 2. Methods 2.1 Literature screening. A comprehensive literature search was conducted across multiple electronic databases, including PubMed, EMBASE, and the Cochrane Library, encompassing the period from database inception to March 2025. The search strategy employed the following Boolean search terms: ("immunotherapy" OR "immune therapy" OR "immune checkpoint inhibitors" OR "PD-1" OR "PD-L1" OR "pembrolizumab" OR "nivolumab" OR "atezolizumab" OR "avelumab" OR "tremelimumab" OR "durvalumab" OR "spartalizumab" OR "toripalimab" OR "dostarlimab" OR "camrelizumab" OR "sintilimab" OR "cemiplimab" OR "ivosidenib" OR "bemarituzumab" OR "707 injection") AND ("cervical squamous cell carcinoma" OR "cervical adenocarcinoma" OR "cervical adenosquamous carcinoma"). Additionally, a manual search of reference lists from retrieved articles was performed to identify potentially relevant studies that may not have been captured through the electronic search. 2.2. Inclusion and Exclusion Criteria The inclusion criteria were restricted to RCTs that assessed the efficacy of ICI therapy in patients with recurrent or metastatic cervical cancer. Non-RCTs, review articles, meta-analyses, case reports, and studies published in languages other than English were systematically excluded. Additionally, studies with ambiguous or insufficient data were not considered for inclusion. In instances of duplicate publications, only the study presenting the most comprehensive and up-to-date dataset was retained for analysis. 2.3. Data Extraction and Quality Assessment Two independent reviewers (L.L.F. and M.D.C.) conducted the initial screening of the literature to identify relevant studies for inclusion, with any discrepancies resolved through consensus by a third reviewer (C.Y.J.). The primary clinical outcomes assessed in this meta-analysis included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Two additional reviewers (Y.F. and L.W.Y.) independently extracted data pertaining to study characteristics, including study name, author information, publication year, study phase, sample size, patient age, treatment regimens, and treatment outcomes (PFS, OS, and ORR). PFS and OS were quantified using hazard ratios (HRs), while ORR was evaluated using odds ratios (ORs). The risk of bias in the included RCTs was assessed by the same two reviewers (Y.F. and L.W.Y.) utilizing the Cochrane risk of bias tool [11], which evaluates seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other potential biases. Each domain was categorized as "high risk," "unclear risk," or "low risk" based on the assessment criteria. Publication bias was evaluated using funnel plots, with any disagreements resolved by the third reviewer (C.Y.J.). 2.4 Statistical analysis Comprehensive meta-analyses were performed for all outcome measures utilizing Review Manager 5.4 software (The Cochrane Collaboration). OS and PFS were quantitatively synthesized through HR with corresponding 95% confidence intervals (CI), while complete pathological response was evaluated using OR accompanied by 95% CI. Study heterogeneity was systematically assessed through the I-squared (I 2 ) statistic. Given the restricted number of eligible studies, a random-effects model was consistently applied across all meta-analyses to mitigate potential bias and enhance the robustness of the findings. Statistical significance was determined at a threshold of p < 0.05 for all analyses. 3. Results 3.1. Literature selection Through a systematic search strategy, a total of 718 relevant publications were initially identified. Following rigorous screening and the removal of duplicate entries, data from 2,080 patients across four RCTs—BEATcc [9], EMPOWERCervical 1 [10], KEYNOTE-826 [5], and COMPASSION-16 [12]—published between 2021 and 2024 were ultimately included in the analysis. The screening process is comprehensively illustrated in the PRISMA flow diagram (Figure 1). 3.2.Characteristics of Included Studies The four RCTs were conducted across diverse geographical regions: BEATcc involved 92 clinical research centers in Europe and Japan, EMPOWERCervical 1 encompassed 111 centers across 14 countries globally, KEYNOTE-826 included 151 centers in 19 countries worldwide, and COMPASSION-16 was conducted at 59 clinical trial institutions in China. All enrolled patients were pathologically confirmed to have recurrent or metastatic cervical cancer and were randomized to receive either ICI monotherapy or combination therapy (ICI combined with chemotherapy with or without bevacizumab) , compared to standard treatment regimens (chemotherapy with or without bevacizumab). The therapeutic agents evaluated across these studies comprised two anti-PD-1 antibodies (pembrolizumab and cemiplimab), one anti-PD-L1 antibody (atezolizumab), and one anti-PD-1/CTLA-4 bispecific antibody (cadonilimab). Comprehensive characteristics and detailed information for each study are presented in Table 1. 3.3. Therapeutic effect 3.3.1 OS The four included studies consistently reported OS outcomes. Meta-analysis, as illustrated in Figure 2, revealed that ICI treatment significantly improved OS compared to standard therapy in both SCC patients (HR=0.68, 95% CI: 0.59–0.78, p<0.00001; Figure 2A) and non-SCC patients (HR=0.68, 95% CI: 0.53–0.87, p=0.002; Figure 2B). Subgroup analysis demonstrated that anti-PD-1 therapy enhanced OS in both SCC (HR=0.68, 95% CI: 0.57–0.80, p<0.00001; Figure 2A) and non-SCC cohorts (HR=0.64, 95% CI: 0.46–0.88, p=0.006; Figure 2B). Conversely, anti-PD-L1 therapy was associated with improved OS only in SCC patients (HR=0.72, 95% CI: 0.54–0.97, p=0.03; Figure 2A), with no significant benefit observed in non-SCC patients (HR=0.62, 95% CI: 0.36–1.06, p=0.08; Figure 2B). In the dual blockade subgroup, anti-PD-1/CTLA-4 combination therapy significantly improved OS in SCC patients (HR=0.64, 95% CI: 0.47–0.88, p=0.006; Figure 2A), whereas no statistically significant difference was observed in non-SCC patients (HR=0.94, 95% CI: 0.52–1.69, p=0.83; Figure 2B). 3.3.2 PFS All four included studies provided PFS data, with the analytical outcomes presented in Figure 3. ICI therapy demonstrated a significant improvement in PFS for both SCC patients (HR=0.66, 95% CI: 0.58-0.75, p<0.00001; Figure 3A) and non-SCC patients (HR=0.72, 95% CI: 0.56-0.91, p=0.007; Figure 3B). Subgroup analysis revealed that anti-PD-1 therapy significantly enhanced PFS in SCC patients (HR=0.67, 95% CI: 0.58-0.78, p<0.00001; Figure 3A), but not in non-SCC patients (HR=0.78, 95% CI: 0.57-1.08, p=0.13; Figure 3B). In contrast, PD-L1 inhibition did not significantly improve PFS in SCC patients (HR=0.75, 95% CI: 0.47-1.19, p=0.22; Figure 3A), but did show a significant benefit in non-SCC patients (HR=0.58, 95% CI: 0.45-0.76, p<0.0001; Figure 3B). Additionally, combined anti-PD-1/CTLA-4 therapy significantly improved PFS in SCC patients (HR=0.58, 95% CI: 0.44-0.76, p<0.0001; Figure 3A), but not in non-SCC patients (HR=0.94, 95% CI: 0.52-1.69, p=0.83; Figure 3B). 