Second-Line Immune Checkpoint Trials in Mesothelioma: The Impact of Censoring and Predictive Biological Factors

Second-Line Immune Checkpoint Trials in Mesothelioma: The Impact of Censoring and Predictive Biological Factors | 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 Short Report Second-Line Immune Checkpoint Trials in Mesothelioma: The Impact of Censoring and Predictive Biological Factors Tomer Meirson, Hadas Ditzian Kugler, Mor Moskovitz1, Francesco Cerza, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8327625/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immune checkpoint inhibitors have shown inconsistent benefit in second-line malignant pleural mesothelioma. Although histology and several molecular biomarkers, such as BAP1 and others, reveal substantial heterogeneity, their contribution to treatment selection remains uncertain. Because informative censoring may bias time-to-event analyses, we re-evaluated key second-line trials to determine whether censoring patterns contributed to discordant efficacy results. Methods Published Kaplan–Meier curves from CONFIRM (nivolumab vs placebo), the CONFIRM update, and PROMISE-Meso (pembrolizumab vs chemotherapy) were reconstructed. Censoring distributions were quantified using reverse-KM, and differential censoring between arms and across endpoints (overall survival [OS] vs progression-free survival [PFS]) was evaluated over time. Sensitivity analyses were applied to address excessive censoring, and hazard ratios and restricted mean survival time differences were calculated. Results In CONFIRM, the initially reported OS advantage coincided with short follow-up and a differential censoring pattern consistent with post-progression censoring. The updated CONFIRM dataset, with longer follow-up, demonstrated no OS benefit and no evidence of post-progression censoring. In contrast, PROMISE-Meso showed no evidence of post-progression censoring at any time and remained negative throughout. When general differential censoring was addressed using sensitivity analyses, both the PFS effect and the OS advantage in CONFIRM lost statistical significance. Conclusions Post-progression censoring is an under-recognized source of bias that can generate misleading survival signals and may have contributed to the initial CONFIRM findings that were based on a premature early data lock. Although a modest treatment effect in a biologically defined subgroup cannot be excluded, current evidence remains inconclusive. Future studies should ensure comprehensive ascertainment of survival outcomes and include adequately powered biomarker programs, including histology and BAP1 status. Oncology malignant mesothelioma immunotherapy censoring analysis biomarkers Figures Figure 1 Figure 2 Figure 3 Introduction Immune checkpoint inhibitors represent a meaningful advance in oncology, yet in mesothelioma their trial results are inconsistent, and the absolute benefits are small. The phase III CONFIRM trial reported initially an OS advantage for nivolumab over placebo, whereas PROMISE-Meso showed no benefit for pembrolizumab over chemotherapy [ 1 , 2 ]. Such discordant outcomes raise concerns about methodological drivers of apparent efficacy rather than true biological advantage. Time-to-event analyses are vulnerable to informative censoring including in unblinded or partially blinded trials, and trials with suboptimal control [ 3 ]. We therefore conducted a targeted reanalysis of two second-line randomized trials—CONFIRM (nivolumab vs placebo) and PROMISE-Meso (pembrolizumab vs chemotherapy)—to determine whether censoring imbalance could account for reported effects and to assess and contextualize exploratory biomarker signals. Materials & Methods We reconstructed published Kaplan–Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) in the CONFIRM, updated CONFIRM, and PROMISE-Meso trials [ 1 , 2 , 4 ]. Censoring distributions were characterized with reverse-KM (rKM) by arm, and Δcens(t) was defined as the difference in censoring proportion between the experimental and control arms at each time point. Our censoring-sensitivity analysis followed prespecified rules [ 5 ]. When excess control-arm censoring was observed, we hypothesized perceived-inferiority censoring: better-prognosis, controls drop out to seek alternatives. Operationally, censored controls in excess were iteratively mapped to the survival of the longest-surviving controls. When excess experimental-arm censoring was present, censored experimental patients were conservatively treated as events. Hazard ratios (HRs) and differences in restricted mean survival time (RMST-D), which does not assume PH, were calculated. Cross-endpoint censoring Δcens (OS vs PFS) was examined to identify potential post-progression censoring. Results