Atezolizumab versus Pembrolizumab in The Treatment of Advanced Triple-Negative Breast Cancer: A Bayesian Network Meta-Analysis of ITT and PD-L1 Positive Populations

Atezolizumab versus Pembrolizumab in The Treatment of Advanced Triple-Negative Breast Cancer: A Bayesian Network Meta-Analysis of ITT and PD-L1 Positive Populations | 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 Atezolizumab versus Pembrolizumab in The Treatment of Advanced Triple-Negative Breast Cancer: A Bayesian Network Meta-Analysis of ITT and PD-L1 Positive Populations I Gede Wikania Wira Wiguna, I Gede Krisna Arim Sadeva, Christo Timothy Mamangdean, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8627114/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Background Immune checkpoint inhibitors (ICIs) combined with chemotherapy are a standard treatment for advanced or metastatic triple-negative breast cancer (mTNBC). However, comparative evidence regarding relative efficacy and optimal use of different ICI regimens, specifically atezolizumab (A) versus pembrolizumab (P), remains limited. This study aims to evaluate the comparative efficacy and ranking of ICIs + chemotherapy regimens in treating advanced TNBC. Methods This study conducted a Bayesian network meta-analysis of phase III randomized controlled trials (RCTs) comparing ICI + chemotherapy versus chemotherapy alone in mTNBC patients following PRISMA 2020 guidelines. Outcomes analysed included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in both intention-to-treat (ITT) and PD-L1-positive populations. Indirect comparison was performed using R software (v.4.4.0). Results The network analysis included six studies from four RCTs (n = 2,776). A + CT (Odd ratio (OR) 1.36; 95% CrI 1.13–1.64) and P + CT (OR 1.18; 95% CrI 0.88–1.56) both showed improved ORR vs. chemotherapy alone in the ITT population. This benefit was most pronounced in the PD-L1-positive population, where A + CT demonstrated the highest ORR (OR 1.64; 95% CrI 1.26–2.13). A + CT consistently ranked highest by SUCRA for short-term efficacy measures (ORR, DCR, PFS) in the PD-L1-positive population, and also achieved the highest SUCRA rank for long-term OS (36 months) in this subgroup. Conversely, P + CT achieved the highest SUCRA rank for long-term OS in the heterogeneous ITT population. Conclusion Both ICI regimens demonstrate clinical benefit. While A + CT is favoured for high probability of early response in PD-L1-positive patients, the trend for superior long-term OS with P + CT in the ITT population underscores the need to carefully weigh treatment goals, strongly supporting PD-L1 status as a key predictive factor. However, this trend favoring P + CT in the ITT population is likely attributable to the statistical dilution of A + CT efficacy caused by methodological confounders in certain atezolizumab trials. Bayesian network meta-analysis Immune-checkpoint inhibitor chemotherapy triple-negative breast cancer Figures Figure 1 Figure 2 Figure 3 1. Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis compared to other breast cancer subtypes. 1 The incidence of TNBC reaches 10–25% of all breast cancer cases. 2 TNBC has a poorer prognosis with a five-year overall survival rate of 61.4% for TNBC, compared with 79.1% for hormone receptor-positive, indicating an 8–16% lower survival for TNBC across cohorts. 3 Moreover, patients with metastatic TNBC had a median survival of 8–13 months, corresponding to a five-year relative survival of roughly 11–12% in advanced stages with distant metastases. 4 Subtype TNBC lacks estrogen receptor (ER), progesterone receptor (PR), and HER2 expression, making it unresponsive to hormone therapies and HER2-targeted treatments that are effective in other breast cancer subtypes. This causes TNBC to tend to have a faster progression compared to other breast cancer subtypes and thus has a worse prognosis. 5 This condition makes the choice of therapy very limited and worsens the patient's prognosis. Although TNBC is often characterized by a high tumor mutational burden and substantial immune cell infiltration, classifying it as an immunologically hot tumor, the response to single-agent immunotherapy remains unsatisfactory. 6 A key challenge lies in the tumor microenvironment (TME), where the ability of TNBC cells to evade the immune system, primarily through the PD-L1/PD-1 axis, attenuates the efficacy of checkpoint blockade. Several ICIs have been developed, including pembrolizumab (anti-PD-1) and atezolizumab (anti-PD-L1), which have been approved by the FDA, especially for patients with advanced-TNBC. Based on the KEYNOTE-355 study, the FDA has approved the use of pembrolizumab for advanced TNBC in combination with chemotherapy as a first-line treatment for patients with metastatic TNBC (mTNBC) whose tumors express PD-L1 (combined positive score [CPS] ≥ 10). 7 This inconsistency, highlighted by the subsequent withdrawal of atezolizumab's accelerated FDA approval for this indication, has created clinical uncertainty regarding the optimal first-line ICI regimen. Atezolizumab had previously received FDA approval based on the IMpassion130 trial due to its significant improvement in PFS (7.4 vs. 4.8 months) in the PD-L1-positive population treated with atezolizumab plus nab-paclitaxel compared to chemotherapy alone. 8 However, in 2021, based on the findings of the IMpassion131 trial, which failed to meet its primary endpoint of PFS and changes in the treatment landscape that led the FDA to conclude that continued approval was no longer appropriate, 9 as well as the results of the study based on the IMpassion132 trial, which had not succeeded in showing optimal outcomes. 10 Given the absence of direct head-to-head trials, comparative evidence regarding the relative efficacy and optimal use of atezolizumab versus pembrolizumab regimens remains limited. This raises several hypotheses about how the results of these studies failed to produce the expected clinical outcomes. Several hypotheses have emerged based on a comparison of the methodologies carried out in RCT studies evaluating ICIs in advanced-TNBC, one of which is that the analysis was carried out on the general TNBC population in the intention-to-treat (ITT) population without considering the quantity of PD-L1 expression of patients so that the presence of these non-specific conditions is likely to be the cause of less than optimal therapy outcomes collectively. Therefore, this study aims to conduct an indirect comparison of the ITT and PD-L1-positive advanced-TNBC populations receiving ICIs using a Bayesian network meta-analysis design. 2. Methods 2.1 Study design and registration This Bayesian network meta-analysis study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. It was conducted in compliance with the PRISMA declaration standards; 11 see Supplementary Information File S1 . This study was prospectively registered through PROSPERO ( www.crd.york.ac.uk/prospero/ ) with registration number CRD420251118179. 2.2 Database search and strategies Studies published in the English language from March 21st, 2020, to April 21st, 2025, were comprehensively searched from the databases of PubMed (pubmed.ncbi.nlm.nih.gov), Cochrane Library ( www.cochranelibrary.com ), and Science Direct ( www.sciencedirect.com ). The search terms used were: “Immune-Checkpoint Inhibitors” OR “ICIs” OR “Atezolizumab” OR “Pembrolizumab”, combined with “Triple-Negative Breast Cancer” OR “TNBC”, “Locally-Advanced” OR “Metastatic”, and “Prognosis” OR “Overall Survival” OR “Progression-Free Survival” OR “Clinical Outcome”. 2.3 Study selection Phase III randomized controlled trials (RCTs) enrolling patients with advanced or metastatic triple-negative breast cancer were included. Eligible trials had to compare an immune checkpoint inhibitor (ICI) plus chemotherapy versus placebo plus chemotherapy, reporting outcomes for both the intention-to-treat (ITT) and PD-L1-positive populations. Inclusion required reporting of at least one major clinical outcome: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), or overall survival (OS). Additional requirements included documentation of adequate organ function, no prior targeted therapy for advanced disease, and completion of any previous curative treatment ≥ 12 months before enrolment. Trials were specifically excluded if they involved patients with active central nervous system (CNS) metastases or mandated the use of chronic corticosteroid therapy. Sourced publications identified from the databases were imported into the Covidence platform ( www.covidence.org/ ) for systematic screening, which was conducted by 2 independent reviewers. 2.4 Data extraction Following independent screening of titles/abstracts and full texts, the extracted articles were comprehensively evaluated by two independent reviewers. It was carried out using a predefined table that includes the author name, publication year, trial ID, country, study design, sample size, TNBC type, treatment regimen, control group, and clinical outcomes. 2.5 Risk of bias assessment The Cochrane Risk of Bias 2 (RoB2) tool was utilised to evaluate potential bias in selected studies. 12 Three independent reviewers conducted the assessments, and disagreements were resolved by discussion. 2.6 Certainty of evidence The quality of evidence for each outcome was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. 13 Evidence quality was categorized as high, moderate, low, or very low based on five standard GRADE domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. For this network meta-analysis, particular attention was given to indirectness regarding PD-L1 assay variability and imprecision in the credible intervals. Certainty was evaluated separately for the ITT and PD-L1-positive populations, with individual assessments conducted for Overall Survival and Progression-Free Survival across all specified time points (6, 12, 24, and 36 months). 2.7 Statistical analysis A Bayesian network meta-analysis (NMA) using random-effects frameworks was performed to estimate the comparative efficacy of the intervention regimens. Pooled effects were expressed as odds ratios for objective response rate (ORR) and disease control rate (DCR), and hazard ratios for OS and PFS, each with corresponding 95% credible intervals (95% CrI). Estimates were derived using Markov Chain Monte Carlo (MCMC) algorithms. Treatment effectiveness ranking was calculated using the surface under the cumulative ranking curve (SUCRA). 14 Clinical relevance was interpreted in relation to established minimal clinically important differences (MCID). 3. Results 3.1 Study selection A total of 6,006 articles were identified through database searches. Following the removal of 22 duplicates and applying database-specific filters, 5,300 studies were excluded, leaving 684 articles for title and abstract screening. After excluding 669 for breaking the inclusion criteria, 15 articles were assessed. Then, one study was excluded due to a lack of full paper and 8 studies were excluded due to inclusion of subgroup analyses, incomplete reporting, or irrelevant outcomes (e.g., pCR or monotherapy-focused trials). 15–22 Ultimately, six studies met all inclusion criteria and were included in the study (Fig. 1 ). 3.2 Study characteristics The final analysis included four phase III RCTs (three IMpassion trials, one KEYNOTE trial) from six published studies (Table 1 ). Where multiple publications were available for a single trial, the most recent and complete data for each outcome were prioritized. Specifically, three follow-up reports from IMpassion130, at which the initial report by Schmid et. al. (2018) was added manually,were included to capture time-to-event outcomes at different follow-up milestones. Patients with unresectable locally advanced or metastatic TNBC were enrolled, with sample sizes ranging from 595 to 902 participants. Table 1 Study characteristics of included studies Author, Years Study Protocol Country Study Design Sample Size Median Age (years) TNBC Type Treatment Control Schmid et al. , 2018 * IMpassion130 Multiple Countries Phase III RCT 902 ITT: 55, Control: 56 PD-L1+: 53, Control: 53 Unresectable locally advanced or metastatic Atezolizumab + paclitaxel Placebo + Paclitaxel Schmid et al. , 2020 * IMpassion130 Multiple Countries Phase III RCT 902 ITT: 55, Control: 56 PD-L1+: 53, Control: 53 Unresectable locally advanced or metastatic Atezolizumab + paclitaxel Placebo + Paclitaxel Emens et al. , 2021 * IMpassion130 Multiple Countries Phase III RCT 451 ITT: 55, Control: 56 PD-L1+: 53, Control: 53 Unresectable locally advanced or metastatic Atezolizumab + paclitaxel Placebo + Paclitaxel Miles et al. , 2021 IMpassion131 Multiple Countries Phase III RCT 651 ITT: 54, Control: 53 PD-L1+: 55, Control: 53 Unresectable locally advanced or metastatic Atezolizumab + paclitaxel Placebo + Paclitaxel Dent et al. , 2024 IMpassion132 Multiple Countries Phase III RCT 595 ITT: 49, Control: 49 PD-L1+: 48, Control: 48 Unresectable locally advanced or metastatic Atezolizumab + CT Placebo + CT Cortes et al. , 2022 KEYNOTE-355 Multiple Countries Phase III RCT 847 ITT: 53, Control: 53 PD-L1+: 52, Control: 52 PD-L1+ (CPS ≥ 10): 52, Control: 55 Unresectable locally advanced or metastatic Pembrolizumab + CT Placebo + CT *These studies relate to the same clinical trial. Abbreviation: CT = Chemotherapy; ITT = intention-to-treat population; PD-L1 + = PD-L1 positive; RCT = randomised controlled trial; TNBC = triple negative breast cancer. Amongst, recruited population were from multiple countries, and the reported median age range was 48–53 years. Three studies evaluated a combination of atezolizumab and chemotherapy compared to a group receiving a placebo and chemotherapy. Meanwhile, one study compared the treatment effect of pembrolizumab plus chemotherapy against chemotherapy alone. 3.3 Risk of bias assessment No significant risk of bias was found in the included studies (Fig. 2 ) . 