3.3.3 ORR Among the four studies analyzed, ORR outcomes stratified by pathological subtypes were exclusively reported in two trials: KEYNOTE-826 [5] and EMPOWERCervical 1 [10], both of which evaluated single-agent PD-1 inhibitors. The meta-analysis, as illustrated in Figure 4, demonstrated that PD-1 inhibitor monotherapy significantly enhanced ORR in SCC patients compared to standard treatment (OR=2.96, 95% CI: 1.70-5.15, p=0.0001; Figure 4A). Conversely, in non-SCC patients, no statistically significant difference in ORR was observed between the treatment groups (OR=1.54, 95% CI: 0.76-3.10, p=0.23; Figure 4B). 3.4 Assessments of RCT s qualit ies The risk of bias assessment for the four included RCTs is presented in Figure 5. Following a comprehensive evaluation, all studies were determined to exhibit a low risk of bias, thereby meeting the criteria for high-quality RCTs. 4. Discussion To the best of our knowledge, this study represents the first comprehensive meta-analysis of RCTs to systematically evaluate the differential therapeutic efficacy of ICI therapy between cervical SCC and non-SCC subtypes. Our findings demonstrate a statistically significant disparity in ICI treatment outcomes between metastatic SCC and non-SCC cohorts. Specifically, SCC patients exhibited enhanced sensitivity to immunotherapy compared to their non-SCC counterparts, while non-SCC patients demonstrated a greater propensity for OS benefit from anti-PD-1 therapy. These observations align with emerging evidence from recent studies [8,13,14], underscoring the imperative for judicious, individualized ICI strategy selection in clinical practice. From a mechanistic standpoint, the therapeutic advantage observed in SCC may be attributed to distinct biological characteristics. First, SCC demonstrates markedly higher PD-L1 expression rates compared to adenocarcinoma (80% vs. 15%-20%), with metastatic SCC exhibiting even greater PD-L1 positivity [15]. Second, SCC typically presents with a higher tumor mutation burden (TMB); for instance, head and neck SCC displays a 3.5-fold greater TMB than adenocarcinoma, potentially facilitating enhanced tumor antigen presentation and CD8+ T cell activation [16]. Furthermore, HPV-associated SCC frequently manifests as an "immunologically hot" tumor phenotype, characterized by robust CD8+ T cell infiltration within the tumor microenvironment, whereas adenocarcinoma may establish immune evasion mechanisms through the suppression of cytokines such as TGF-β [17]. Clinical evidence further substantiated this distinction: the KEYNOTE-826 trial demonstrated that in patients with combined positive score (CPS)≥1, SCC treated with pembrolizumab plus chemotherapy exhibited a significantly greater overall survival benefit (HR=0.60) compared to non-SCC (HR=0.70), a difference that persisted across both platinum-based and carboplatin-based regimens [5]. Similarly, the CheckMate-358 study reported a higher ORR for SCC (45.8%) than for non-SCC (31.6%) [14]. Notably, the reduced efficacy in non-SCC may be attributed to its distinct molecular profile; for instance, HER2 overexpression is more prevalent in adenocarcinoma (approximately 15%-20%) [18,19], and the HER2 signaling pathway can suppress T cell function via the PI3K/AKT/mTOR axis [20,21], potentially contributing to its diminished responsiveness to immunotherapy. Nevertheless, therapeutic advancements for non-SCC are emerging. Recent studies highlight promising combination strategies: for example, the integration of pembrolizumab (PD-1/CTLA-4 dual blockade) with trastuzumab deruxtecan (HER2 ADC) in HER2-positive non-SCC achieved an ORR of 92.3% [22], underscoring the synergistic potential of targeted and immunotherapeutic approaches. Additionally, the combination of the oncolytic virus CAN-2409 with PD-1 inhibitors yielded a median OS of 25.4 months in non-squamous non-small cell lung cancer, likely mediated by viral-induced tumor cell lysis, antigen release, and subsequent systemic immune activation [23]. These innovative strategies offer new therapeutic avenues for non-SCC patients. The predictive utility of biomarkers exhibits significant heterogeneity across different histological subtypes. In non-SCC, immunotherapy demonstrates a response rate of 81.8% in patients with PD-L1 CPS≥10, whereas the predictive value of PD-L1 in SCC appears less robust [24], necessitating comprehensive assessment through integration with TMB or HPV status [25,26]. Furthermore, the prevalence of microsatellite instability-high/mismatch repair deficiency (MSI-H/dMMR) in cervical cancer is relatively low (3%-11.3%), with even lower incidence observed in non-SCC subtypes [27,28], thereby restricting its applicability as a universal biomarker [29,30]. While this study has yielded promising findings, several limitations warrant consideration. First, the limited number of included studies, comprising only two anti-PD-1 antibodies, one anti-PD-L1 antibody, and one anti-PD-1/CTLA4 antibody, introduces potential selection bias. Nevertheless, the study's strength lies in its exclusive inclusion of high-quality clinical randomized trials, coupled with comprehensive and detailed analyses that provide valuable insights for clinical management and future research directions in cervical cancer. Second, the subgroup analysis is constrained by resource limitations, with only one study each in the anti-PD-L1 and anti-PD-1/CTLA4 subgroups, necessitating cautious interpretation of these specific findings. Third, the PD-L1 expression status of patients within the SCC and non-SCC subgroups remains uncharacterized, precluding further stratified analysis based on PD-L1 status, which may potentially influence the overall result interpretation. 