Across trials, N = 476 patients were included (CONFIRM n = 332; PROMISE-Meso n = 144); the median age was 70 years (IQR 65–75), and 78% were male. Baseline characteristics are summarized in Supplementary Tables S1–S2. In CONFIRM, PFS favored nivolumab (HR 0.66, 95% CI 0.52–0.84, P < 0.001) (Fig. 1 A), but censoring patterns differed between the arms. Early in follow-up, censoring was higher in the nivolumab arm, later shifting toward greater censoring in the control arm. After adjustment for excessive censoring in the experimental arm alone, the PFS effect remained similar (HR 0.68, 95% CI 0.53–0.86), but the RMST-D comparison—more robust under non-proportional hazards—was no longer statistically significant (p = 0.11). For OS, differential censoring diverged from approximately 6 months onward, with higher censoring in the control arm (Fig. 2 A). The unadjusted OS HR was 0.68 (95% CI 0.51–0.90, P = 0.008), which lost statistical significance after adjustment (HR 0.78, 95% CI 0.59–1.04, P = 0.09). In contrast, in PROMISE-Meso, no significant differences were detected for PFS (HR 1.05, 95% CI 0.73–1.51, P = 0.79) or OS (HR 1.11, 95% CI 0.74–1.68, P = 0.61) (Fig. 1 B- 2 B). Adjusted effect estimates overlapped the unadjusted values. Differential censoring proportions were overall lower in magnitude compared to CONFIRM, particularly in the period without low numbers at risk. In CONFIRM, censoring rates across endpoints showed higher OS than PFS censoring in both study arms, indicating that a greater proportion of patients were no longer captured in OS analyses soon after progression—a pattern consistent with post-progression censoring. In contrast, PROMISE-Meso demonstrated the expected relationship between endpoints, with PFS censoring exceeding OS censoring throughout follow-up and no evidence of post-progression censoring (Fig. 3 ). Notably, when we examined the updated CONFIRM dataset with longer follow-up (Supplementary Fig. 1–2), this post-progression censoring pattern was no longer observed, and the OS versus PFS censoring relationship aligned with expected behavior, indicating that the earlier imbalance was a consequence of premature follow-up truncation rather than an inherent feature of the dataset. Discussion The CONFIRM trial reported an overall survival advantage for nivolumab over placebo and contributed to guideline adoption [ 1 , 6 ]; however, the negative results of PROMISE-Meso [ 2 ] highlight ongoing uncertainty regarding the effectiveness of immune checkpoint inhibition in malignant mesothelioma. Our re-analysis demonstrates that the apparent benefit in CONFIRM was not statistically robust after accounting for censoring imbalance, whereas PROMISE-Meso—without such imbalance—remained consistently negative. These findings call for a more cautious interpretation of the evidence supporting ICIs in this setting. Several methodological limitations in CONFIRM weaken confidence in its survival results. The absence of blinded independent central review, reliance on investigator-assessed RECIST and iRECIST endpoints, use of a placebo rather than an active control, and an early data cut-off all raise concerns regarding outcome ascertainment and trial validity. Most importantly, our analysis identifies and introduces post-progression censoring as a previously unrecognized source of bias in time-to-event oncology trials. This phenomenon—characterized by disproportionate loss of OS follow-up after progression—can obscure subsequent deaths and inflate apparent treatment effects, leading to misleading OS estimates. After applying censoring-sensitivity methods to address the observed differential censoring, neither PFS nor OS remained statistically significant in CONFIRM, indicating that the originally reported survival benefit was not robust. In contrast, PROMISE-Meso showed less differential censoring and no evidence of post-progression censoring, yielding stable estimates and a consistent lack of benefit. The updated CONFIRM analysis [ 4 ] further reinforces these concerns, failing to demonstrate an OS advantage and reporting a substantial incidence of grade ≥ 3 toxicity (20.4%). In second-line malignant mesothelioma, where prognosis is poor and most deaths occur shortly after progression, complete post-progression follow-up is essential to avoid overinterpreting survival. Early study termination or premature data lock can introduce post-progression censoring bias, favoring the investigational arm. In CONFIRM, both enrollment and follow-up were concluded ahead of schedule, with results released approximately one year early, raising concerns about the adequacy of follow-up and the reliability of the original survival estimates. Notably, when the updated CONFIRM results were subsequently reported, the OS