7–10,23,24 3.4 Overall Response Rate (ORR) and Disease Control Rate (DCR) The network meta-analysis for ORR and DCR included data from six Phase III randomized controlled trials (Impassion130, Impassion131, Impassion132, and KEYNOTE-355), representing a network of 2,776 patients for ORR and 2,396 patients for DCR in the Intention-to-Treat (ITT) population, and 1,650 patients for ORR and 1,296 patients for DCR in the PD-L1-positive population (Table 2 ). Table 2 GRADE assessment on objective response rate and disease control rate for the treatment effect of Atezolizumab-Chemotherapy vs. Pembrolizumab-Chemotherapy for triple-negative breast cancer Summary of findings: Clinical Outcomes of Atezolizumab-Chemotherapy and Pembrolizumab-Chemotherapy for Triple-Negative Breast Cancer Outcome Population № of participants (№ of studies) Anticipated relative effects (95% CrI) Certainty What happens Odd Ratio (OR) ORR ITT 2776 (4) A + CT vs PL + CT: 1.33 (0.95 to 1.79) ⨁⨁⨁◯ Moderate A + CT probably increases ORR compared to CT, while P + CT may result in little to no difference in ITT patients. P + CT vs PL + CT: 1.17 (0.70 to 1.97) ⨁⨁◯◯ Low PD-L1+ 1650 (4) A + CT vs PL + CT: 1.63 (1.05 to 2.49) ⨁⨁⨁◯ Moderate A + CT probably increases ORR compared to CT, while P + CT may result in little to no difference in PD-L1 + patients. P + CT vs PL + CT: 1.29 (0.64 to 2.57) ⨁⨁◯◯ Low DCR ITT 2396 (4) A + CT vs PL + CT: 1.17 (0.66 to 2.01) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in DCR. P + CT vs PL + CT: 0.81 (0.37 to 1.77) ⨁⨁◯◯ Low PD-L1+ 1296 (4) A + CT vs PL + CT: 1.22 (0.63 to 2.22) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in DCR. P + CT vs PL + CT: 0.89 (0.39 to 2.00) ⨁⨁◯◯ Low * The risk in the intervention group (and its 95% credible interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CrI). Abbreviations : A + CT: Atezolizumab-Chemotherapy; CrI: credible interval; CT: Chemotherapy; DCR: Disease Control Rate; ITT: Intention-To-Treat; ORR: Overall Response Rate; OS: Odds Ratio; P + CT: Pembrolizumab-Chemotherapy; PD-L1 + = PD-L1 positive. GRADE Working Group grades of evidence High certainty : We are very confident that the true effect lies close to the estimated effect. Moderate certainty : We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty : our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty : we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimated effect. Looking through the ORR, both atezolizumab plus chemotherapy (A + CT) and pembrolizumab plus chemotherapy (P + CT) demonstrated a higher ORR compared to chemotherapy alone in the ITT population. The A + CT group showed a stronger pooled effect (OR 1.36; 95% CrI 1.13–1.64) and achieved the highest SUCRA score (Table 2 ). Regarding the PD-L1-positive population, the benefit of combination therapy was more pronounced, with A + CT showing the most substantial effect (OR 1.64; 95% CrI 1.26–2.13) and the highest SUCRA ranking, though the comparative efficacy between the two ICIs did not reach statistical significance (Table 2 ). For the DCR, a trend toward improved disease stabilization was consistently observed across both populations. A + CT showed numerically higher DCR odds than P + CT and control in both the ITT and PD-L1-positive populations (Table 2 ). SUCRA analysis ranked A + CT highest for DCR in both groups, suggesting a better probability of achieving disease control compared to P + CT (Table 4 ). The consistent trends and higher rank probabilities in the PD-L1-positive network support the role of PD-L1 expression as a predictive biomarker for ICI-mediated cytostatic benefit. 3.5 Overall Survival (OS) and Progression-Free Survival (PFS) The analysis of time-to-event outcomes (OS and PFS; Table 3 ) revealed a complex interplay between the regimen, population, and follow-up time. In the early follow-up about OS (6 months, Table 3 ), A + CT group demonstrated a better 6-month OS than the P + CT in both the ITT (HR 0.88 vs 0.85) and PD-L1-positive populations (HR 1.01 vs 0.87). During an extended follow-up (12–36 months, Table 3 ), the relative benefits shifted over time. P + CT trended toward better OS compared with A + CT at 12–36 months in the ITT population. However, at 36 months in the PD-L1-positive population, A + CT was associated with a better outcome (HR 1.65 vs 1.26), achieving the highest SUCRA rank, suggesting a potential long-term survival advantage in this enriched subgroup (Table 4 , Fig. 3 ). Table 3 GRADE assessment on overall survival and progression-free survival for the treatment effect of Atezolizumab-Chemotherapy vs. Pembrolizumab-Chemotherapy for triple-negative breast cancer Summary of findings: Efficacy of Atezolizumab-Chemotherapy and Pembrolizumab-Chemotherapy for Triple-Negative Breast Cancer Outcome Population № of participants (№ of studies) Timepoint Anticipated relative effects (95% CrI) Certainty What happens Hazard Ratio (HR) OS ITT 2780 (4) 6-months A + CT vs PL + CT: 0.88 (0.79 to 0.97) ⨁⨁⨁◯ Moderate A + CT probably reduces the hazard of mortality, while P + CT may result in little to no difference. P + CT vs PL + CT: 0.85 (0.73 to 0.99) ⨁⨁◯◯ Low 12-months A + CT vs PL + CT: 0.95 (0.84 to 1.07) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in OS. P + CT vs PL + CT: 0.97 (0.81 to 1.16) ⨁⨁◯◯ Low 24-months A + CT vs PL + CT: 0.92 (0.77 to 1.09) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in OS. P + CT vs PL + CT: 1.03 (0.81 to 1.32) ⨁⨁◯◯ Low 36-months A + CT vs PL + CT: 0.97 (0.75 to 1.26) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in OS. P + CT vs PL + CT: 1.16 (0.85 to 1.62) ⨁⨁◯◯ Low PD-L1+ 1651 (4) 6-months A + CT vs PL + CT: 1.01 (0.87 to 1.18) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in OS. P + CT vs PL + CT: 0.87 (0.71 to 1.07) ⨁⨁◯◯ Low 12-months A + CT vs PL + CT: 1.06 (0.89 to 1.25) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in OS. P + CT vs PL + CT: 1.00 (0.80 to 1.25) ⨁⨁◯◯ Low 24-months A + CT vs PL + CT: 1.18 (0.92 to 1.52) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in OS. P + CT vs PL + CT: 1.27 (0.95 to 1.72) ⨁⨁◯◯ Low 36-months A + CT vs PL + CT: 1.64 (1.10 to 2.45) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in OS. P + CT vs PL + CT: 1.26 (0.85 to 1.88) ⨁⨁◯◯ Low PFS ITT 2568 (4) 6-months A + CT vs PL + CT: 1.11 (0.95 to 1.30) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in PFS. P + CT vs PL + CT: 1.24 (0.98 to 1.57) ⨁⨁◯◯ Low 12-months A + CT vs PL + CT: 1.25 (0.97 to 1.61) ⨁⨁◯◯ Low A + CT may result in little to no difference while P + CT probably reduces the hazard of progression. P + CT vs PL + CT: 1.47 (1.02 to 2.18) ⨁⨁⨁◯ Moderate 24-months A + CT vs PL + CT: 0.64 (0.40 to 1.05) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in PFS. P + CT vs PL + CT: 1.08 (0.67 to 1.76) ⨁⨁◯◯ Low 36-months A + CT vs PL + CT: 0.33 (0.15 to 0.69) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in PFS. P + CT vs PL + CT: 1.00 (0.58 to 1.72) ⨁⨁◯◯ Low PD-L1+ 1561 (4) 6-months A + CT vs PL + CT: 1.57 (1.22 to 2.02) ⨁⨁⨁◯ Moderate A + CT probably reduces the hazard of progression even though P + CT may result in little to no difference. P + CT vs PL + CT: 1.33 (0.94 to 1.88) ⨁⨁◯◯ Low 12-months A + CT vs PL + CT: 1.58 (1.14 to 2.20) ⨁⨁⨁◯ Moderate Both regimens probably reduce the hazard of progression. P + CT vs PL + CT: 1.68 (1.10 to 2.64) ⨁⨁⨁◯ Moderate 24-months A + CT vs PL + CT: 1.19 (0.72 to 1.99) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in PFS. P + CT vs PL + CT: 1.52 (0.87 to 2.76) ⨁⨁◯◯ Low 36-months A + CT vs PL + CT: 1.46 (0.69 to 3.20) ⨁⨁◯◯ Low Both regimens demonstrated comparable efficacy with no statistically significant difference in PFS. P + CT vs PL + CT: 1.97 (0.93 to 4.61) ⨁⨁◯◯ Low * The risk in the intervention group (and its 95% credible interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CrI). Abbreviations : CrI: credible interval; OS: Odd Ratio; HR: Hazard Ratio; OS: Overall Survival; PFS: Progression-Free Survival; CT: Chemotherapy; A + CT: Atezolizumab-Chemotherapy; ITT: Intention-To-Treat; P + CT: Pembrolizumab-Chemotherapy; PD-L1+: PD-L1-positive. GRADE Working Group grades of evidence High certainty : We are very confident that the true effect lies close to the estimated effect. Moderate certainty : we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty : our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty : we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimated effect. During the first follow-up of PFS (6 months), A + CT showed a better 6-month PFS in the PD-L1-positive population (HR 1.57 vs 1.33) (Table 3 ) and was ranked highest by SUCRA (Table 4 , Fig. 3 ). P + CT, conversely, was favored in the ITT population. In the extended follow-up (12–36 months, Table 3 ), the majority of extended follow-up time points (12, 24, and 36 months) showed P + CT trending towards better PFS than A + CT in both the ITT and PD-L1-positive populations. SUCRA analysis consistently favored P + CT at 12 months in both groups and at 24 and 36 months in the PD-L1-positive population (Table 4 , Fig. 3 ). 3.6 GRADE assessment The certainty of evidence for all outcomes, assessed using the GRADE) approach, ranged from moderate to low. The primary reasons for downgrading included imprecision based on wide Bayesian credible intervals (CrI), inconsistency of effect across time points, and indirectness of evidence relative to the typical clinical question. Evidence for ORR was generally graded as moderate certainty. This outcome showed consistent directional benefit favoring atezolizumab plus chemotherapy (A + CT) over chemotherapy alone in both the ITT (n = 2,776) and PD-L1-positive patients (n = 1,650). ORR was downgraded one level for indirectness due to the restriction to metastatic TNBC, heterogeneity in chemotherapy backbones, and the variability in PD-L1 assays and cut-offs used across the four included studies. Evidence for DCR was assessed as low certainty. Although A + CT trended favorably, particularly in the PD-L1-positive network, the outcome was downgraded for both indirectness (as above) and imprecision. The wide credible intervals for comparisons involving A + CT and P + CT often crossed the null effect (OR = 1), limiting confidence in the estimated magnitude of the disease control benefit. All time-to-event outcomes (OS and PFS) across all time points (6, 12, 24, and 36 months) and populations were graded as low certainty. Downgrading for inconsistency was applied due to the unstable nature of the treatment rankings over time. For example, ICI-based regimens showed varying SUCRA advantages at 24 months but failed to maintain a consistent rank at 36 months, indicating uncertainty regarding durable benefit. Downgrading for imprecision was required because many Hazard Ratios clustered close to 1, with CrIs spanning from modest benefit to no effect or minor harm, suggesting a lack of certainty about a true clinically significant effect. Additional downgrading for indirectness was noted, especially in the ITT analyses, as the evidence was predominantly confined to metastatic TNBC treated with taxane-based regimens, and the long-term data reflected highly selected survivor cohorts. Formal assessment of publication bias was not feasible using funnel plot-based methods due to the network meta-analysis design, the Bayesian approach utilized, and the limited number of studies (four per outcome). Therefore, no formal downgrading was applied in this domain, although the possibility of small-study effects or selective non-publication cannot be excluded. The full GRADE certainty assessment is detailed in the accompanying tables (Table 2 and Table 3 ). 4. Discussion This Bayesian network meta-analysis was conducted under the hypothesis that immune checkpoint inhibitors (ICIs), when combined with chemotherapy, provide differential but clinically meaningful benefit in advanced TNBC and that the magnitude and durability of benefit differ between pembrolizumab plus chemotherapy (P + CT) and atezolizumab plus chemotherapy (A + CT) based on biomarker methodology, chemotherapy backbone, and biological context. This Bayesian network meta-analysis was designed to evaluate these dynamics across ITT and PD-L1-positive populations and multiple time-dependent outcomes, thereby extending beyond the conclusions that individual trials could provide. The results of this analysis largely support the hypothesis and provide a more nuanced understanding of regimen-specific performance in advanced TNBC. Across the ITT population, P + CT showed a more consistent, stable, and durable improvement in PFS compared with A + CT and chemotherapy alone. In our Bayesian network model, the P + CT regimen demonstrated favorable HR at nearly all follow-up intervals, and SUCRA rankings indicated that P + CT had the highest probability of being the most effective regimen across almost all time points, except at 24 months. In contrast, A + CT exhibited diminishing benefit at later time points, ranking below the control arm at 24 and 36 months. These findings suggest that pembrolizumab may provide more stable immunologic pressure across heterogeneous TNBC populations, whereas atezolizumab’s benefit appears more dependent on specific trial conditions and population characteristics. Among PD-L1-positive populations, both ICI regimens demonstrated favorable PFS relative to chemotherapy alone at each follow-up interval, confirming the well-recognized enrichment effect of PD-L1 positivity on immunotherapy outcomes. Although A + CT showed more substantial early benefit at 6 months, this advantage did not persist. This study found that by 12 months, the trend shifted in favor of P + CT, which maintained its superiority through 36 months. These findings closely align with observations from KEYNOTE-355, which showed that pembrolizumab produced proportionally greater benefit at higher Combined Positive Score (CPS) thresholds, particularly in tumors with CPS ≥ 10 (median PFS 9.7 vs 5.6 months). 17 Similarly, atezolizumab demonstrated benefit in the PD-L1-positive population in IMpassion130 (median OS 25.4 vs 17.9 months). 8,23,24 However, this efficacy did not extend to IMpassion131 or IMpassion132, where population-level factors, such as early-relapsing, chemo-refractory biology, and the need for corticosteroid premedication in paclitaxel-based regimens, were expected to attenuate atezolizumab’s immune-mediated activity. 9,16,25 Taken together, these findings reinforce that pembrolizumab provides more consistent benefit across heterogeneous PD-L1-positive settings. In contrast, the clinical efficacy of atezolizumab is more sensitive to assay selection, chemotherapy backbone, and underlying population characteristics. This study found the pooled ORR increased by 27–31% with ICI-chemotherapy combinations compared with chemotherapy alone, which also supports our hypothesis. Partial responses and stable disease were the most common, while complete responses were rare (< 3%). This is consistent with the immunological mechanism of ICIs, which prolongs antitumor immune pressure rather than driving immediate deep cytoreduction, as shown in other meta-analyses. 