5. Conclusion This meta-analysis revealed significant differences in therapeutic efficacy between ICI treatments for SCC and non-SCC subtypes. Patients with SCC seemed to exhibit enhanced responsiveness to various ICI agents, whereas non-SCC patients were more likely to achieve OS benefit from anti-PD-1 therapy. These findings underscore the necessity of implementing distinct, pathology-specific ICI treatment strategies in clinical practice to optimize therapeutic precision for cervical cancer patients. Given the inherent limitations of this study, further large-scale meta-analyses are warranted to establish more robust evidence-based recommendations. Abbreviations ICI, immune checkpoint inhibitor; RCT, randomized controlled trial; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; PD-1, programmed cell death protein-1; PD-L1, programmed cell death ligand-1; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; SCC, squamous cell carcinoma. Declarations Acknowledgment The authors would like to thank Liuzhou People's Hospital affiliated to Guangxi Medical University. Competing interests The authors declare no competing interests Funding None Ethics approval and consent to participate The study is deemed to exempt to receive ethical approval. Human ethics and consent to participate Not applicable Consent to participate Not applicable Consent for publication Not applicable Clinical Trial Number Not applicable Data Availability Statement All data are available upon request. CRedit authorship contribution statement Wen-yi Li coordinated the data collection and conceived the original idea, Li-fang Lan and Yu-jie Chen provided statistical analysis, Li-fang Lan and Dun-chang Mo wrote the manuscript, all other Authors facilitated data collection and critically reviewed the manuscript for important intellectual contents. Li-fang Lan and Yu-jie Chen accept direct responsibility for the manuscript. References Sung H, Ferlay J, Siegel R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA: A Cancer Journal for Clinicians, 2021, 71(3): 209-249. Global strategy to accelerate the elimination of cervical cancer As a public health problem[M]. 1st ed. 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Howitt B E, Shukla S A, Sholl L M, et al. Association of polymerase e–mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1[J]. JAMA Oncology, 2015, 1(9): 1319. NCCN Guidelines for Cervical Cancer, Version 1.2023[J]. National Comprehensive Cancer Network (NCCN). (2023). Le D T, Durham J N, Smith K N, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 2017, 357(6349): 409-413. Tables Table 1 Baseline characteristics of the studies included in the meta-analysis. Study (year) Study design Phase Number of patients Age (year), median (IQR or SD) Number of patients with squamous cell carcinoma, n (%) Intervention Median follow-up of the study group (months) EMPOWERCervical 1(2022) [10] RCT 3 608 Exp: 51 (22–81) Con: 50 (24–87) Exp: 240 (78.9%) Con: 233 (76.6%) Exp: Cemiplimab Con: Chemotherapy 16.8 KEYNOTE-826 (2021) [5] RCT 3 617 Exp: 51 (25–82) Con: 50 (22–79) Exp: 235(76.8%) Con: 211 (68.3%) Exp: Pembrolizumab Con: Chemotherapy 22 BEATcc(2023) [9] RCT 3 410 Exp: 51.0(43.0–60.0) Con: 52.5 (43.5–61.0) Exp: 164(79.6%) Con: 157 (77.0%) Exp: Atezolizumab plus bevacizumab plus chemotherapy Con: Bevacizumab plus chemotherapy 32.9 COMPASSION-16 (2024) [12] RCT 3 445 Exp: 56(23–75) Con: 56(23–75) Exp: 182(82.0%) Con: 188 (84.3%) Exp: Cadonilimab plus bevacizumab plus chemotherapy Con: Bevacizumab plus chemotherapy 25.6 RCT = Randomized controlled trial; IQR = Interquartile range; SD = Standard deviation; Exp = Experiment; Con = Control. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7024411","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":496527562,"identity":"81ac720e-580c-4670-9226-61b9819ae2e2","order_by":0,"name":"Li-fang Lan","email":"","orcid":"","institution":"Liuzhou People's Hospital affiliated to Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li-fang","middleName":"","lastName":"Lan","suffix":""},{"id":496527563,"identity":"c6c01f14-9dd5-4eb6-88cb-f329d8e39081","order_by":1,"name":"Yu-jie Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIie3RrwvCQBTA8TeEneEwPxHmXyCcDMQV/5Z3CCaxWM4mDLYyu8H/Qlg+ELSc/eqKyWKziLKmaWcTvG//wPsB4PP9YCHLT3dUz6jPUu1GOtwQjk0rHhZHciMRksBV1pJg58JxMCQS1oQUFOZmrzCJBusmwistt4ovGNvskx1M45FuIozogAaXQXEuexy0LBsJ0DB9ZEKu7fziSNoUQzejmoSOhJsZoNH1keNkJxx26ef5EVDp+pWVvapJ1Eg+Qu74mnfyrfD5fL6/6AWGCERV3/ijJgAAAABJRU5ErkJggg==","orcid":"","institution":"Liuzhou People's Hospital affiliated to Guangxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yu-jie","middleName":"","lastName":"Chen","suffix":""},{"id":496527564,"identity":"aaeab740-fd80-42d2-9c3d-15c665fa96be","order_by":2,"name":"Dun-chang Mo","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dun-chang","middleName":"","lastName":"Mo","suffix":""},{"id":496527565,"identity":"18c44a08-01e9-419b-97e7-d0f3d6e9d39b","order_by":3,"name":"Wen-yi Li","email":"","orcid":"","institution":"Liuzhou People's Hospital affiliated to Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wen-yi","middleName":"","lastName":"Li","suffix":""},{"id":496527566,"identity":"9ca30d66-7789-4442-b5ee-272b1d6161f0","order_by":4,"name":"Fei Yu","email":"","orcid":"","institution":"Liuzhou People's Hospital affiliated to Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Yu","suffix":""}],"badges":[],"createdAt":"2025-07-02 02:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7024411/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7024411/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88778173,"identity":"be5fc37e-4959-4cc2-b66a-97cb2a2af389","added_by":"auto","created_at":"2025-08-11 10:21:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":553044,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart illustrating the literature review process.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7024411/v1/924b240d0cf6e79fa4776705.png"},{"id":88777603,"identity":"5f13941b-727b-46b8-86a9-2e14022953c1","added_by":"auto","created_at":"2025-08-11 10:13:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":333301,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of overall survival. A, Forest plot of overall survival in squamous cell carcinoma. B, Forest plot of overall survival in non-squamous cell carcinoma.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7024411/v1/81da56754a294dba56473358.png"},{"id":88775538,"identity":"7e4bbaa4-28bf-418f-ad25-d673c6708884","added_by":"auto","created_at":"2025-08-11 10:05:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":333626,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of progression-free survival. A, Forest plot of progression-free survival in squamous cell carcinoma. B, Forest plot of progression-free survival in non-squamous cell carcinoma.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7024411/v1/b012e1b51a1dd78953c8308e.png"},{"id":88775547,"identity":"789af357-c4f2-43d8-bb66-b6b6bc5f4b36","added_by":"auto","created_at":"2025-08-11 10:05:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":679085,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of objective response rate. A, Forest plot of objective response rate in squamous cell carcinoma. B, Forest plot of objective response rate in non-squamous cell carcinoma.