advantage was no longer observed and the censoring pattern no longer demonstrated evidence of post-progression censoring. This alignment—loss of the OS benefit together with resolution of the censoring imbalance—supports our conclusion that the initial OS signal was driven, at least in part, by disproportionate censoring after progression rather than by a durable treatment effect. Taken together, these data reinforce the concern that truncated follow-up and premature analysis in the original release introduced bias into the survival estimates, overstating the apparent benefit of nivolumab. Beyond statistical artifacts, the biological rationale for differential response remains uncertain. The updated CONFIRM report [ 4 ] included exploratory biomarker analyses suggesting a possible association between ICI response and a pre-existing inflamed tumor microenvironment. However, such immune signatures are known to be non-specific predictors in other solid tumors [ 7 – 9 ], and the study lacked broader genomic profiling that could clarify mechanisms of resistance or sensitivity in MMe. In this context, other studies have reported that patients with somatic and/or germline BAP1 mutations treated with either ipilimumab/nivolumab or standard chemotherapy experienced improved survival compared with BAP1-wild-type cases [ 10 – 12 ], although additional real-world data found no such benefit. While BAP1-mutant tumors may occasionally display an inflamed microenvironment, there is no convincing evidence that this translates into immune-mediated sensitivity, as no significant differences in immune infiltration were observed between responders and non-responders in MMe patients [ 12 ]. Rather, the apparent advantage associated with BAP1 alterations likely reflects the prognostic nature of this mutation, which is linked to a more indolent disease course. In the exploratory analysis [ 4 ], somatic BAP1 status was available for only 21 patients, with a numerically higher mutation rate among responders. Given the small sample size, no statistically reliable conclusions can be drawn; however, these exploratory findings are hypothesis-generating and raise the possibility of a genomic contribution to outcome. Importantly, germline BAP1 status was not assessed, despite substantial overlap between germline and somatic alterations. Germline BAP1 mutations, found in 9–12% of MMe patients, have been associated with less aggressive disease and improved therapeutic response and may confer a more favorable prognosis than somatic variants [ 13 , 14 ]. Therefore, although the reported survival advantage in CONFIRM was small and not statistically significant, it remains possible that outcomes in BAP1-mutated patients contributed to this marginal signal. However, multiple limitations in the exploratory biomarker analysis, including the absence of germline data, preclude definitive interpretation. Moreover, the epithelioid versus non-epithelioid histologic subtype is a well-recognized determinant of treatment outcomes in mesothelioma [ 6 , 15 ]. However, the CONFIRM update did not report a subgroup analysis comparing responders and non-responders by histologic subtype, limiting interpretation of differential treatment effects. The modest and inconsistent benefits of immune checkpoint inhibitors in MMe, combined with methodological flaws of the clinical trials, and limited mechanistic insights, underscore the need for a more cautious and evidence-based approach. Future researches should focus on identifying reliable predictive biomarkers employed to target therapy for MMe beyond immunotherapy, improving trial design and conduction, and ensuring robust translational analyses to guide therapy selection in this challenging disease. In conclusion, in second-line mesothelioma reanalysis indicates that excessive and post-progression censoring weakens the evidence for nivolumab benefit in MMe. Future trials should predefine censoring-sensitivity analyses, ensure comprehensive ascertainment of survival outcomes, and include adequately powered biomarker programs—including histology and germline BAP1—before adopting selection strategies. Declarations Declaration of interests : Dr. Meirson, Mrs. Kugler, Dr. Moskovitz, Dr. Cerza and Dr. Belli have not conflict of interest to declare. Dr. Gray and Prof. Mutti disclose receiving funding for an investigator-initiated study from Portage Biotech Supplementary Fig. 1. Graphs show reconstructed data from the CONFIRM 2025 progression-free survival (A) and CONFIRM 2025 overall survival (B) trials. The left, middle, and right panels depict reconstructed progression-free survival, excess censoring, and sensitivity analyses, respectively. Sensitivity analyses were adjusted for excess censoring in the control groups for