26,27 The stronger ORR performance of A + CT in our ranking analysis parallels IMpassion130 (56% vs 46%), 8,23,24 while pembrolizumab’s performance aligns with KEYNOTE-355 (53.2% vs 39.8% in CPS ≥ 10). 16,17 These findings indicate that while both ICIs enhance early disease control, their long-term durability diverges depending on population characteristics, biomarker methodology, and chemotherapy backbone. This study found that the variability between A + CT and P + CT across trials can be explained by several well-characterized confounders, the first of which is PD-L1 assay heterogeneity. IMpassion trials used SP142, which identifies PD-L1 expression exclusively on immune cells and categorizes tumors as positive or negative. This approach is specific but tends to classify fewer tumors as PD-L1-positive, thereby influencing apparent efficacy outcomes. 9,23,25 In contrast, KEYNOTE-355 used the CPS, which incorporates PD-L1 expression on both tumor and immune cells and allows stratification into CPS ≥ 1, ≥10, and ≥ 20. Pembrolizumab efficacy increased proportionally with higher CPS levels, particularly in tumors with CPS 10-19. 7,16,17 These fundamental methodological differences create non-overlapping PD-L1-positive populations across trials, limiting direct comparability. Thus, what appears as a comparative drug difference often reflects biomarker discordance. Population heterogeneity represents the second influential factor. IMpassion132 enrolled 595 rapid-relapse patients with a disease-free interval < 12 months, representing one of the most aggressive and chemo-refractory TNBC subtypes. 10 These tumors frequently harbor immune exhaustion signatures, myeloid-driven suppression, low antigen presentation capacity, and poor interferon signaling, all of which impede response to PD-L1 blockade, underscoring that immunologically “cold” and rapidly recurring tumors remain refractory to checkpoint inhibition despite PD-L1 status. 28 IMpassion132, therefore, showed minimal benefit (median OS 11.2 vs 12.1 months), and this large negative dataset substantially impacted A + CT’s pooled rankings at longer follow-up. 10 This finding reinforces that PD-L1 positivity alone is insufficient to predict therapeutic responsiveness in biologically aggressive early-relapsing disease. The chemotherapy backbone further contributed to regimen-specific heterogeneity. IMpassion130 used nab-paclitaxel, which does not require corticosteroid premedication, thus preserving dendritic cell maturation and T-cell priming, key mechanisms needed for atezolizumab activity. 23,29 In contrast, IMpassion131 utilized solvent-based paclitaxel, which requires repeated corticosteroid administration to prevent hypersensitivity reactions. These corticosteroids suppress antigen presentation, inhibit dendritic cell function, and blunt T-cell activation, thereby directly counteracting the mechanism of PD-L1 blockade. 25 This pharmacologic antagonism likely explains the lack of benefit observed in IMpassion131 despite nearly identical design and eligibility criteria to IMpassion130, reinforcing the importance of selecting steroid-free chemotherapy partners when combining ICIs with taxanes. This analysis also illuminates the time-dependent nature of immunotherapy benefit. In the ITT populations, both ICI regimens demonstrated lower OS in the first 12 months compared with chemotherapy alone, reflecting delayed kinetics of immune activation. After 12 months, P + CT showed progressive improvement through 36 months, while A + CT plateaued with minimal late benefit. In PD-L1-positive tumors, A + CT produced a more substantial early OS improvement, peaking at 36 months, whereas pembrolizumab demonstrated a more consistent, gradually increasing benefit. These patterns align with existing clinical observations that atezolizumab’s activity is tightly tied to PD-L1 expression and chemotherapy synergy, while pembrolizumab demonstrates broader immunologic applicability. 30 Several biological mechanisms may underlie the decline in ICI benefit over prolonged follow-up. TNBC is known to evolve toward immune-resistant phenotypes over time, characterized by increasing myeloid-derived suppressor cell activity, neutrophil extracellular trap formation, exhaustion of cytotoxic T cells, and macrophage polarization toward immunosuppressive states. 31–33 Organ-specific metastatic microenvironments further constrain immune activity, such as in liver metastases generate tolerogenic macrophage-dominant niches, 34,35 lung metastases harbor TREM2 + macrophages and PD-L1-expressing alveolar cells, 36,37 and bone metastases activate RANK-RANKL pathways that disrupt antigen presentation. 38,39 Given that the majority of participants across included trials had visceral or bone disease, these microenvironmental pressures likely contributed to the modest long-term survival seen in both regimens. The strengths of this study include rigorous adherence to the PRISMA methodology, the use of Bayesian network modelling to allow indirect comparisons across multiple time points, and the inclusion of large, multinational phase III randomized trials. These strengths enhance the reliability of comparative estimates and support a comprehensive appraisal of regimen-specific temporal effects. However, limitations remain. The number of eligible RCTs is small, and the absence of direct head-to-head comparisons between pembrolizumab and atezolizumab restricts causal inference. Heterogeneity in PD-L1 assays and chemotherapy partners limits cross-trial comparability, and long-term outcomes are imprecise due to small event counts and trial maturity. Despite these limitations, the consistency of the trends across multiple datasets strengthens the interpretability of the findings. 5. Conclusion Overall, this meta-analysis suggests that the combination of ICIs with chemotherapy provides a clinically favorable benefit in mTNBC, particularly in the PD-L1-positive population. Atezolizumab plus chemotherapy showed the strongest probability of efficacy in the PD-L1-positive population with the highest SUCRA ratings for objective response, disease control, and 36-month survival. Pembrolizumab plus chemotherapy performed more consistently in the heterogeneous ITT population with the highest SUCRA ratings for long-term OS and PFS, although this superiority likely influenced dilution of atezolizumab efficacy due to the use of steroid-based chemotherapy and the inclusion of highly resistant patients in the IMpassion trial. These findings emphasize the importance of more precise biomarker selection, optimization of adjuvant chemotherapy regimens, and identification of biologic subgroups, and support the need for head-to-head trials, development of biomarkers beyond PD-L1, and combination strategies targeting the TME to overcome immune resistance and improve longevity. Declarations Ethics approval and consent to participate Ethical approval was not required for this study as it is a meta-analysis of previously published, publicly available data and does not involve the collection of primary data from human participants. Consent for publication Not applicable. Availability of data and materials All data analysed during this study are included in this published article and its supplementary information files. Competing interests All authors declare no financial or non-financial competing interests. Funding This project was funded by the National Research Council of Thailand (NRCT): High Potential Research Team Grant Program (N42A680423) and Ratchadapisek Somphot Matching Fund, Faculty of Medicine, Chulalongkorn University (RA-MF-01/69). The academic endeavors of the Thailand Hub of Talents in Cancer Immunotherapy (TTCI) receive support from the National Research Council of Thailand. Authors’ contribution I.G.W.W.W., M.S.T., S.K., and N.H. managed conceptualization, supervision, and project administration. C.T.M. managed formal analysis. I.G.W.W.W., I.G.K.A.S., N.P.K.M., P.M.W.S.P., K.M.K.T., A.B.N.K., K.I.P.A., and I.K.R.P.P. contributed to data curation, investigation, methodology, and writing - original draft. M.S.T., S.K., and N.H. aided in conceptualization and contributed to writing - original draft. I.G.W.W.W., M.S.T., S.K., and N.H. participated in methodology and writing - review & editing. I.G.W.W.W., M.S.T., and C.T.M. were involved in data curation, investigation, and visualization. N.H. and M.S.T. provided critical writing – review & editing, supervision, and secured funding acquisition. Acknowledgements We would like to express our gratitude to the National Research Council of Thailand (NRCT), Faculty of Medicine, Chulalongkorn University, and the Thailand Hub of Talents in Cancer Immunotherapy for supporting this study. References Xiong N, Wu H, Yu Z. Advancements and challenges in triple-negative breast cancer: a comprehensive review of therapeutic and diagnostic strategies. Front Oncol. 2024;14:1405491. Almansour NM. Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. Front Mol Biosci. 2022;9:836417. Darida M, Rubovszky G, Kiss Z, Székely B, Madaras B, Horváth Z, et al. Improvement in breast cancer survival across molecular subtypes in Hungary between 2011 and 2020: a nationwide, retrospective study. Front Oncol. 2025;15:1465511. Kesireddy M, Elsayed L, Shostrom VK, Agarwal P, Asif S, Yellala A, et al. Overall Survival and Prognostic Factors in Metastatic Triple-Negative Breast Cancer: A National Cancer Database Analysis. Cancers (Basel). 2024 May;16(10). Jie H, Ma W, Huang C. Diagnosis, Prognosis, and Treatment of Triple-Negative Breast Cancer: A Review. Breast cancer (Dove Med Press. 2025;17:265–74. Li L, Zhang F, Liu Z, Fan Z. Immunotherapy for Triple-Negative Breast Cancer: Combination Strategies to Improve Outcome. Cancers (Basel). 2023 Jan;15(1). Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022 Jul;387(3):217–26. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018;379(22):2108–21. Miles D, Gligorov J, André F, Cameron D, Schneeweiss A, Barrios C, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2021 Aug;32(8):994–1004. Dent R, André F, Gonçalves A, Martin M, Schmid P, Schütz F, et al. IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2024 Jul;35(7):630–42. Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021 Mar;372:n160. Higgins JPT, Altman DG. Chapter 8: Assessing risk of bias in included studies. In 2008. Available from: https://api.semanticscholar.org/CorpusID:76535584 Bezerra CT, Grande AJ, Galvão VK, Santos DHM Dos, Atallah ÁN, Silva V. Assessment of the strength of recommendation and quality of evidence: GRADE checklist. A descriptive study. Sao Paulo Med J. 2022;140(6):829–36. Mbuagbaw L, Rochwerg B, Jaeschke R, Heels-Andsell D, Alhazzani W, Thabane L, et al. Approaches to interpreting and choosing the best treatments in network meta-analyses. Vol. 6, Systematic reviews. England; 2017. p. 79. Adams S, Diéras V, Barrios CH, Winer EP, Schneeweiss A, Iwata H, et al. Patient-reported outcomes from the phase III IMpassion130 trial of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2020 May;31(5):582–9. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817–28. Hattori M, Masuda N, Takano T, Tsugawa K, Inoue K, Matsumoto K, et al. Pembrolizumab plus chemotherapy in Japanese patients with triple-negative breast cancer: Results from KEYNOTE-355. Cancer Med. 2023 May;12(9):10280–93. Gianni L, Huang CS, Egle D, Bermejo B, Zamagni C, Thill M, et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol Off J Eur Soc Med Oncol. 2022 May;33(5):534–43. Im SA, Cortes J, Cescon DW, Yusof MM, Iwata H, Masuda N, et al. Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC. NPJ breast cancer. 2024 Sep;10(1):79. Narayan P, Wahby S, Gao JJ, Amiri-Kordestani L, Ibrahim A, Bloomquist E, et al. FDA Approval Summary: Atezolizumab plus Paclitaxel Protein-bound for the Treatment of Patients with Advanced or Metastatic TNBC Whose Tumors Express PD-L1. Clin Cancer Res. 2020;26(10):2284–9. Schmid P, Oliveira M, O’Shaughnessy J, Cristofanilli M, Graff SL, Im SA, et al. TROPION-Breast05: a randomized phase III study of Dato-DXd with or without durvalumab versus chemotherapy plus pembrolizumab in patients with PD-L1-high locally recurrent inoperable or metastatic triple-negative breast cancer. Ther Adv Med Oncol. 2025;17:17588359251327992. Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):499–511. Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):44–59. Emens LA, Adams S, Barrios CH, Diéras V, Iwata H, Loi S, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol Off J Eur Soc Med Oncol. 2021 Aug;32(8):983–93. de Moura A, Vuagnat P, Renouf B, Pierga JY, Loirat D, Vaflard P, et al. Atezolizumab and paclitaxel as first line therapy in advanced triple-negative breast cancer patients included in the French early access program. Sci Rep. 2023 Aug;13(1):13427. Li Y, Xing L, Li F, Liu H, Gan L, Yang D, et al. Efficacy and Safety of Adding Immune Checkpoint Inhibitors to Neoadjuvant Chemotherapy Against Triple-Negative Breast Cancer: A Meta-Analysis of Randomized Controlled Trials. Front Oncol. 2021;11:657634. Ji Q, Ding J, Hao M, Luo N, Huang J, Zhang W. Immune Checkpoint Inhibitors Combined With Chemotherapy Compared With Chemotherapy Alone for Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis. Front Oncol. 2021;11:795650. Zheng Y, Li S, Tang H, Meng X, Zheng Q. Molecular mechanisms of immunotherapy resistance in triple-negative breast cancer. Front Immunol. 2023;14:1153990. Mohan N, Hosain S, Zhao J, Shen Y, Luo X, Jiang J, et al. Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1(+) triple negative breast cancer cells. Oncoimmunology. 2019;8(9):e1624128. Fabi A, Carbognin L, Botticelli A, Paris I, Fuso P, Savastano MC, et al. Real-world ANASTASE study of atezolizumab+nab-paclitaxel as first-line treatment of PD-L1-positive metastatic triple-negative breast cancer. NPJ breast cancer. 2023 Sep;9(1):73. Ritchie S, Reed DA, Pereira BA, Timpson P. The cancer cell secretome drives cooperative manipulation of the tumour microenvironment to accelerate tumourigenesis. Fac Rev. 2021;10:4. Mukai H, Miki N, Yamada H, Goto H, Kawakami T, Suzuki A, et al. Pannexin1 channel-dependent secretome from apoptotic tumor cells shapes immune-escape microenvironment. Biochem Biophys Res Commun [Internet]. 2022;628:116–22. Available from: https://www.sciencedirect.com/science/article/pii/S0006291X22011998 Li J, Sun J, Rong R, Li L, Shang W, Song D, et al. HMGB1 promotes myeloid-derived suppressor cells and renal cell carcinoma immune escape. Oncotarget. 