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7024411/v1/0557eb0ca49fd6694627f416.png"},{"id":88775548,"identity":"0333b67b-6888-4a24-906b-27b137ffcb72","added_by":"auto","created_at":"2025-08-11 10:05:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":244693,"visible":true,"origin":"","legend":"\u003cp\u003eThe assessment of bias of included studies.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-7024411/v1/8c3ea2a811da35231b8b7f26.png"},{"id":92572087,"identity":"8637e46d-e940-48b8-ab26-5b29320dd1be","added_by":"auto","created_at":"2025-10-01 07:54:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2953580,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7024411/v1/5d14333b-5071-47f5-914e-c543d70cd09f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative effectiveness of immune checkpoint inhibitors in squamous vs. non-aquamous cervical carcinoma: a meta-analysis of randomized controlled trials","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCervical cancer represents a prevalent malignancy that significantly impacts women's health, ranking as the second most common gynecological cancer in terms of both incidence and mortality [1]. The implementation of (human papillomavirus) HPV vaccination programs and cervical cancer screening initiatives has contributed to a global decline in cervical cancer incidence and mortality rates over the past decade [2]. Nevertheless, disease recurrence and metastasis remain substantial challenges in clinical management, with patients experiencing these complications demonstrating poor prognostic outcomes, thereby presenting a persistent therapeutic challenge in gynecological oncology [3,4]. Recent advancements in immunotherapy, particularly the development of immune checkpoint inhibitors (ICIs), have demonstrated significant potential in cervical cancer treatment, offering improved long-term survival prospects [5]. ICIs have been shown to potentiate the efficacy of conventional radiotherapy and chemotherapy through immune system modulation [6\u0026ndash;8]. Clinical evidence indicates that the combination of ICIs with radiotherapy and chemotherapy yields superior outcomes for locally advanced cervical cancer patients compared to radiotherapy and chemotherapy alone [8]. In the context of recurrent or metastatic cervical cancer, multiple studies have established that first-line treatment incorporating ICIs in combination with chemotherapy, with or without bevacizumab, significantly enhances long-term survival outcomes [5,9]. Consequently, this combination therapy has emerged as a recommended standard therapeutic strategy for recurrent or metastatic cervical cancer [5,9,10].\u003c/p\u003e\u003cp\u003eDespite the widespread recommendation of ICIs for recurrent or metastatic cervical cancer, there remains a paucity of evidence regarding the differential efficacy of ICI strategies across various histological subtypes, particularly between squamous cell carcinoma (SCC) and non-squamous cell carcinoma (non-SCC). To address this knowledge gap, we conducted a comprehensive meta-analysis of randomized controlled trials (RCTs) to evaluate the comparative efficacy of ICI treatments in recurrent or metastatic SCC versus non-SCC, thereby providing more nuanced evidence to inform clinical decision-making in cervical cancer management.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e\u003cem\u003e2.1 Literature screening.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA comprehensive literature search was conducted across multiple electronic databases, including PubMed, EMBASE, and the Cochrane Library, encompassing the period from database inception to March 2025. The search strategy employed the following Boolean search terms: (\"immunotherapy\" OR \"immune therapy\" OR \"immune checkpoint inhibitors\" OR \"PD-1\" OR \"PD-L1\" OR \"pembrolizumab\" OR \"nivolumab\" OR \"atezolizumab\" OR \"avelumab\" OR \"tremelimumab\" OR \"durvalumab\" OR \"spartalizumab\" OR \"toripalimab\" OR \"dostarlimab\" OR \"camrelizumab\" OR \"sintilimab\" OR \"cemiplimab\" OR \"ivosidenib\" OR \"bemarituzumab\" OR \"707 injection\") AND (\"cervical squamous cell carcinoma\" OR \"cervical adenocarcinoma\" OR \"cervical adenosquamous carcinoma\"). Additionally, a manual search of reference lists from retrieved articles was performed to identify potentially relevant studies that may not have been captured through the electronic search.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Inclusion and Exclusion Criteria\u003c/h2\u003e\u003cp\u003eThe inclusion criteria were restricted to RCTs that assessed the efficacy of ICI therapy in patients with recurrent or metastatic cervical cancer. Non-RCTs, review articles, meta-analyses, case reports, and studies published in languages other than English were systematically excluded. Additionally, studies with ambiguous or insufficient data were not considered for inclusion. In instances of duplicate publications, only the study presenting the most comprehensive and up-to-date dataset was retained for analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Data Extraction and Quality Assessment\u003c/h2\u003e\u003cp\u003eTwo independent reviewers (L.L.F. and M.D.C.) conducted the initial screening of the literature to identify relevant studies for inclusion, with any discrepancies resolved through consensus by a third reviewer (C.Y.J.). The primary clinical outcomes assessed in this meta-analysis included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Two additional reviewers (Y.F. and L.W.Y.) independently extracted data pertaining to study characteristics, including study name, author information, publication year, study phase, sample size, patient age, treatment regimens, and treatment outcomes (PFS, OS, and ORR). PFS and OS were quantified using hazard ratios (HRs), while ORR was evaluated using odds ratios (ORs).\u003c/p\u003e\u003cp\u003eThe risk of bias in the included RCTs was assessed by the same two reviewers (Y.F. and L.W.Y.) utilizing the Cochrane risk of bias tool [11], which evaluates seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other potential biases. Each domain was categorized as \"high risk,\" \"unclear risk,\" or \"low risk\" based on the assessment criteria. Publication bias was evaluated using funnel plots, with any disagreements resolved by the third reviewer (C.Y.J.).