the PFS (A) and OS (B) endpoints. HR = hazard ratio; RMST-D = restricted mean survival time difference. Supplementary Fig. 2. Graphs show reconstructed data from the CONFIRM 2025 trial. The left, middle, and right panels depict reconstructed overall survival and progression-free survival, reverse Kaplan-Meier, and excess censoring, respectively. Proportions of excess censoring in OS and PFS, defined as % censored (OS) − % censored (PFS), were estimated using the reverse Kaplan–Meier method. References Fennel DA, Ewings S, Ottensmeier C et al (2021) Nivolumab versus placebo in patients with relapsed malignant Mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 22:1530–1540 Popat S, Curioni-Fontecedro A, Dafni U et al (2020) A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural Mesothelioma: the European Thoracic Oncology Platform (ETOP 9–15) PROMISE-meso trial. Ann Oncol 31:1734–1745 Hsu EJ, Lin TA, Dabush DR et al (2024) Association of differential censoring with survival and suboptimal control arms among oncology clinical trials. J Natl Cancer Inst 116:990–994 Fennell DA, Hill K, Zhang M et al (2025) Constitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomized phase III trial. Nat Commun 16:6688 Meirson T, Ofer J, Zimhony-Nissim N et al (2025) Reanalysis of Urothelial Cancer Chemoimmunotherapy Trials With Differential Censoring. JAMA Netw Open 8:e2455630 Kindler HL, Hismaila N, Bazhenova L et al (2025) Treatment of Pleural Mesothelioma: ASCO Guideline Update. J Clin Oncol 43:1006–10382025 Jeong H, Koh J, Kim S et al (2024) Epithelial – mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer. Br J Cancer 131:23–36 Cabria R et al (2019) Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 19:307–325 Litchfield K et al (2021) Meta-analysis of tumor and T cell-intrinsic mechanism of sensitization to checkpoint inhibition. Cell 184:596–614 e514 Louw A, Panou V, Szejniuk WM et al (2022) BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study. J Thorac Oncol 17:921–930 Wu X, Hernandez FV, Wang H et al Prospective Analysis of Mesotheliomas in Subjects With BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease. J Thorac Oncol 2025 Aug 6:S1556-0864(25)0098 Dagogo-Jack I, Mitchell O, Codd E et al (2025) Immune Composition and Immunotherapy Outcomes of Mesothelioma with BAP1, CDKN2A, MTAP, and NF2 Alteration. J Thorac Oncol ;S1556-0864(25)00806-8 Carbone M, Minaai M, Kittaneh M et al (2025) Clinical and pathological phenotyping of mesothelioma developing in carriers of germline BAP1 mutations. J Thorac Oncol ;S1556-0864(25)00808-1 Dudnik E, Bar J, Moore A et al (2021) BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors. Front Oncol 11:603223 Brcic L, Kern L (2020) Clinical significance of histologic subtyping of malignant pleural mesothelioma. Transl Lung Cancer Res 9:924–933 Additional Declarations The authors declare potential competing interests as follows: LM and SG are recipients of a research grant from Cyncado/Portage Biotech Supplementary Files figureetabelle.zip Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8327625","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":558248751,"identity":"9079191b-d720-40ea-9bd2-088ef5759dcc","order_by":0,"name":"Tomer Meirson","email":"","orcid":"","institution":"Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Faculty of Medicine and Health Sciences, Tel Aviv University, Tel Aviv, Israel.","correspondingAuthor":false,"prefix":"","firstName":"Tomer","middleName":"","lastName":"Meirson","suffix":""},{"id":558248752,"identity":"ecfb9271-2630-491d-8cb2-42745cbcae54","order_by":1,"name":"Hadas Ditzian Kugler","email":"","orcid":"","institution":"Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel","correspondingAuthor":false,"prefix":"","firstName":"Hadas","middleName":"Ditzian","lastName":"Kugler","suffix":""},{"id":558248753,"identity":"c70e9ce8-c8f6-4d16-bf99-40a1ac5fbe6f","order_by":2,"name":"Mor Moskovitz1","email":"","orcid":"","institution":"Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel","correspondingAuthor":false,"prefix":"","firstName":"Mor","middleName":"","lastName":"Moskovitz1","suffix":""},{"id":558248754,"identity":"241f2602-7000-43df-8c57-96b6db98c363","order_by":3,"name":"Francesco Cerza","email":"","orcid":"","institution":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Cerza","suffix":""},{"id":558248755,"identity":"24922e13-ffd7-4141-a980-3412f4921823","order_by":4,"name":"Steven G. 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The left, middle, and right panels depict reconstructed progression-free survival, excess censoring, and sensitivity analyses, respectively. Sensitivity analyses were adjusted for excess censoring in the control groups for the CONFIRM (A) and PROMISE-meso (B) trials. HR = hazard ratio; RMST-D = restricted mean survival time difference.