2017;8(38):63290–8. Yang M, Zhang C. The role of liver sinusoidal endothelial cells in cancer liver metastasis. Am J Cancer Res. 2021;11(5):1845–60. Wu K, Zhang G, Shen C, Zhu L, Yu C, Sartorius K, et al. Role of T cells in liver metastasis. Cell Death Dis. 2024 May;15(5):341. Cha YJ, Kim HM, Koo JS. Inherent PD-L1 22C3 Expression in Alveolar Macrophages Impacts the Combined Positive Score Status in Breast Cancer With Pulmonary Metastasis. Thorac cancer. 2025 Mar;16(5):e70004. Yofe I, Shami T, Cohen N, Landsberger T, Sheban F, Stoler-Barak L, et al. Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary. Cancer Discov. 2023 Dec;13(12):2610–31. Okamoto K. Role of RANKL in cancer development and metastasis. J Bone Miner Metab. 2021 Jan;39(1):71–81. Wu X, Li F, Dang L, Liang C, Lu A, Zhang G. RANKL/RANK System-Based Mechanism for Breast Cancer Bone Metastasis and Related Therapeutic Strategies. Front cell Dev Biol. 2020;8:76. Table 4 Table 4 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files S1PRISMA2020checklist.docx Table4.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 06 Apr, 2026 Reviews received at journal 29 Mar, 2026 Reviewers agreed at journal 28 Mar, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviews received at journal 26 Feb, 2026 Reviews received at journal 11 Feb, 2026 Reviewers agreed at journal 07 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 05 Feb, 2026 Reviewers agreed at journal 05 Feb, 2026 Reviewers invited by journal 05 Feb, 2026 Editor invited by journal 23 Jan, 2026 Editor assigned by journal 22 Jan, 2026 Submission checks completed at journal 22 Jan, 2026 First submitted to journal 17 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8627114","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":587638471,"identity":"288d4338-c3bb-4237-9de9-cfe4760bb214","order_by":0,"name":"I Gede Wikania Wira Wiguna","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"I","middleName":"Gede Wikania Wira","lastName":"Wiguna","suffix":""},{"id":587638474,"identity":"359556e9-9f8f-4c65-8f62-6abea10b14f9","order_by":1,"name":"I Gede Krisna Arim Sadeva","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"I","middleName":"Gede Krisna Arim","lastName":"Sadeva","suffix":""},{"id":587638479,"identity":"9b21a018-dfa6-4e5a-9b03-ea7837004deb","order_by":2,"name":"Christo Timothy Mamangdean","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"Christo","middleName":"Timothy","lastName":"Mamangdean","suffix":""},{"id":587638484,"identity":"d1dc42c2-9cc9-431b-bceb-58f67210fd7a","order_by":3,"name":"Ngakan Putu Krishna Mahayana","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"Ngakan","middleName":"Putu Krishna","lastName":"Mahayana","suffix":""},{"id":587638497,"identity":"1a62d859-71e2-4f87-a0c3-c067839369cb","order_by":4,"name":"Suparada Khanaruksombat","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"prefix":"","firstName":"Suparada","middleName":"","lastName":"Khanaruksombat","suffix":""},{"id":587638498,"identity":"66b6f161-ebdd-4c92-abe9-9c605fa43f35","order_by":5,"name":"May Soe Thu","email":"","orcid":"","institution":"Chulalongkorn University","correspondingAuthor":false,"prefix":"","firstName":"May","middleName":"Soe","lastName":"Thu","suffix":""},{"id":587638499,"identity":"22fed977-b21d-46d7-8205-40fa6f72acf3","order_by":6,"name":"Putu Mirah Wahyu Subagia Putri","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"Putu","middleName":"Mirah Wahyu Subagia","lastName":"Putri","suffix":""},{"id":587638501,"identity":"38bfca56-db68-4a35-8d4e-4af53d9a8eb5","order_by":7,"name":"Kadek Meryndha Kumala Tungga","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"Kadek","middleName":"Meryndha Kumala","lastName":"Tungga","suffix":""},{"id":587638506,"identity":"1311d0c5-7cc7-4241-86af-f80cb25f3100","order_by":8,"name":"Agung Brahmanthya Nadine Kepakisan","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"Agung","middleName":"Brahmanthya Nadine","lastName":"Kepakisan","suffix":""},{"id":587638508,"identity":"ed09aa29-8f7e-4e2d-9580-6a0423571490","order_by":9,"name":"Komang Indra Parama Arta","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"Komang","middleName":"Indra Parama","lastName":"Arta","suffix":""},{"id":587638515,"identity":"043427ef-a439-4373-b30c-5e2d2d15d4b7","order_by":10,"name":"I Komang Raditya Putra Pratama","email":"","orcid":"","institution":"Udayana University","correspondingAuthor":false,"prefix":"","firstName":"I","middleName":"Komang Raditya Putra","lastName":"Pratama","suffix":""},{"id":587638518,"identity":"c19c2318-9333-4e4a-90fc-9edeb3160e06","order_by":11,"name":"Nattiya Hirankarn","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIie3RMQrCMBSA4RcKdQm4KkK9wiuCOohepaXg5OAkgoMVQa8g6GECHbIEu1ZclICTi7g4OJhEcEwdBfMP5RHykYQCuFw/GDL1ifTAUx9g/F71bKTLPJIaIpgiaBbJ0kZ6mpjjiuhbwnN+Oq/6gAd5kRT7UF2zihxbSFskJI1XCQyOw06LYgI1EZHlxkaYIR7gceQ3KKqHF+pi1EJaudRkri4mNJlDs4yEhTklU8+nmuihlMhwE+05RTFs13fIaSjixdZGMI9Pt8dkFiDPLrXrdBYEPGN3GzERHz571PD+USU9v9jjcrlc/9sL3eVOMfbXgYMAAAAASUVORK5CYII=","orcid":"","institution":"Chulalongkorn University","correspondingAuthor":true,"prefix":"","firstName":"Nattiya","middleName":"","lastName":"Hirankarn","suffix":""}],"badges":[],"createdAt":"2026-01-17 15:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8627114/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8627114/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102239552,"identity":"ed5f1858-685e-4a68-b207-ccf9fb60c944","added_by":"auto","created_at":"2026-02-09 16:45:47","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":349337,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA Flowchart for the systematic literature review and meta-analysis\u003c/p\u003e\n\u003cp\u003eAbbreviation: n = Number\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8627114/v1/5b1539023213fa5fe8345b22.jpeg"},{"id":102239556,"identity":"a0055347-b9e8-462c-969f-adac3d55d5c6","added_by":"auto","created_at":"2026-02-09 16:45:47","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":239726,"visible":true,"origin":"","legend":"\u003cp\u003eAssessment of risk of bias in the included studies\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8627114/v1/a0b24b9ec4d011d4fa6a5db1.jpeg"},{"id":102297196,"identity":"97770fcb-366b-4974-9bec-a2cbb95740a8","added_by":"auto","created_at":"2026-02-10 10:26:25","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":84367,"visible":true,"origin":"","legend":"\u003cp\u003eSUCRA plots for 6-month, 12-month, 24-month, 36-month overall survival (OS) and prolong free survival (PFS) in ITT and PD-L1-positive population.\u003c/p\u003e\n\u003cp\u003eAbbreviation: CT = Chemotherapy; ITT = intention-to-treat population; PD-L1+ = PD-L1 positive.\u003c/p\u003e","description":"","filename":"groupimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8627114/v1/5bcb089c57060a2c01198d8d.jpeg"},{"id":102301749,"identity":"f5afb6d6-e545-491d-a25d-c8b4eaa2153b","added_by":"auto","created_at":"2026-02-10 11:23:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2471755,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8627114/v1/3100e594-69a4-45c6-bb22-996a2b8769e5.pdf"},{"id":102239554,"identity":"14e57fdc-b098-4f92-b79e-d7df7dc97dcb","added_by":"auto","created_at":"2026-02-09 16:45:47","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33587,"visible":true,"origin":"","legend":"","description":"","filename":"S1PRISMA2020checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-8627114/v1/8bfe198eb3b65c3d90c6c2c5.docx"},{"id":102239555,"identity":"cad7538e-1edf-4371-bd5e-f842f6c84bc3","added_by":"auto","created_at":"2026-02-09 16:45:47","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":169564,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-8627114/v1/bf68fd62017786e6e0417220.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Atezolizumab versus Pembrolizumab in The Treatment of Advanced Triple-Negative Breast Cancer: A Bayesian Network Meta-Analysis of ITT and PD-L1 Positive Populations","fulltext":[{"header":"1. Background","content":"\u003cp\u003eTriple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis compared to other breast cancer subtypes.\u003csup\u003e1\u003c/sup\u003e The incidence of TNBC reaches 10\u0026ndash;25% of all breast cancer cases.\u003csup\u003e2\u003c/sup\u003e TNBC has a poorer prognosis with a five-year overall survival rate of 61.4% for TNBC, compared with 79.1% for hormone receptor-positive, indicating an 8\u0026ndash;16% lower survival for TNBC across cohorts.\u003csup\u003e3\u003c/sup\u003e Moreover, patients with metastatic TNBC had a median survival of 8\u0026ndash;13 months, corresponding to a five-year relative survival of roughly 11\u0026ndash;12% in advanced stages with distant metastases.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSubtype TNBC lacks estrogen receptor (ER), progesterone receptor (PR), and HER2 expression, making it unresponsive to hormone therapies and HER2-targeted treatments that are effective in other breast cancer subtypes. This causes TNBC to tend to have a faster progression compared to other breast cancer subtypes and thus has a worse prognosis.\u003csup\u003e5\u003c/sup\u003e This condition makes the choice of therapy very limited and worsens the patient's prognosis. Although TNBC is often characterized by a high tumor mutational burden and substantial immune cell infiltration, classifying it as an immunologically hot tumor, the response to single-agent immunotherapy remains unsatisfactory.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA key challenge lies in the tumor microenvironment (TME), where the ability of TNBC cells to evade the immune system, primarily through the PD-L1/PD-1 axis, attenuates the efficacy of checkpoint blockade. Several ICIs have been developed, including pembrolizumab (anti-PD-1) and atezolizumab (anti-PD-L1), which have been approved by the FDA, especially for patients with advanced-TNBC. Based on the KEYNOTE-355 study, the FDA has approved the use of pembrolizumab for advanced TNBC in combination with chemotherapy as a first-line treatment for patients with metastatic TNBC (mTNBC) whose tumors express PD-L1 (combined positive score [CPS]\u0026thinsp;\u0026ge;\u0026thinsp;10).\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis inconsistency, highlighted by the subsequent withdrawal of atezolizumab's accelerated FDA approval for this indication, has created clinical uncertainty regarding the optimal first-line ICI regimen. Atezolizumab had previously received FDA approval based on the IMpassion130 trial due to its significant improvement in PFS (7.4 vs. 4.8 months) in the PD-L1-positive population treated with atezolizumab plus nab-paclitaxel compared to chemotherapy alone.\u003csup\u003e8\u003c/sup\u003e However, in 2021, based on the findings of the IMpassion131 trial, which failed to meet its primary endpoint of PFS and changes in the treatment landscape that led the FDA to conclude that continued approval was no longer appropriate,\u003csup\u003e9\u003c/sup\u003e as well as the results of the study based on the IMpassion132 trial, which had not succeeded in showing optimal outcomes.\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eGiven the absence of direct head-to-head trials, comparative evidence regarding the relative efficacy and optimal use of atezolizumab versus pembrolizumab regimens remains limited. This raises several hypotheses about how the results of these studies failed to produce the expected clinical outcomes. Several hypotheses have emerged based on a comparison of the methodologies carried out in RCT studies evaluating ICIs in advanced-TNBC, one of which is that the analysis was carried out on the general TNBC population in the intention-to-treat (ITT) population without considering the quantity of PD-L1 expression of patients so that the presence of these non-specific conditions is likely to be the cause of less than optimal therapy outcomes collectively. Therefore, this study aims to conduct an indirect comparison of the ITT and PD-L1-positive advanced-TNBC populations receiving ICIs using a Bayesian network meta-analysis design.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1 Study design and registration\u003c/h2\u003e\n \u003cp\u003eThis Bayesian network meta-analysis study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. It was conducted in compliance with the PRISMA declaration standards;\u003csup\u003e11\u003c/sup\u003e see \u003cstrong\u003eSupplementary Information File S1\u003c/strong\u003e. This study was prospectively registered through PROSPERO (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.crd.york.ac.uk/prospero/\u003c/span\u003e\u003c/span\u003e) with registration number CRD420251118179.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Database search and strategies\u003c/h2\u003e\n \u003cp\u003eStudies published in the English language from March 21st, 2020, to April 21st, 2025, were comprehensively searched from the databases of PubMed (pubmed.ncbi.nlm.nih.gov), Cochrane Library (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.cochranelibrary.com\u003c/span\u003e\u003c/span\u003e), and Science Direct (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.sciencedirect.com\u003c/span\u003e\u003c/span\u003e). The search terms used were: \u0026ldquo;Immune-Checkpoint Inhibitors\u0026rdquo; OR \u0026ldquo;ICIs\u0026rdquo; OR \u0026ldquo;Atezolizumab\u0026rdquo; OR \u0026ldquo;Pembrolizumab\u0026rdquo;, combined with \u0026ldquo;Triple-Negative Breast Cancer\u0026rdquo; OR \u0026ldquo;TNBC\u0026rdquo;, \u0026ldquo;Locally-Advanced\u0026rdquo; OR \u0026ldquo;Metastatic\u0026rdquo;, and \u0026ldquo;Prognosis\u0026rdquo; OR \u0026ldquo;Overall Survival\u0026rdquo; OR \u0026ldquo;Progression-Free Survival\u0026rdquo; OR \u0026ldquo;Clinical Outcome\u0026rdquo;.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 Study selection\u003c/h2\u003e\n \u003cp\u003ePhase III randomized controlled trials (RCTs) enrolling patients with advanced or metastatic triple-negative breast cancer were included. Eligible trials had to compare an immune checkpoint inhibitor (ICI) plus chemotherapy versus placebo plus chemotherapy, reporting outcomes for both the intention-to-treat (ITT) and PD-L1-positive populations. Inclusion required reporting of at least one major clinical outcome: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), or overall survival (OS). Additional requirements included documentation of adequate organ function, no prior targeted therapy for advanced disease, and completion of any previous curative treatment\u0026thinsp;\u0026ge;\u0026thinsp;12 months before enrolment. Trials were specifically excluded if they involved patients with active central nervous system (CNS) metastases or mandated the use of chronic corticosteroid therapy.