\u003c/p\u003e\u003cp\u003e\u003cem\u003e2.4 Statistical analysis\u003c/em\u003e\u003c/p\u003e\u003cp\u003eComprehensive meta-analyses were performed for all outcome measures utilizing Review Manager 5.4 software (The Cochrane Collaboration). OS and PFS were quantitatively synthesized through HR with corresponding 95% confidence intervals (CI), while complete pathological response was evaluated using OR accompanied by 95% CI. Study heterogeneity was systematically assessed through the I-squared (I\u003csup\u003e2\u003c/sup\u003e) statistic. Given the restricted number of eligible studies, a random-effects model was consistently applied across all meta-analyses to mitigate potential bias and enhance the robustness of the findings. Statistical significance was determined at a threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all analyses.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cem\u003e3.1.\u003c/em\u003e\u003cem\u003eLiterature selection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThrough a systematic search strategy, a total of 718 relevant publications were initially identified. Following rigorous screening and the removal of duplicate entries, data from 2,080 patients across four RCTs\u0026mdash;BEATcc [9], EMPOWERCervical 1 [10], KEYNOTE-826 [5], and COMPASSION-16 [12]\u0026mdash;published between 2021 and 2024 were ultimately included in the analysis. The screening process is comprehensively illustrated in the PRISMA flow diagram (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.2.Characteristics of Included Studies\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe four RCTs were conducted across diverse geographical regions: BEATcc involved 92 clinical research centers in Europe and Japan, EMPOWERCervical 1 encompassed 111 centers across 14 countries globally, KEYNOTE-826 included 151 centers in 19 countries worldwide, and COMPASSION-16 was conducted at 59 clinical trial institutions in China. All enrolled patients were pathologically confirmed to have recurrent or metastatic cervical cancer and were randomized to receive either ICI monotherapy or combination therapy (ICI combined with chemotherapy with or without bevacizumab) , compared to standard treatment regimens (chemotherapy with or without bevacizumab). The therapeutic agents evaluated across these studies comprised two anti-PD-1 antibodies (pembrolizumab and cemiplimab), one anti-PD-L1 antibody (atezolizumab), and one anti-PD-1/CTLA-4 bispecific antibody (cadonilimab). Comprehensive characteristics and detailed information for each study are presented in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.3.\u003c/em\u003e\u003cem\u003eTherapeutic effect\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.3.1\u0026nbsp;\u003c/em\u003e\u003cem\u003eOS\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe four included studies consistently reported OS outcomes. Meta-analysis, as illustrated in Figure 2, revealed that ICI treatment significantly improved OS compared to standard therapy in both SCC patients (HR=0.68, 95% CI: 0.59\u0026ndash;0.78, p\u0026lt;0.00001; Figure 2A) and non-SCC patients (HR=0.68, 95% CI: 0.53\u0026ndash;0.87, p=0.002; Figure 2B). Subgroup analysis demonstrated that anti-PD-1 therapy enhanced OS in both SCC (HR=0.68, 95% CI: 0.57\u0026ndash;0.80, p\u0026lt;0.00001; Figure 2A) and non-SCC cohorts (HR=0.64, 95% CI: 0.46\u0026ndash;0.88, p=0.006; Figure 2B). Conversely, anti-PD-L1 therapy was associated with improved OS only in SCC patients (HR=0.72, 95% CI: 0.54\u0026ndash;0.97, p=0.03; Figure 2A), with no significant benefit observed in non-SCC patients (HR=0.62, 95% CI: 0.36\u0026ndash;1.06, p=0.08; Figure 2B). In the dual blockade subgroup, anti-PD-1/CTLA-4 combination therapy significantly improved OS in SCC patients (HR=0.64, 95% CI: 0.47\u0026ndash;0.88, p=0.006; Figure 2A), whereas no statistically significant difference was observed in non-SCC patients (HR=0.94, 95% CI: 0.52\u0026ndash;1.69, p=0.83; Figure 2B).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.3.2 PFS\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll four included studies provided PFS data, with the analytical outcomes presented in Figure 3. ICI therapy demonstrated a significant improvement in PFS for both SCC patients (HR=0.66, 95% CI: 0.58-0.75, p\u0026lt;0.00001; Figure 3A) and non-SCC patients (HR=0.72, 95% CI: 0.56-0.91, p=0.007; Figure 3B). Subgroup analysis revealed that anti-PD-1 therapy significantly enhanced PFS in SCC patients (HR=0.67, 95% CI: 0.58-0.78, p\u0026lt;0.00001; Figure 3A), but not in non-SCC patients (HR=0.78, 95% CI: 0.57-1.08, p=0.13; Figure 3B). In contrast, PD-L1 inhibition did not significantly improve PFS in SCC patients (HR=0.75, 95% CI: 0.47-1.19, p=0.22; Figure 3A), but did show a significant benefit in non-SCC patients (HR=0.58, 95% CI: 0.45-0.76, p\u0026lt;0.0001; Figure 3B). Additionally, combined anti-PD-1/CTLA-4 therapy significantly improved PFS in SCC patients (HR=0.58, 95% CI: 0.44-0.76, p\u0026lt;0.0001; Figure 3A), but not in non-SCC patients (HR=0.94, 95% CI: 0.52-1.69, p=0.83; Figure 3B).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.3.3 ORR \u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong the four studies analyzed, ORR outcomes stratified by pathological subtypes were exclusively reported in two trials: KEYNOTE-826 [5] and EMPOWERCervical 1 [10], both of which evaluated single-agent PD-1 inhibitors. The meta-analysis, as illustrated in Figure 4, demonstrated that PD-1 inhibitor monotherapy significantly enhanced ORR in SCC patients compared to standard treatment (OR=2.96, 95% CI: 1.70-5.15, p=0.0001; Figure 4A). Conversely, in non-SCC patients, no statistically significant difference in ORR was observed between the treatment groups (OR=1.54, 95% CI: 0.76-3.10, p=0.23; Figure 4B).\u003c/p\u003e\n\u003cp\u003e3.4\u0026nbsp;\u003cem\u003eAssessments\u003c/em\u003e\u003cem\u003e\u0026nbsp;of RCT\u003c/em\u003e\u003cem\u003es\u003c/em\u003e\u003cem\u003e\u0026nbsp;qualit\u003c/em\u003e\u003cem\u003eies\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias assessment for the four included RCTs is presented in Figure 5. Following a comprehensive evaluation, all studies were determined to exhibit a low risk of bias, thereby meeting the criteria for high-quality RCTs.