\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8327625/v1/1b488aa8910de899c9b39b9e.jpeg"},{"id":98321637,"identity":"ffcd39ac-0eab-42c7-98f0-1296444edb61","added_by":"auto","created_at":"2025-12-16 14:07:35","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":966237,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFig 2. \u003c/strong\u003eReconstructed OS data from the CONFIRM (A) and PROMISE-meso (B) trials. The left, middle, and right panels depict reconstructed overall survival, excess censoring, and sensitivity analyses, respectively. Sensitivity analyses were adjusted for excess censoring in the control groups for the CONFIRM (A) and PROMISE-meso (B) trials. HR = hazard ratio; RMST-D = restricted mean survival time difference.\u003c/p\u003e","description":"","filename":"Figure2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8327625/v1/9cf911f481fdb70d7ca542cf.jpeg"},{"id":98321639,"identity":"7880d841-2164-4c27-bf80-f77f150e6de6","added_by":"auto","created_at":"2025-12-16 14:07:35","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":719492,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFig 3. \u003c/strong\u003eReconstructed PFS and OS data from the CONFIRM (A) and PROMISE-meso (B) trials. The left, middle, and right panels depict reconstructed overall survival and progression-free survival, reverse Kaplan-Meier, and excess censoring, respectively. Proportions of excess censoring in OS and PFS, defined as % censored (OS) − % censored (PFS), were estimated using the reverse Kaplan–Meier method.\u003c/p\u003e","description":"","filename":"Figure3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8327625/v1/210e77b5fd129a9b0bd7652f.jpeg"},{"id":98445520,"identity":"c6a83774-a695-499c-b63b-989ff2a11fef","added_by":"auto","created_at":"2025-12-17 17:19:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2974439,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8327625/v1/ceff1059-4029-4f9b-8cbb-69518b7b56aa.pdf"},{"id":98436591,"identity":"8dbc98e4-cd88-46a3-95a0-9d7f56ee8537","added_by":"auto","created_at":"2025-12-17 16:55:57","extension":"zip","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1876272,"visible":true,"origin":"","legend":"","description":"","filename":"figureetabelle.zip","url":"https://assets-eu.researchsquare.com/files/rs-8327625/v1/3cd772ffe170ecaf0db448ac.zip"}],"financialInterests":"The authors declare potential competing interests as follows: LM and SG are recipients of a research grant from Cyncado/Portage Biotech","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSecond-Line Immune Checkpoint Trials in Mesothelioma: The Impact of Censoring and Predictive Biological Factors\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune checkpoint inhibitors represent a meaningful advance in oncology, yet in mesothelioma their trial results are inconsistent, and the absolute benefits are small. The phase III CONFIRM trial reported initially an OS advantage for nivolumab over placebo, whereas PROMISE-Meso showed no benefit for pembrolizumab over chemotherapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Such discordant outcomes raise concerns about methodological drivers of apparent efficacy rather than true biological advantage. Time-to-event analyses are vulnerable to informative censoring including in unblinded or partially blinded trials, and trials with suboptimal control [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. We therefore conducted a targeted reanalysis of two second-line randomized trials\u0026mdash;CONFIRM (nivolumab vs placebo) and PROMISE-Meso (pembrolizumab vs chemotherapy)\u0026mdash;to determine whether censoring imbalance could account for reported effects and to assess and contextualize exploratory biomarker signals.\u003c/p\u003e"},{"header":"Materials \u0026 Methods","content":"\u003cp\u003eWe reconstructed published Kaplan\u0026ndash;Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) in the CONFIRM, updated CONFIRM, and PROMISE-Meso trials [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Censoring distributions were characterized with reverse-KM (rKM) by arm, and Δcens(t) was defined as the difference in censoring proportion between the experimental and control arms at each time point. Our censoring-sensitivity analysis followed prespecified rules [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. When excess control-arm censoring was observed, we hypothesized perceived-inferiority censoring: better-prognosis, controls drop out to seek alternatives. Operationally, censored controls in excess were iteratively mapped to the survival of the longest-surviving controls. When excess experimental-arm censoring was present, censored experimental patients were conservatively treated as events. Hazard ratios (HRs) and differences in restricted mean survival time (RMST-D), which does not assume PH, were calculated. Cross-endpoint censoring Δcens (OS vs PFS) was examined to identify potential post-progression censoring.