\u003c/p\u003e\n \u003cp\u003eSourced publications identified from the databases were imported into the Covidence platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.covidence.org/\u003c/span\u003e\u003c/span\u003e) for systematic screening, which was conducted by 2 independent reviewers.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e2.4 Data extraction\u003c/h2\u003e\n \u003cp\u003eFollowing independent screening of titles/abstracts and full texts, the extracted articles were comprehensively evaluated by two independent reviewers. It was carried out using a predefined table that includes the author name, publication year, trial ID, country, study design, sample size, TNBC type, treatment regimen, control group, and clinical outcomes.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e2.5 Risk of bias assessment\u003c/h2\u003e\n \u003cp\u003eThe Cochrane Risk of Bias 2 (RoB2) tool was utilised to evaluate potential bias in selected studies.\u003csup\u003e12\u003c/sup\u003e Three independent reviewers conducted the assessments, and disagreements were resolved by discussion.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e2.6 Certainty of evidence\u003c/h2\u003e\n \u003cp\u003eThe quality of evidence for each outcome was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.\u003csup\u003e13\u003c/sup\u003e Evidence quality was categorized as high, moderate, low, or very low based on five standard GRADE domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. For this network meta-analysis, particular attention was given to indirectness regarding PD-L1 assay variability and imprecision in the credible intervals. Certainty was evaluated separately for the ITT and PD-L1-positive populations, with individual assessments conducted for Overall Survival and Progression-Free Survival across all specified time points (6, 12, 24, and 36 months).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e2.7 Statistical analysis\u003c/h2\u003e\n \u003cp\u003eA Bayesian network meta-analysis (NMA) using random-effects frameworks was performed to estimate the comparative efficacy of the intervention regimens. Pooled effects were expressed as odds ratios for objective response rate (ORR) and disease control rate (DCR), and hazard ratios for OS and PFS, each with corresponding 95% credible intervals (95% CrI). Estimates were derived using Markov Chain Monte Carlo (MCMC) algorithms. Treatment effectiveness ranking was calculated using the surface under the cumulative ranking curve (SUCRA).\u003csup\u003e14\u003c/sup\u003e Clinical relevance was interpreted in relation to established minimal clinically important differences (MCID).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study selection\u003c/h2\u003e \u003cp\u003eA total of 6,006 articles were identified through database searches. Following the removal of 22 duplicates and applying database-specific filters, 5,300 studies were excluded, leaving 684 articles for title and abstract screening. After excluding 669 for breaking the inclusion criteria, 15 articles were assessed. Then, one study was excluded due to a lack of full paper and 8 studies were excluded due to inclusion of subgroup analyses, incomplete reporting, or irrelevant outcomes (e.g., pCR or monotherapy-focused trials).\u003csup\u003e15\u0026ndash;22\u003c/sup\u003e Ultimately, six studies met all inclusion criteria and were included in the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Study characteristics\u003c/h2\u003e \u003cp\u003eThe final analysis included four phase III RCTs (three IMpassion trials, one KEYNOTE trial) from six published studies (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Where multiple publications were available for a single trial, the most recent and complete data for each outcome were prioritized. Specifically, three follow-up reports from IMpassion130, at which the initial report by Schmid \u003cem\u003eet. al.\u003c/em\u003e (2018) was added manually,were included to capture time-to-event outcomes at different follow-up milestones. Patients with unresectable locally advanced or metastatic TNBC were enrolled, with sample sizes ranging from 595 to 902 participants.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy characteristics of included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor, Years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy Protocol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStudy Design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSample Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedian Age (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTNBC Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSchmid \u003cem\u003eet al.\u003c/em\u003e, 2018\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIMpassion130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMultiple Countries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhase III RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e902\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eITT: 55,\u003c/p\u003e \u003cp\u003eControl: 56\u003c/p\u003e \u003cp\u003ePD-L1+: 53, Control: 53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnresectable locally advanced or metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAtezolizumab\u0026thinsp;+\u0026thinsp;paclitaxel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePlacebo\u0026thinsp;+\u0026thinsp;Paclitaxel\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSchmid \u003cem\u003eet al.\u003c/em\u003e, 2020\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIMpassion130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMultiple Countries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhase III RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e902\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eITT: 55,\u003c/p\u003e \u003cp\u003eControl: 56\u003c/p\u003e \u003cp\u003ePD-L1+: 53, Control: 53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnresectable locally advanced or metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAtezolizumab\u0026thinsp;+\u0026thinsp;paclitaxel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePlacebo\u0026thinsp;+\u0026thinsp;Paclitaxel\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmens \u003cem\u003eet al.\u003c/em\u003e, 2021\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIMpassion130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMultiple Countries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhase III RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e451\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eITT: 55,\u003c/p\u003e \u003cp\u003eControl: 56\u003c/p\u003e \u003cp\u003ePD-L1+: 53, Control: 53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnresectable locally advanced or metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAtezolizumab\u0026thinsp;+\u0026thinsp;paclitaxel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePlacebo\u0026thinsp;+\u0026thinsp;Paclitaxel\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiles \u003cem\u003eet al.\u003c/em\u003e, 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIMpassion131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMultiple Countries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhase III RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e651\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eITT: 54,\u003c/p\u003e \u003cp\u003eControl: 53\u003c/p\u003e \u003cp\u003ePD-L1+: 55, Control: 53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnresectable locally advanced or metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAtezolizumab\u0026thinsp;+\u0026thinsp;paclitaxel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePlacebo\u0026thinsp;+\u0026thinsp;Paclitaxel\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDent \u003cem\u003eet al.\u003c/em\u003e, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIMpassion132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMultiple Countries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhase III RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e595\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eITT: 49,\u003c/p\u003e \u003cp\u003eControl: 49\u003c/p\u003e \u003cp\u003ePD-L1+: 48, Control: 48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnresectable locally advanced or metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAtezolizumab\u0026thinsp;+\u0026thinsp;CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePlacebo\u0026thinsp;+\u0026thinsp;CT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCortes \u003cem\u003eet al.\u003c/em\u003e, 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKEYNOTE-355\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMultiple Countries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhase III RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e847\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eITT: 53,\u003c/p\u003e \u003cp\u003eControl: 53\u003c/p\u003e \u003cp\u003ePD-L1+: 52, Control: 52\u003c/p\u003e \u003cp\u003ePD-L1+ (CPS\u0026thinsp;\u0026ge;\u0026thinsp;10): 52,\u003c/p\u003e \u003cp\u003eControl: 55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnresectable locally advanced or metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePembrolizumab\u0026thinsp;+\u0026thinsp;CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePlacebo\u0026thinsp;+\u0026thinsp;CT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e*These studies relate to the same clinical trial.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviation: CT\u0026thinsp;=\u0026thinsp;Chemotherapy; ITT\u0026thinsp;=\u0026thinsp;intention-to-treat population; PD-L1\u0026thinsp;+\u0026thinsp;=\u0026thinsp;PD-L1 positive; RCT\u0026thinsp;=\u0026thinsp;randomised controlled trial; TNBC\u0026thinsp;=\u0026thinsp;triple negative breast cancer.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmongst, recruited population were from multiple countries, and the reported median age range was 48\u0026ndash;53 years. Three studies evaluated a combination of atezolizumab and chemotherapy compared to a group receiving a placebo and chemotherapy. Meanwhile, one study compared the treatment effect of pembrolizumab plus chemotherapy against chemotherapy alone.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk of bias assessment\u003c/h2\u003e \u003cp\u003eNo significant risk of bias was found in the included studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003csup\u003e7\u0026ndash;10,23,24\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Overall Response Rate (ORR) and Disease Control Rate (DCR)\u003c/h2\u003e \u003cp\u003eThe network meta-analysis for ORR and DCR included data from six Phase III randomized controlled trials (Impassion130, Impassion131, Impassion132, and KEYNOTE-355), representing a network of 2,776 patients for ORR and 2,396 patients for DCR in the Intention-to-Treat (ITT) population, and 1,650 patients for ORR and 1,296 patients for DCR in the PD-L1-positive population (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGRADE assessment on objective response rate and disease control rate for the treatment effect of Atezolizumab-Chemotherapy vs. Pembrolizumab-Chemotherapy for triple-negative breast cancer\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eSummary of findings:\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eClinical Outcomes of Atezolizumab-Chemotherapy and Pembrolizumab-Chemotherapy for Triple-Negative Breast Cancer\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e№ of participants\u003c/p\u003e \u003cp\u003e(№ of studies)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eAnticipated relative effects (95% CrI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCertainty\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eWhat happens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eOdd Ratio (OR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eITT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2776 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.33\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.95 to 1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT probably increases ORR compared to CT, while P\u0026thinsp;+\u0026thinsp;CT may result in little to no difference in ITT patients.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.17\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.70 to 1.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePD-L1+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1650 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.63\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(1.05 to 2.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT probably increases ORR compared to CT, while P\u0026thinsp;+\u0026thinsp;CT may result in little to no difference in PD-L1\u0026thinsp;+\u0026thinsp;patients.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.29\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.64 to 2.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eDCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eITT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2396 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.17\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.66 to 2.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in DCR.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.81\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.37 to 1.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePD-L1+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1296 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.22\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.63 to 2.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in DCR.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.89\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.39 to 2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e*\u003cb\u003eThe risk in the intervention group\u003c/b\u003e (and its 95% credible interval) is based on the assumed risk in the comparison group and the \u003cb\u003erelative effect\u003c/b\u003e of the intervention (and its 95% CrI).