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eTo the best of our knowledge, this study represents the first comprehensive meta-analysis of RCTs to systematically evaluate the differential therapeutic efficacy of ICI therapy between cervical SCC and non-SCC subtypes. Our findings demonstrate a statistically significant disparity in ICI treatment outcomes between metastatic SCC and non-SCC cohorts. Specifically, SCC patients exhibited enhanced sensitivity to immunotherapy compared to their non-SCC counterparts, while non-SCC patients demonstrated a greater propensity for OS benefit from anti-PD-1 therapy. These observations align with emerging evidence from recent studies [8,13,14], underscoring the imperative for judicious, individualized ICI strategy selection in clinical practice. From a mechanistic standpoint, the therapeutic advantage observed in SCC may be attributed to distinct biological characteristics. First, SCC demonstrates markedly higher PD-L1 expression rates compared to adenocarcinoma (80% vs. 15%-20%), with metastatic SCC exhibiting even greater PD-L1 positivity [15]. Second, SCC typically presents with a higher tumor mutation burden (TMB); for instance, head and neck SCC displays a 3.5-fold greater TMB than adenocarcinoma, potentially facilitating enhanced tumor antigen presentation and CD8+ T cell activation [16]. Furthermore, HPV-associated SCC frequently manifests as an \u0026quot;immunologically hot\u0026quot; tumor phenotype, characterized by robust CD8+ T cell infiltration within the tumor microenvironment, whereas adenocarcinoma may establish immune evasion mechanisms through the suppression of cytokines such as TGF-\u0026beta; [17].\u003c/p\u003e\n\u003cp\u003eClinical evidence further substantiated this distinction: the KEYNOTE-826 trial demonstrated that in patients with combined positive score (CPS)\u0026ge;1, SCC treated with pembrolizumab plus chemotherapy exhibited a significantly greater overall survival benefit (HR=0.60) compared to non-SCC (HR=0.70), a difference that persisted across both platinum-based and carboplatin-based regimens [5]. Similarly, the CheckMate-358 study reported a higher ORR for SCC (45.8%) than for non-SCC (31.6%) [14]. Notably, the reduced efficacy in non-SCC may be attributed to its distinct molecular profile; for instance, HER2 overexpression is more prevalent in adenocarcinoma (approximately 15%-20%) [18,19], and the HER2 signaling pathway can suppress T cell function via the PI3K/AKT/mTOR axis [20,21], potentially contributing to its diminished responsiveness to immunotherapy. Nevertheless, therapeutic advancements for non-SCC are emerging. Recent studies highlight promising combination strategies: for example, the integration of pembrolizumab (PD-1/CTLA-4 dual blockade) with trastuzumab deruxtecan (HER2 ADC) in HER2-positive non-SCC achieved an ORR of 92.3% [22], underscoring the synergistic potential of targeted and immunotherapeutic approaches. Additionally, the combination of the oncolytic virus CAN-2409 with PD-1 inhibitors yielded a median OS of 25.4 months in non-squamous non-small cell lung cancer, likely mediated by viral-induced tumor cell lysis, antigen release, and subsequent systemic immune activation [23]. These innovative strategies offer new therapeutic avenues for non-SCC patients.\u003c/p\u003e\n\u003cp\u003eThe predictive utility of biomarkers exhibits significant heterogeneity across different histological subtypes. In non-SCC, immunotherapy demonstrates a response rate of 81.8% in patients with PD-L1 CPS\u0026ge;10, whereas the predictive value of PD-L1 in SCC appears less robust [24], necessitating comprehensive assessment through integration with TMB or HPV status [25,26]. Furthermore, the prevalence of microsatellite instability-high/mismatch repair deficiency (MSI-H/dMMR) in cervical cancer is relatively low (3%-11.3%), with even lower incidence observed in non-SCC subtypes [27,28], thereby restricting its applicability as a universal biomarker [29,30].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhile this study has yielded promising findings, several limitations warrant consideration. First, the limited number of included studies, comprising only two anti-PD-1 antibodies, one anti-PD-L1 antibody, and one anti-PD-1/CTLA4 antibody, introduces potential selection bias. Nevertheless, the study\u0026apos;s strength lies in its exclusive inclusion of high-quality clinical randomized trials, coupled with comprehensive and detailed analyses that provide valuable insights for clinical management and future research directions in cervical cancer. Second, the subgroup analysis is constrained by resource limitations, with only one study each in the anti-PD-L1 and anti-PD-1/CTLA4 subgroups, necessitating cautious interpretation of these specific findings. Third, the PD-L1 expression status of patients within the SCC and non-SCC subgroups remains uncharacterized, precluding further stratified analysis based on PD-L1 status, which may potentially influence the overall result interpretation.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis meta-analysis revealed significant differences in therapeutic efficacy between ICI treatments for SCC and non-SCC subtypes. Patients with SCC seemed to exhibit enhanced responsiveness to various ICI agents, whereas non-SCC patients were more likely to achieve OS benefit from anti-PD-1 therapy. These findings underscore the necessity of implementing distinct, pathology-specific ICI treatment strategies in clinical practice to optimize therapeutic precision for cervical cancer patients. Given the inherent limitations of this study, further large-scale meta-analyses are warranted to establish more robust evidence-based recommendations.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eICI, immune checkpoint inhibitor; RCT, randomized controlled trial; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; PD-1, programmed cell death protein-1; PD-L1, programmed cell death ligand-1; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; SCC, squamous cell carcinoma.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank\u0026nbsp;Liuzhou People\u0026apos;s Hospital affiliated to Guangxi Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The authors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is deemed to exempt to receive ethical approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman ethics and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are available upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRedit authorship contribution statement\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWen-yi Li coordinated the data collection and conceived the original idea, Li-fang Lan and Yu-jie Chen provided statistical analysis, Li-fang Lan and Dun-chang Mo wrote the manuscript, all other Authors facilitated data collection and critically reviewed the manuscript for important intellectual contents. Li-fang Lan and Yu-jie Chen accept direct responsibility for the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA: A Cancer Journal for Clinicians, 2021, 71(3): 209-249.\u003c/li\u003e\n\u003cli\u003eGlobal strategy to accelerate the elimination of cervical cancer As a public health problem[M]. 1st ed. Geneva: World Health Organization, 2020.\u003c/li\u003e\n\u003cli\u003eSong D, Kong W, Zhang T, et al. A retrospective analysis of cisplatin/carboplatin plus paclitaxel in advanced or recurrent cervical cancer[J]. Journal of Obstetrics and Gynaecology, 2019, 39(3): 389-394.