\u003c/p\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: A\u0026thinsp;+\u0026thinsp;CT: Atezolizumab-Chemotherapy; CrI: credible interval; CT: Chemotherapy; DCR: Disease Control Rate; ITT: Intention-To-Treat; ORR: Overall Response Rate; OS: Odds Ratio; P\u0026thinsp;+\u0026thinsp;CT: Pembrolizumab-Chemotherapy; PD-L1\u0026thinsp;+\u0026thinsp;=\u0026thinsp;PD-L1 positive.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003eGRADE Working Group grades of evidence\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003eHigh certainty\u003c/b\u003e: We are very confident that the true effect lies close to the estimated effect.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003eModerate certainty\u003c/b\u003e: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003eLow certainty\u003c/b\u003e: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003eVery low certainty\u003c/b\u003e: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimated effect.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eLooking through the ORR, both atezolizumab plus chemotherapy (A\u0026thinsp;+\u0026thinsp;CT) and pembrolizumab plus chemotherapy (P\u0026thinsp;+\u0026thinsp;CT) demonstrated a higher ORR compared to chemotherapy alone in the ITT population. The A\u0026thinsp;+\u0026thinsp;CT group showed a stronger pooled effect (OR 1.36; 95% CrI 1.13\u0026ndash;1.64) and achieved the highest SUCRA score (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Regarding the PD-L1-positive population, the benefit of combination therapy was more pronounced, with A\u0026thinsp;+\u0026thinsp;CT showing the most substantial effect (OR 1.64; 95% CrI 1.26\u0026ndash;2.13) and the highest SUCRA ranking, though the comparative efficacy between the two ICIs did not reach statistical significance (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor the DCR, a trend toward improved disease stabilization was consistently observed across both populations. A\u0026thinsp;+\u0026thinsp;CT showed numerically higher DCR odds than P\u0026thinsp;+\u0026thinsp;CT and control in both the ITT and PD-L1-positive populations (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). SUCRA analysis ranked A\u0026thinsp;+\u0026thinsp;CT highest for DCR in both groups, suggesting a better probability of achieving disease control compared to P\u0026thinsp;+\u0026thinsp;CT (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The consistent trends and higher rank probabilities in the PD-L1-positive network support the role of PD-L1 expression as a predictive biomarker for ICI-mediated cytostatic benefit.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Overall Survival (OS) and Progression-Free Survival (PFS)\u003c/h2\u003e \u003cp\u003eThe analysis of time-to-event outcomes (OS and PFS; Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e) revealed a complex interplay between the regimen, population, and follow-up time. In the early follow-up about OS (6 months, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e), A\u0026thinsp;+\u0026thinsp;CT group demonstrated a better 6-month OS than the P\u0026thinsp;+\u0026thinsp;CT in both the ITT (HR 0.88 vs 0.85) and PD-L1-positive populations (HR 1.01 vs 0.87). During an extended follow-up (12\u0026ndash;36 months, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e), the relative benefits shifted over time. P\u0026thinsp;+\u0026thinsp;CT trended toward better OS compared with A\u0026thinsp;+\u0026thinsp;CT at 12\u0026ndash;36 months in the ITT population. However, at 36 months in the PD-L1-positive population, A\u0026thinsp;+\u0026thinsp;CT was associated with a better outcome (HR 1.65 vs 1.26), achieving the highest SUCRA rank, suggesting a potential long-term survival advantage in this enriched subgroup (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGRADE assessment on overall survival and progression-free survival for the treatment effect of Atezolizumab-Chemotherapy vs. Pembrolizumab-Chemotherapy for triple-negative breast cancer\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eSummary of findings:\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eEfficacy of Atezolizumab-Chemotherapy and Pembrolizumab-Chemotherapy for Triple-Negative Breast Cancer\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e№ of participants\u003c/p\u003e \u003cp\u003e(№ of studies)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTimepoint\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eAnticipated relative effects (95% CrI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCertainty\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eWhat happens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eHazard Ratio (HR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"15\" rowspan=\"16\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eITT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e2780 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.88\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.79 to 0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT probably reduces the hazard of mortality, while P\u0026thinsp;+\u0026thinsp;CT may result in little to no difference.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.85\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.73 to 0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e12-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.95\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.84 to 1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in OS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.97\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.81 to 1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e24-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.92\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.77 to 1.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in OS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.03\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.81 to 1.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e36-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.97\u003c/b\u003e \u003c/p\u003e \u003cp\u003e(0.75 to 1.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in OS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.16\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.85 to 1.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003ePD-L1+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e1651 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.01\u003c/b\u003e \u003c/p\u003e \u003cp\u003e(0.87 to 1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in OS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.87\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.71 to 1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e12-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.06\u003c/b\u003e \u003c/p\u003e \u003cp\u003e(0.89 to 1.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in OS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.00\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.80 to 1.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e24-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.18\u003c/b\u003e \u003c/p\u003e \u003cp\u003e(0.92 to 1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in OS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.27\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.95 to 1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e36-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.64\u003c/b\u003e \u003c/p\u003e \u003cp\u003e(1.10 to 2.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in OS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.26\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.85 to 1.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"15\" rowspan=\"16\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eITT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e2568 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.11\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.95 to 1.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in PFS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.24\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.98 to 1.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e12-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.25\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.97 to 1.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT may result in little to no difference while P\u0026thinsp;+\u0026thinsp;CT probably reduces the hazard of progression.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.47\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(1.02 to 2.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e24-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.64\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.40 to 1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in PFS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.08\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.67 to 1.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e36-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e0.33\u003c/b\u003e \u003c/p\u003e \u003cp\u003e(0.15 to 0.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in PFS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.00\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.58 to 1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003ePD-L1+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e1561 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.57\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(1.22 to 2.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT probably reduces the hazard of progression even though P\u0026thinsp;+\u0026thinsp;CT may result in little to no difference.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.33\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.94 to 1.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e12-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.58\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(1.14 to 2.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens probably reduce the hazard of progression.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.68\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(1.10 to 2.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e24-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.19\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.72 to 1.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in PFS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.52\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.87 to 2.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e36-months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.46\u003c/b\u003e \u003c/p\u003e \u003cp\u003e(0.69 to 3.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBoth regimens demonstrated comparable efficacy with no statistically significant difference in PFS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;CT vs PL\u0026thinsp;+\u0026thinsp;CT: \u003cb\u003e1.97\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.93 to 4.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e*\u003cb\u003eThe risk in the intervention group\u003c/b\u003e (and its 95% credible interval) is based on the assumed risk in the comparison group and the \u003cb\u003erelative effect\u003c/b\u003e of the intervention (and its 95% CrI).\u003c/p\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: CrI: credible interval; OS: Odd Ratio; HR: Hazard Ratio; OS: Overall Survival; PFS: Progression-Free Survival; CT: Chemotherapy; A\u0026thinsp;+\u0026thinsp;CT: Atezolizumab-Chemotherapy; ITT: Intention-To-Treat; P\u0026thinsp;+\u0026thinsp;CT: Pembrolizumab-Chemotherapy; PD-L1+: PD-L1-positive.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cb\u003eGRADE Working Group grades of evidence\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cb\u003eHigh certainty\u003c/b\u003e: We are very confident that the true effect lies close to the estimated effect.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cb\u003eModerate certainty\u003c/b\u003e: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cb\u003eLow certainty\u003c/b\u003e: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cb\u003eVery low certainty\u003c/b\u003e: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimated effect.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDuring the first follow-up of PFS (6 months), A\u0026thinsp;+\u0026thinsp;CT showed a better 6-month PFS in the PD-L1-positive population (HR 1.57 vs 1.33) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e) and was ranked highest by SUCRA (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). P\u0026thinsp;+\u0026thinsp;CT, conversely, was favored in the ITT population. In the extended follow-up (12\u0026ndash;36 months, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e), the majority of extended follow-up time points (12, 24, and 36 months) showed P\u0026thinsp;+\u0026thinsp;CT trending towards better PFS than A\u0026thinsp;+\u0026thinsp;CT in both the ITT and PD-L1-positive populations. SUCRA analysis consistently favored P\u0026thinsp;+\u0026thinsp;CT at 12 months in both groups and at 24 and 36 months in the PD-L1-positive population (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.6 GRADE assessment\u003c/h2\u003e \u003cp\u003eThe certainty of evidence for all outcomes, assessed using the GRADE) approach, ranged from moderate to low. The primary reasons for downgrading included imprecision based on wide Bayesian credible intervals (CrI), inconsistency of effect across time points, and indirectness of evidence relative to the typical clinical question.\u003c/p\u003e \u003cp\u003eEvidence for ORR was generally graded as moderate certainty. This outcome showed consistent directional benefit favoring atezolizumab plus chemotherapy (A\u0026thinsp;+\u0026thinsp;CT) over chemotherapy alone in both the ITT (n\u0026thinsp;=\u0026thinsp;2,776) and PD-L1-positive patients (n\u0026thinsp;=\u0026thinsp;1,650). ORR was downgraded one level for indirectness due to the restriction to metastatic TNBC, heterogeneity in chemotherapy backbones, and the variability in PD-L1 assays and cut-offs used across the four included studies.\u003c/p\u003e \u003cp\u003eEvidence for DCR was assessed as low certainty. Although A\u0026thinsp;+\u0026thinsp;CT trended favorably, particularly in the PD-L1-positive network, the outcome was downgraded for both indirectness (as above) and imprecision. The wide credible intervals for comparisons involving A\u0026thinsp;+\u0026thinsp;CT and P\u0026thinsp;+\u0026thinsp;CT often crossed the null effect (OR\u0026thinsp;=\u0026thinsp;1), limiting confidence in the estimated magnitude of the disease control benefit.\u003c/p\u003e \u003cp\u003eAll time-to-event outcomes (OS and PFS) across all time points (6, 12, 24, and 36 months) and populations were graded as low certainty. Downgrading for inconsistency was applied due to the unstable nature of the treatment rankings over time. For example, ICI-based regimens showed varying SUCRA advantages at 24 months but failed to maintain a consistent rank at 36 months, indicating uncertainty regarding durable benefit. Downgrading for imprecision was required because many Hazard Ratios clustered close to 1, with CrIs spanning from modest benefit to no effect or minor harm, suggesting a lack of certainty about a true clinically significant effect. Additional downgrading for indirectness was noted, especially in the ITT analyses, as the evidence was predominantly confined to metastatic TNBC treated with taxane-based regimens, and the long-term data reflected highly selected survivor cohorts.\u003c/p\u003e \u003cp\u003eFormal assessment of publication bias was not feasible using funnel plot-based methods due to the network meta-analysis design, the Bayesian approach utilized, and the limited number of studies (four per outcome). Therefore, no formal downgrading was applied in this domain, although the possibility of small-study effects or selective non-publication cannot be excluded. The full GRADE certainty assessment is detailed in the accompanying tables (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis Bayesian network meta-analysis was conducted under the hypothesis that immune checkpoint inhibitors (ICIs), when combined with chemotherapy, provide differential but clinically meaningful benefit in advanced TNBC and that the magnitude and durability of benefit differ between pembrolizumab plus chemotherapy (P\u0026thinsp;+\u0026thinsp;CT) and atezolizumab plus chemotherapy (A\u0026thinsp;+\u0026thinsp;CT) based on biomarker methodology, chemotherapy backbone, and biological context. This Bayesian network meta-analysis was designed to evaluate these dynamics across ITT and PD-L1-positive populations and multiple time-dependent outcomes, thereby extending beyond the conclusions that individual trials could provide.\u003c/p\u003e \u003cp\u003eThe results of this analysis largely support the hypothesis and provide a more nuanced understanding of regimen-specific performance in advanced TNBC. Across the ITT population, P\u0026thinsp;+\u0026thinsp;CT showed a more consistent, stable, and durable improvement in PFS compared with A\u0026thinsp;+\u0026thinsp;CT and chemotherapy alone. In our Bayesian network model, the P\u0026thinsp;+\u0026thinsp;CT regimen demonstrated favorable HR at nearly all follow-up intervals, and SUCRA rankings indicated that P\u0026thinsp;+\u0026thinsp;CT had the highest probability of being the most effective regimen across almost all time points, except at 24 months. In contrast, A\u0026thinsp;+\u0026thinsp;CT exhibited diminishing benefit at later time points, ranking below the control arm at 24 and 36 months. These findings suggest that pembrolizumab may provide more stable immunologic pressure across heterogeneous TNBC populations, whereas atezolizumab\u0026rsquo;s benefit appears more dependent on specific trial conditions and population characteristics.\u003c/p\u003e \u003cp\u003eAmong PD-L1-positive populations, both ICI regimens demonstrated favorable PFS relative to chemotherapy alone at each follow-up interval, confirming the well-recognized enrichment effect of PD-L1 positivity on immunotherapy outcomes. Although A\u0026thinsp;+\u0026thinsp;CT showed more substantial early benefit at 6 months, this advantage did not persist. This study found that by 12 months, the trend shifted in favor of P\u0026thinsp;+\u0026thinsp;CT, which maintained its superiority through 36 months. These findings closely align with observations from KEYNOTE-355, which showed that pembrolizumab produced proportionally greater benefit at higher Combined Positive Score (CPS) thresholds, particularly in tumors with CPS\u0026thinsp;\u0026ge;\u0026thinsp;10 (median PFS 9.7 vs 5.6 months).\u003csup\u003e17\u003c/sup\u003e Similarly, atezolizumab demonstrated benefit in the PD-L1-positive population in IMpassion130 (median OS 25.4 vs 17.9 months).\u003csup\u003e8,23,24\u003c/sup\u003e However, this efficacy did not extend to IMpassion131 or IMpassion132, where population-level factors, such as early-relapsing, chemo-refractory biology, and the need for corticosteroid premedication in paclitaxel-based regimens, were expected to attenuate atezolizumab\u0026rsquo;s immune-mediated activity.\u003csup\u003e9,16,25\u003c/sup\u003e Taken together, these findings reinforce that pembrolizumab provides more consistent benefit across heterogeneous PD-L1-positive settings. In contrast, the clinical efficacy of atezolizumab is more sensitive to assay selection, chemotherapy backbone, and underlying population characteristics.\u003c/p\u003e \u003cp\u003eThis study found the pooled ORR increased by 27\u0026ndash;31% with ICI-chemotherapy combinations compared with chemotherapy alone, which also supports our hypothesis. Partial responses and stable disease were the most common, while complete responses were rare (\u0026lt;\u0026thinsp;3%). This is consistent with the immunological mechanism of ICIs, which prolongs antitumor immune pressure rather than driving immediate deep cytoreduction, as shown in other meta-analyses.\u003csup\u003e26,27\u003c/sup\u003e The stronger ORR performance of A\u0026thinsp;+\u0026thinsp;CT in our ranking analysis parallels IMpassion130 (56% vs 46%),\u003csup\u003e8,23,24\u003c/sup\u003e while pembrolizumab\u0026rsquo;s performance aligns with KEYNOTE-355 (53.2% vs 39.8% in CPS\u0026thinsp;\u0026ge;\u0026thinsp;10).\u003csup\u003e16,17\u003c/sup\u003e These findings indicate that while both ICIs enhance early disease control, their long-term durability diverges depending on population characteristics, biomarker methodology, and chemotherapy backbone.\u003c/p\u003e \u003cp\u003eThis study found that the variability between A\u0026thinsp;+\u0026thinsp;CT and P\u0026thinsp;+\u0026thinsp;CT across trials can be explained by several well-characterized confounders, the first of which is PD-L1 assay heterogeneity. IMpassion trials used SP142, which identifies PD-L1 expression exclusively on immune cells and categorizes tumors as positive or negative. This approach is specific but tends to classify fewer tumors as PD-L1-positive, thereby influencing apparent efficacy outcomes.\u003csup\u003e9,23,25\u003c/sup\u003e In contrast, KEYNOTE-355 used the CPS, which incorporates PD-L1 expression on both tumor and immune cells and allows stratification into CPS\u0026thinsp;\u0026ge;\u0026thinsp;1, \u0026ge;10, and \u0026ge;\u0026thinsp;20. Pembrolizumab efficacy increased proportionally with higher CPS levels, particularly in tumors with CPS 10-19.\u003csup\u003e7,16,17\u003c/sup\u003e These fundamental methodological differences create non-overlapping PD-L1-positive populations across trials, limiting direct comparability. Thus, what appears as a comparative drug difference often reflects biomarker discordance.\u003c/p\u003e \u003cp\u003ePopulation heterogeneity represents the second influential factor. IMpassion132 enrolled 595 rapid-relapse patients with a disease-free interval\u0026thinsp;\u0026lt;\u0026thinsp;12 months, representing one of the most aggressive and chemo-refractory TNBC subtypes.\u003csup\u003e10\u003c/sup\u003e These tumors frequently harbor immune exhaustion signatures, myeloid-driven suppression, low antigen presentation capacity, and poor interferon signaling, all of which impede response to PD-L1 blockade, underscoring that immunologically \u0026ldquo;cold\u0026rdquo; and rapidly recurring tumors remain refractory to checkpoint inhibition despite PD-L1 status.\u003csup\u003e28\u003c/sup\u003e IMpassion132, therefore, showed minimal benefit (median OS 11.2 vs 12.1 months), and this large negative dataset substantially impacted A\u0026thinsp;+\u0026thinsp;CT\u0026rsquo;s pooled rankings at longer follow-up.\u003csup\u003e10\u003c/sup\u003e This finding reinforces that PD-L1 positivity alone is insufficient to predict therapeutic responsiveness in biologically aggressive early-relapsing disease.\u003c/p\u003e \u003cp\u003eThe chemotherapy backbone further contributed to regimen-specific heterogeneity. IMpassion130 used nab-paclitaxel, which does not require corticosteroid premedication, thus preserving dendritic cell maturation and T-cell priming, key mechanisms needed for atezolizumab activity.\u003csup\u003e23,29\u003c/sup\u003e In contrast, IMpassion131 utilized solvent-based paclitaxel, which requires repeated corticosteroid administration to prevent hypersensitivity reactions. These corticosteroids suppress antigen presentation, inhibit dendritic cell function, and blunt T-cell activation, thereby directly counteracting the mechanism of PD-L1 blockade.\u003csup\u003e25\u003c/sup\u003e This pharmacologic antagonism likely explains the lack of benefit observed in IMpassion131 despite nearly identical design and eligibility criteria to IMpassion130, reinforcing the importance of selecting steroid-free chemotherapy partners when combining ICIs with taxanes.\u003c/p\u003e \u003cp\u003eThis analysis also illuminates the time-dependent nature of immunotherapy benefit. In the ITT populations, both ICI regimens demonstrated lower OS in the first 12 months compared with chemotherapy alone, reflecting delayed kinetics of immune activation. After 12 months, P\u0026thinsp;+\u0026thinsp;CT showed progressive improvement through 36 months, while A\u0026thinsp;+\u0026thinsp;CT plateaued with minimal late benefit. In PD-L1-positive tumors, A\u0026thinsp;+\u0026thinsp;CT produced a more substantial early OS improvement, peaking at 36 months, whereas pembrolizumab demonstrated a more consistent, gradually increasing benefit. These patterns align with existing clinical observations that atezolizumab\u0026rsquo;s activity is tightly tied to PD-L1 expression and chemotherapy synergy, while pembrolizumab demonstrates broader immunologic applicability.\u003csup\u003e30\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSeveral biological mechanisms may underlie the decline in ICI benefit over prolonged follow-up. TNBC is known to evolve toward immune-resistant phenotypes over time, characterized by increasing myeloid-derived suppressor cell activity, neutrophil extracellular trap formation, exhaustion of cytotoxic T cells, and macrophage polarization toward immunosuppressive states.\u003csup\u003e31\u0026ndash;33\u003c/sup\u003e Organ-specific metastatic microenvironments further constrain immune activity, such as in liver metastases generate tolerogenic macrophage-dominant niches,\u003csup\u003e34,35\u003c/sup\u003e lung metastases harbor TREM2\u0026thinsp;+\u0026thinsp;macrophages and PD-L1-expressing alveolar cells,\u003csup\u003e36,37\u003c/sup\u003e and bone metastases activate RANK-RANKL pathways that disrupt antigen presentation.\u003csup\u003e38,39\u003c/sup\u003e Given that the majority of participants across included trials had visceral or bone disease, these microenvironmental pressures likely contributed to the modest long-term survival seen in both regimens.\u003c/p\u003e \u003cp\u003eThe strengths of this study include rigorous adherence to the PRISMA methodology, the use of Bayesian network modelling to allow indirect comparisons across multiple time points, and the inclusion of large, multinational phase III randomized trials. These strengths enhance the reliability of comparative estimates and support a comprehensive appraisal of regimen-specific temporal effects. However, limitations remain. The number of eligible RCTs is small, and the absence of direct head-to-head comparisons between pembrolizumab and atezolizumab restricts causal inference. Heterogeneity in PD-L1 assays and chemotherapy partners limits cross-trial comparability, and long-term outcomes are imprecise due to small event counts and trial maturity. Despite these limitations, the consistency of the trends across multiple datasets strengthens the interpretability of the findings.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eOverall, this meta-analysis suggests that the combination of ICIs with chemotherapy provides a clinically favorable benefit in mTNBC, particularly in the PD-L1-positive population. Atezolizumab plus chemotherapy showed the strongest probability of efficacy in the PD-L1-positive population with the highest SUCRA ratings for objective response, disease control, and 36-month survival. Pembrolizumab plus chemotherapy performed more consistently in the heterogeneous ITT population with the highest SUCRA ratings for long-term OS and PFS, although this superiority likely influenced dilution of atezolizumab efficacy due to the use of steroid-based chemotherapy and the inclusion of highly resistant patients in the IMpassion trial. These findings emphasize the importance of more precise biomarker selection, optimization of adjuvant chemotherapy regimens, and identification of biologic subgroups, and support the need for head-to-head trials, development of biomarkers beyond PD-L1, and combination strategies targeting the TME to overcome immune resistance and improve longevity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was not required for this study as it is a meta-analysis of previously published, publicly available data and does not involve the collection of primary data from human participants.\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\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no financial or non-financial competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was funded by the National Research Council of Thailand (NRCT): High Potential Research Team Grant Program (N42A680423) and Ratchadapisek Somphot Matching Fund, Faculty of Medicine, Chulalongkorn University (RA-MF-01/69). The academic endeavors of the Thailand Hub of Talents in Cancer Immunotherapy (TTCI) receive support from the National Research Council of Thailand.