\u003c/li\u003e\n\u003cli\u003eGupta S, Maheshwari A, Parab P, et al. Neoadjuvant chemotherapy followed by radical surgery versus concomitant chemotherapy and radiotherapy in patients with stage IB2, IIA, or IIB squamous cervical cancer: a randomized controlled trial[J]. Journal of Clinical Oncology, 2018, 36(16): 1548-1555.\u003c/li\u003e\n\u003cli\u003eColombo N, Dubot C, Lorusso D, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer[J]. New England Journal of Medicine, 2021, 385(20): 1856-1867.\u003c/li\u003e\n\u003cli\u003eLorenzo Galluzzi ,Aitziber Buqu\u0026eacute;,et al. Immunogenic cell death in cancer and infectious disease[J]. CELL DEATH AND IMMUNITY, 2017(107): 97-111.\u003c/li\u003e\n\u003cli\u003eSharabi A B, Lim M, DeWeese T L, et al. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy[J]. Lancet Oncology, 2015, 16(13): e498-e509.\u003c/li\u003e\n\u003cli\u003eChung H, Delord J P, Perets R, et al. Pembrolizumab treatment of advanced cervical cancer: updated results from the phase II KEYNOTE-158 study[J]. Gynecologic Oncology, 2021, 162: S27.\u003c/li\u003e\n\u003cli\u003eOaknin A, Gladieff L, Mart\u0026iacute;nez-Garc\u0026iacute;a J, et al. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial[J]. Lancet, 2024, 403(10421): 31-43.\u003c/li\u003e\n\u003cli\u003eTewari K S, Monk B J, Vergote I, et al. Survival with cemiplimab in recurrent cervical cancer[J]. New England Journal of Medicine, 2022, 386(6): 544-555.\u003c/li\u003e\n\u003cli\u003eHiggins J P T, Altman D G, Gotzsche P C, et al. The cochrane collaboration\u0026rsquo;s tool for assessing risk of bias in randomised trials[J]. BMJ, 2011, 343(oct18 2): d5928-d5928.\u003c/li\u003e\n\u003cli\u003eWu X, Sun Y, Yang H, et al. Cadonilimab plus platinum-based chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer (COMPASSION-16): a randomised, double-blind, placebo-controlled phase 3 trial in China[J]. Lancet, 2024, 404(10463): 1668-1676.\u003c/li\u003e\n\u003cli\u003eChung H C, Ros W, Delord J P, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study[J]. Journal of Clinical Oncology, 2019, 37(17): 1470-1478.\u003c/li\u003e\n\u003cli\u003eOaknin A, Moore K, Meyer T, et al. Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial[J]. The Lancet. Oncology, 2024, 25(5): 588-602.\u003c/li\u003e\n\u003cli\u003eBaandrup L, Sand F L, Aalborg G L, et al. PD-L1 expression in vulvar cancer: a systematic review and meta‐analysis[J]. Histopathology, 2024, 84(5): 742-752.\u003c/li\u003e\n\u003cli\u003eAustralian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, et al. Signatures of mutational processes in human cancer[J]. Nature, 2013, 500(7463): 415-421.\u003c/li\u003e\n\u003cli\u003eWalsh R J, Tan D S P. The role of immunotherapy in the treatment of advanced cervical cancer: current status and future perspectives[J]. Journal of Clinical Medicine, 2021, 10(19): 4523.\u003c/li\u003e\n\u003cli\u003eKojima, A., et al. Comprehensive genomic profiling of gastric-type endocervical adenocarcinoma[J]. Gynecologic Oncology, 2017(145(1)): 114-120.\u003c/li\u003e\n\u003cli\u003eZhao, S., et a. HER2 amplification and protein overexpression in cervical adenocarcinoma: a clinicopathological analysis[J]. Modern Pathology, 2020(33(6)): 1155-1164.\u003c/li\u003e\n\u003cli\u003eStagg, J., et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1/PD-L1 mAb.[J]. Cancer Research, 2011(71(17)): 5690-5699.\u003c/li\u003e\n\u003cli\u003eMittendorf, E. A., et al. Breast cancer cell HER2 expression directly regulates NLRP3 inflammasome activation and IL-1\u0026beta; secretion[J]. Journal of Immunology, 2014(193(10)): 5044-5052.\u003c/li\u003e\n\u003cli\u003eZheng M, et al. A phase II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus vidicitumab (HER2 ADC) in HER2-positive recurrent/metastatic cervical cancer.[J]. 2024 IGCS Annual Meeting.\u003c/li\u003e\n\u003cli\u003eZheng X, et al. Oncolytic virus CAN-2409 combined with PD-1 inhibitor in non-small cell lung cancer[J]. Journal of Immunotherapy Cancer, 2024(12(1)): 152.\u003c/li\u003e\n\u003cli\u003eFrenel JS, et al. PD-L1 expression as a biomarker in cervical cancer: current status and future perspectives[J]. Gynecology Oncology, 2021(161（2）): 433-440.\u003c/li\u003e\n\u003cli\u003eCastle PE, et al. Human papillomavirus integration and carcinogenesis in cervical cancer[J]. Nature Review Cancer, 2022(22(11)): 657-672.\u003c/li\u003e\n\u003cli\u003eLi X, et al. Tumor mutational burden in cervical cancer: a systematic review and meta-analysis[J]. Front Oncology, 2023(13（11）): 54-63.\u003c/li\u003e\n\u003cli\u003eThe Cancer Genome Atlas Research Network. Integrated genomic and molecular characterization of cervical cancer[J]. Nature, 2017, 543(7645): 378-384.\u003c/li\u003e\n\u003cli\u003eHowitt B E, Shukla S A, Sholl L M, et al. Association of polymerase e\u0026ndash;mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1[J]. JAMA Oncology, 2015, 1(9): 1319.\u003c/li\u003e\n\u003cli\u003eNCCN Guidelines for Cervical Cancer, Version 1.2023[J]. National Comprehensive Cancer Network (NCCN). (2023).\u003c/li\u003e\n\u003cli\u003eLe D T, Durham J N, Smith K N, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 2017, 357(6349): 409-413.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \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 \u003cp\u003eBaseline characteristics of the studies included in the meta-analysis.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" style=\"width: 10.35%;\"\u003e\n \u003cp\u003eStudy (year)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 3.5507%;\"\u003e\n \u003cp\u003eStudy design\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 3.2486%;\"\u003e\n \u003cp\u003ePhase\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 4.5329%;\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 5.4394%;\"\u003e\n \u003cp\u003eAge (year), median\u003c/p\u003e\n \u003cp\u003e(IQR or SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 5.9683%;\"\u003e\n \u003cp\u003eNumber of patients with squamous cell carcinoma, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 7.857%;\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 4.8351%;\"\u003e\n \u003cp\u003eMedian follow-up of the study group (months)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 10.35%;\"\u003e\n \u003cp\u003eEMPOWERCervical 1(2022)\u003csup\u003e[10]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 3.5507%;\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" style=\"width: 3.2486%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" style=\"width: 4.5329%;\"\u003e\n \u003cp\u003e608\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 5.4394%;\"\u003e\n \u003cp\u003eExp: 51 (22\u0026ndash;81)\u003c/p\u003e\n \u003cp\u003eCon: 50 (24\u0026ndash;87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 5.9683%;\"\u003e\n \u003cp\u003eExp: 240 (78.9%)\u003c/p\u003e\n \u003cp\u003eCon: 233 (76.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.857%;\"\u003e\n \u003cp\u003eExp: Cemiplimab\u003c/p\u003e\n \u003cp\u003eCon: Chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 4.8351%;\"\u003e\n \u003cp\u003e16.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 10.35%;\"\u003e\n \u003cp\u003eKEYNOTE-826 (2021) \u003csup\u003e[5]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 3.5507%;\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" style=\"width: 3.2486%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" style=\"width: 4.5329%;\"\u003e\n \u003cp\u003e617\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 5.4394%;\"\u003e\n \u003cp\u003eExp: 51 (25\u0026ndash;82)\u003c/p\u003e\n \u003cp\u003eCon: 50 (22\u0026ndash;79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 5.9683%;\"\u003e\n \u003cp\u003eExp: 235(76.8%)\u003c/p\u003e\n \u003cp\u003eCon: 211 (68.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.857%;\"\u003e\n \u003cp\u003eExp: Pembrolizumab\u003c/p\u003e\n \u003cp\u003eCon: Chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 4.8351%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 10.35%;\"\u003e\n \u003cp\u003eBEATcc(2023)\u003csup\u003e[9]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 3.5507%;\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" style=\"width: 3.2486%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" style=\"width: 4.5329%;\"\u003e\n \u003cp\u003e410\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 5.4394%;\"\u003e\n \u003cp\u003eExp: 51.0(43.0\u0026ndash;60.0)\u003c/p\u003e\n \u003cp\u003eCon: 52.5 (43.5\u0026ndash;61.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 5.9683%;\"\u003e\n \u003cp\u003eExp: 164(79.6%)\u003c/p\u003e\n \u003cp\u003eCon: 157 (77.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.857%;\"\u003e\n \u003cp\u003eExp: Atezolizumab plus bevacizumab plus chemotherapy\u003c/p\u003e\n \u003cp\u003eCon: Bevacizumab plus chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 4.8351%;\"\u003e\n \u003cp\u003e32.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 10.35%;\"\u003e\n \u003cp\u003eCOMPASSION-16 (2024)\u003csup\u003e[12]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 3.5507%;\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" style=\"width: 3.2486%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" style=\"width: 4.5329%;\"\u003e\n \u003cp\u003e445\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 5.4394%;\"\u003e\n \u003cp\u003eExp: 56(23\u0026ndash;75)\u003c/p\u003e\n \u003cp\u003eCon: 56(23\u0026ndash;75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 5.9683%;\"\u003e\n \u003cp\u003eExp: 182(82.0%)\u003c/p\u003e\n \u003cp\u003eCon: 188 (84.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.857%;\"\u003e\n \u003cp\u003eExp: Cadonilimab plus bevacizumab plus chemotherapy\u003c/p\u003e\n \u003cp\u003eCon: Bevacizumab plus chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 4.8351%;\"\u003e\n \u003cp\u003e25.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 46.3863%;\"\u003eRCT\u0026thinsp;=\u0026thinsp;Randomized controlled trial; IQR\u0026thinsp;=\u0026thinsp;Interquartile range; SD\u0026thinsp;=\u0026thinsp;Standard deviation; Exp\u0026thinsp;=\u0026thinsp;Experiment; Con\u0026thinsp;=\u0026thinsp;Control.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"aquamous cervical carcinoma, non-aquamous cervical carcinoma, immune checkpoint inhibitors, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-7024411/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7024411/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eThe differential efficacy of immune checkpoint inhibitor (ICI) treatment between cervical squamous cell carcinoma (SCC) and non-squamous cell carcinoma(non-SCC) patients was unclear. This study aimed to evaluate the efficacy of ICI therapy in metastatic cervical SCC versus non-SCC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA literature search was conducted across PubMed/Embase/the Cochrane Library to identify randomized controlled trials (RCTs) assessing the efficacy of ICI treatment in metastatic cervical cancer. Primary endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFour RCTs were included in the meta-analysis. ICI treatment demonstrated significant improvements in PFS and OS compared to control treatment in both SCC and non-SCC patients. Anti-PD-1 therapy significantly enhanced ORR in SCC patients (P\u0026thinsp;=\u0026thinsp;0.0001) but not in non-SCC patients (P\u0026thinsp;=\u0026thinsp;0.23). Subgroup analysis revealed anti-PD-1 and anti-PD-1/CTLA4 therapies prolonged PFS in SCC patients (both P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) but not in non-SCC patients (P\u0026thinsp;=\u0026thinsp;0.13 and P\u0026thinsp;=\u0026thinsp;0.83, respectively). Conversely, anti-PD-L1 therapy did not improve PFS in SCC patients (P\u0026thinsp;=\u0026thinsp;0.22) but significantly enhanced PFS in non-SCC patients (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). OS subgroup analysis indicated prolonged OS in SCC patients treated with anti-PD-1, anti-PD-L1, or anti-PD-1/CTLA4. In non-SCC patients, only the anti-PD-1 subgroup exhibited OS benefit (P\u0026thinsp;=\u0026thinsp;0.006), while no significant differences were observed in the anti-PD-L1 and anti-PD-1/CTLA4 subgroups (P\u0026thinsp;=\u0026thinsp;0.08 and P\u0026thinsp;=\u0026thinsp;0.83, respectively).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eICI treatment improves outcomes in metastatic cervical cancer; however, the efficacy varies significantly between SCC and non-SCC patients. These findings deserve high clinical attention.\u003c/p\u003e","manuscriptTitle":"Comparative effectiveness of immune checkpoint inhibitors in squamous vs. non-aquamous cervical carcinoma: a meta-analysis of randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-11 10:05:47","doi":"10.21203/rs.3.rs-7024411/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"80094d4c-6860-45f3-a575-48e798cda89f","owner":[],"postedDate":"August 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-01T07:53:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-11 10:05:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7024411","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7024411","identity":"rs-7024411","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}