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI.G.W.W.W., M.S.T., S.K., and N.H. managed conceptualization, supervision, and project administration. C.T.M. managed formal analysis. I.G.W.W.W., I.G.K.A.S., N.P.K.M., P.M.W.S.P., K.M.K.T., A.B.N.K., K.I.P.A., and I.K.R.P.P. contributed to data curation, investigation, methodology, and writing - original draft. M.S.T., S.K., and N.H. aided in conceptualization and contributed to writing - original draft. I.G.W.W.W., M.S.T., S.K., and N.H. participated in methodology and writing - review \u0026amp; editing. I.G.W.W.W., M.S.T., and C.T.M. were involved in data curation, investigation, and visualization. N.H. and M.S.T. provided critical writing \u0026ndash; review \u0026amp; editing, supervision, and secured funding acquisition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to the National Research Council of Thailand (NRCT), Faculty of Medicine, Chulalongkorn University, and the Thailand Hub of Talents in Cancer Immunotherapy for supporting this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eXiong N, Wu H, Yu Z. Advancements and challenges in triple-negative breast cancer: a comprehensive review of therapeutic and diagnostic strategies. Front Oncol. 2024;14:1405491. \u003c/li\u003e\n\u003cli\u003eAlmansour NM. Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. Front Mol Biosci. 2022;9:836417. \u003c/li\u003e\n\u003cli\u003eDarida M, Rubovszky G, Kiss Z, Sz\u0026eacute;kely B, Madaras B, Horv\u0026aacute;th Z, et al. Improvement in breast cancer survival across molecular subtypes in Hungary between 2011 and 2020: a nationwide, retrospective study. Front Oncol. 2025;15:1465511. \u003c/li\u003e\n\u003cli\u003eKesireddy M, Elsayed L, Shostrom VK, Agarwal P, Asif S, Yellala A, et al. Overall Survival and Prognostic Factors in Metastatic Triple-Negative Breast Cancer: A National Cancer Database Analysis. Cancers (Basel). 2024 May;16(10). \u003c/li\u003e\n\u003cli\u003eJie H, Ma W, Huang C. Diagnosis, Prognosis, and Treatment of Triple-Negative Breast Cancer: A Review. Breast cancer (Dove Med Press. 2025;17:265\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eLi L, Zhang F, Liu Z, Fan Z. Immunotherapy for Triple-Negative Breast Cancer: Combination Strategies to Improve Outcome. Cancers (Basel). 2023 Jan;15(1). \u003c/li\u003e\n\u003cli\u003eCortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022 Jul;387(3):217\u0026ndash;26. \u003c/li\u003e\n\u003cli\u003eSchmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018;379(22):2108\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eMiles D, Gligorov J, Andr\u0026eacute; F, Cameron D, Schneeweiss A, Barrios C, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2021 Aug;32(8):994\u0026ndash;1004. \u003c/li\u003e\n\u003cli\u003eDent R, Andr\u0026eacute; F, Gon\u0026ccedil;alves A, Martin M, Schmid P, Sch\u0026uuml;tz F, et al. IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2024 Jul;35(7):630\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003ePage MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021 Mar;372:n160. \u003c/li\u003e\n\u003cli\u003eHiggins JPT, Altman DG. Chapter 8: Assessing risk of bias in included studies. In 2008. Available from: https://api.semanticscholar.org/CorpusID:76535584\u003c/li\u003e\n\u003cli\u003eBezerra CT, Grande AJ, Galv\u0026atilde;o VK, Santos DHM Dos, Atallah \u0026Aacute;N, Silva V. Assessment of the strength of recommendation and quality of evidence: GRADE checklist. A descriptive study. Sao Paulo Med J. 2022;140(6):829\u0026ndash;36. \u003c/li\u003e\n\u003cli\u003eMbuagbaw L, Rochwerg B, Jaeschke R, Heels-Andsell D, Alhazzani W, Thabane L, et al. Approaches to interpreting and choosing the best treatments in network meta-analyses. Vol. 6, Systematic reviews. England; 2017. p. 79. \u003c/li\u003e\n\u003cli\u003eAdams S, Di\u0026eacute;ras V, Barrios CH, Winer EP, Schneeweiss A, Iwata H, et al. Patient-reported outcomes from the phase III IMpassion130 trial of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2020 May;31(5):582\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eCortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817\u0026ndash;28. \u003c/li\u003e\n\u003cli\u003eHattori M, Masuda N, Takano T, Tsugawa K, Inoue K, Matsumoto K, et al. Pembrolizumab plus chemotherapy in Japanese patients with triple-negative breast cancer: Results from KEYNOTE-355. Cancer Med. 2023 May;12(9):10280\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eGianni L, Huang CS, Egle D, Bermejo B, Zamagni C, Thill M, et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol Off J Eur Soc Med Oncol. 2022 May;33(5):534\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eIm SA, Cortes J, Cescon DW, Yusof MM, Iwata H, Masuda N, et al. Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC. NPJ breast cancer. 2024 Sep;10(1):79. \u003c/li\u003e\n\u003cli\u003eNarayan P, Wahby S, Gao JJ, Amiri-Kordestani L, Ibrahim A, Bloomquist E, et al. FDA Approval Summary: Atezolizumab plus Paclitaxel Protein-bound for the Treatment of Patients with Advanced or Metastatic TNBC Whose Tumors Express PD-L1. Clin Cancer Res. 2020;26(10):2284\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eSchmid P, Oliveira M, O\u0026rsquo;Shaughnessy J, Cristofanilli M, Graff SL, Im SA, et al. TROPION-Breast05: a randomized phase III study of Dato-DXd with or without durvalumab versus chemotherapy plus pembrolizumab in patients with PD-L1-high locally recurrent inoperable or metastatic triple-negative breast cancer. Ther Adv Med Oncol. 2025;17:17588359251327992. \u003c/li\u003e\n\u003cli\u003eWiner EP, Lipatov O, Im SA, Goncalves A, Mu\u0026ntilde;oz-Couselo E, Lee KS, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):499\u0026ndash;511. \u003c/li\u003e\n\u003cli\u003eSchmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):44\u0026ndash;59. \u003c/li\u003e\n\u003cli\u003eEmens LA, Adams S, Barrios CH, Di\u0026eacute;ras V, Iwata H, Loi S, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol Off J Eur Soc Med Oncol. 2021 Aug;32(8):983\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003ede Moura A, Vuagnat P, Renouf B, Pierga JY, Loirat D, Vaflard P, et al. Atezolizumab and paclitaxel as first line therapy in advanced triple-negative breast cancer patients included in the French early access program. Sci Rep. 2023 Aug;13(1):13427. \u003c/li\u003e\n\u003cli\u003eLi Y, Xing L, Li F, Liu H, Gan L, Yang D, et al. Efficacy and Safety of Adding Immune Checkpoint Inhibitors to Neoadjuvant Chemotherapy Against Triple-Negative Breast Cancer: A Meta-Analysis of Randomized Controlled Trials. Front Oncol. 2021;11:657634. \u003c/li\u003e\n\u003cli\u003eJi Q, Ding J, Hao M, Luo N, Huang J, Zhang W. Immune Checkpoint Inhibitors Combined With Chemotherapy Compared With Chemotherapy Alone for Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis. Front Oncol. 2021;11:795650. \u003c/li\u003e\n\u003cli\u003eZheng Y, Li S, Tang H, Meng X, Zheng Q. Molecular mechanisms of immunotherapy resistance in triple-negative breast cancer. Front Immunol. 2023;14:1153990. \u003c/li\u003e\n\u003cli\u003eMohan N, Hosain S, Zhao J, Shen Y, Luo X, Jiang J, et al. Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1(+) triple negative breast cancer cells. Oncoimmunology. 2019;8(9):e1624128. \u003c/li\u003e\n\u003cli\u003eFabi A, Carbognin L, Botticelli A, Paris I, Fuso P, Savastano MC, et al. Real-world ANASTASE study of atezolizumab+nab-paclitaxel as first-line treatment of PD-L1-positive metastatic triple-negative breast cancer. NPJ breast cancer. 2023 Sep;9(1):73. \u003c/li\u003e\n\u003cli\u003eRitchie S, Reed DA, Pereira BA, Timpson P. The cancer cell secretome drives cooperative manipulation of the tumour microenvironment to accelerate tumourigenesis. Fac Rev. 2021;10:4. \u003c/li\u003e\n\u003cli\u003eMukai H, Miki N, Yamada H, Goto H, Kawakami T, Suzuki A, et al. Pannexin1 channel-dependent secretome from apoptotic tumor cells shapes immune-escape microenvironment. Biochem Biophys Res Commun [Internet]. 2022;628:116\u0026ndash;22. Available from: https://www.sciencedirect.com/science/article/pii/S0006291X22011998\u003c/li\u003e\n\u003cli\u003eLi J, Sun J, Rong R, Li L, Shang W, Song D, et al. HMGB1 promotes myeloid-derived suppressor cells and renal cell carcinoma immune escape. Oncotarget. 2017;8(38):63290\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eYang M, Zhang C. The role of liver sinusoidal endothelial cells in cancer liver metastasis. Am J Cancer Res. 2021;11(5):1845\u0026ndash;60. \u003c/li\u003e\n\u003cli\u003eWu K, Zhang G, Shen C, Zhu L, Yu C, Sartorius K, et al. Role of T cells in liver metastasis. Cell Death Dis. 2024 May;15(5):341. \u003c/li\u003e\n\u003cli\u003eCha YJ, Kim HM, Koo JS. Inherent PD-L1 22C3 Expression in Alveolar Macrophages Impacts the Combined Positive Score Status in Breast Cancer With Pulmonary Metastasis. Thorac cancer. 2025 Mar;16(5):e70004. \u003c/li\u003e\n\u003cli\u003eYofe I, Shami T, Cohen N, Landsberger T, Sheban F, Stoler-Barak L, et al. Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary. Cancer Discov. 2023 Dec;13(12):2610\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eOkamoto K. Role of RANKL in cancer development and metastasis. J Bone Miner Metab. 2021 Jan;39(1):71\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eWu X, Li F, Dang L, Liang C, Lu A, Zhang G. RANKL/RANK System-Based Mechanism for Breast Cancer Bone Metastasis and Related Therapeutic Strategies. Front cell Dev Biol. 2020;8:76. \u003cstrong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 4","content":"\u003cp\u003eTable 4 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bayesian network meta-analysis, Immune-checkpoint inhibitor, chemotherapy, triple-negative breast cancer","lastPublishedDoi":"10.21203/rs.3.rs-8627114/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8627114/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eImmune checkpoint inhibitors (ICIs) combined with chemotherapy are a standard treatment for advanced or metastatic triple-negative breast cancer (mTNBC). However, comparative evidence regarding relative efficacy and optimal use of different ICI regimens, specifically atezolizumab (A) versus pembrolizumab (P), remains limited. This study aims to evaluate the comparative efficacy and ranking of ICIs\u0026thinsp;+\u0026thinsp;chemotherapy regimens in treating advanced TNBC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study conducted a Bayesian network meta-analysis of phase III randomized controlled trials (RCTs) comparing ICI\u0026thinsp;+\u0026thinsp;chemotherapy versus chemotherapy alone in mTNBC patients following PRISMA 2020 guidelines. Outcomes analysed included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in both intention-to-treat (ITT) and PD-L1-positive populations. Indirect comparison was performed using R software (v.4.4.0).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe network analysis included six studies from four RCTs (n\u0026thinsp;=\u0026thinsp;2,776). A\u0026thinsp;+\u0026thinsp;CT (Odd ratio (OR) 1.36; 95% CrI 1.13\u0026ndash;1.64) and P\u0026thinsp;+\u0026thinsp;CT (OR 1.18; 95% CrI 0.88\u0026ndash;1.56) both showed improved ORR vs. chemotherapy alone in the ITT population. This benefit was most pronounced in the PD-L1-positive population, where A\u0026thinsp;+\u0026thinsp;CT demonstrated the highest ORR (OR 1.64; 95% CrI 1.26\u0026ndash;2.13). A\u0026thinsp;+\u0026thinsp;CT consistently ranked highest by SUCRA for short-term efficacy measures (ORR, DCR, PFS) in the PD-L1-positive population, and also achieved the highest SUCRA rank for long-term OS (36 months) in this subgroup. Conversely, P\u0026thinsp;+\u0026thinsp;CT achieved the highest SUCRA rank for long-term OS in the heterogeneous ITT population.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBoth ICI regimens demonstrate clinical benefit. While A\u0026thinsp;+\u0026thinsp;CT is favoured for high probability of early response in PD-L1-positive patients, the trend for superior long-term OS with P\u0026thinsp;+\u0026thinsp;CT in the ITT population underscores the need to carefully weigh treatment goals, strongly supporting PD-L1 status as a key predictive factor. However, this trend favoring P\u0026thinsp;+\u0026thinsp;CT in the ITT population is likely attributable to the statistical dilution of A\u0026thinsp;+\u0026thinsp;CT efficacy caused by methodological confounders in certain atezolizumab trials.\u003c/p\u003e","manuscriptTitle":"Atezolizumab versus Pembrolizumab in The Treatment of Advanced Triple-Negative Breast Cancer: A Bayesian Network Meta-Analysis of ITT and PD-L1 Positive Populations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 16:45:42","doi":"10.21203/rs.3.rs-8627114/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-06T07:03:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-29T07:17:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25674512159723797530525816895968623319","date":"2026-03-28T10:39:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"281021418075522654945915284686796174273","date":"2026-03-27T05:53:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-27T03:23:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-11T18:46:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"211482367470480539242314780291558785824","date":"2026-02-07T17:55:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242655142511362059230036666941259848834","date":"2026-02-06T05:03:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66841047309921801752406087500361734871","date":"2026-02-05T12:20:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"299598537881445678346319761391809845389","date":"2026-02-05T11:18:19+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-05T07:59:13+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-23T06:34:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-22T06:15:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-22T06:15:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-01-17T15:38:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6e6aaf8f-0995-4528-aa1e-8e41bb6f18a8","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T16:38:46+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-09 16:45:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8627114","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8627114","identity":"rs-8627114","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}