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAcross trials, N\u0026thinsp;=\u0026thinsp;476 patients were included (CONFIRM n\u0026thinsp;=\u0026thinsp;332; PROMISE-Meso n\u0026thinsp;=\u0026thinsp;144); the median age was 70 years (IQR 65\u0026ndash;75), and 78% were male. Baseline characteristics are summarized in Supplementary Tables S1\u0026ndash;S2.\u003c/p\u003e \u003cp\u003eIn CONFIRM, PFS favored nivolumab (HR 0.66, 95% CI 0.52\u0026ndash;0.84, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA), but censoring patterns differed between the arms. Early in follow-up, censoring was higher in the nivolumab arm, later shifting toward greater censoring in the control arm. After adjustment for excessive censoring in the experimental arm alone, the PFS effect remained similar (HR 0.68, 95% CI 0.53\u0026ndash;0.86), but the RMST-D comparison\u0026mdash;more robust under non-proportional hazards\u0026mdash;was no longer statistically significant (p\u0026thinsp;=\u0026thinsp;0.11). For OS, differential censoring diverged from approximately 6 months onward, with higher censoring in the control arm (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The unadjusted OS HR was 0.68 (95% CI 0.51\u0026ndash;0.90, P\u0026thinsp;=\u0026thinsp;0.008), which lost statistical significance after adjustment (HR 0.78, 95% CI 0.59\u0026ndash;1.04, P\u0026thinsp;=\u0026thinsp;0.09).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn contrast, in PROMISE-Meso, no significant differences were detected for PFS (HR 1.05, 95% CI 0.73\u0026ndash;1.51, P\u0026thinsp;=\u0026thinsp;0.79) or OS (HR 1.11, 95% CI 0.74\u0026ndash;1.68, P\u0026thinsp;=\u0026thinsp;0.61) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB-\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Adjusted effect estimates overlapped the unadjusted values. Differential censoring proportions were overall lower in magnitude compared to CONFIRM, particularly in the period without low numbers at risk.\u003c/p\u003e \u003cp\u003eIn CONFIRM, censoring rates across endpoints showed higher OS than PFS censoring in both study arms, indicating that a greater proportion of patients were no longer captured in OS analyses soon after progression\u0026mdash;a pattern consistent with post-progression censoring. In contrast, PROMISE-Meso demonstrated the expected relationship between endpoints, with PFS censoring exceeding OS censoring throughout follow-up and no evidence of post-progression censoring (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Notably, when we examined the updated CONFIRM dataset with longer follow-up (Supplementary Fig.\u0026nbsp;1\u0026ndash;2), this post-progression censoring pattern was no longer observed, and the OS versus PFS censoring relationship aligned with expected behavior, indicating that the earlier imbalance was a consequence of premature follow-up truncation rather than an inherent feature of the dataset.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe CONFIRM trial reported an overall survival advantage for nivolumab over placebo and contributed to guideline adoption [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]; however, the negative results of PROMISE-Meso [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] highlight ongoing uncertainty regarding the effectiveness of immune checkpoint inhibition in malignant mesothelioma. Our re-analysis demonstrates that the apparent benefit in CONFIRM was not statistically robust after accounting for censoring imbalance, whereas PROMISE-Meso\u0026mdash;without such imbalance\u0026mdash;remained consistently negative. These findings call for a more cautious interpretation of the evidence supporting ICIs in this setting.\u003c/p\u003e \u003cp\u003eSeveral methodological limitations in CONFIRM weaken confidence in its survival results. The absence of blinded independent central review, reliance on investigator-assessed RECIST and iRECIST endpoints, use of a placebo rather than an active control, and an early data cut-off all raise concerns regarding outcome ascertainment and trial validity. Most importantly, our analysis identifies and introduces post-progression censoring as a previously unrecognized source of bias in time-to-event oncology trials. This phenomenon\u0026mdash;characterized by disproportionate loss of OS follow-up after progression\u0026mdash;can obscure subsequent deaths and inflate apparent treatment effects, leading to misleading OS estimates. After applying censoring-sensitivity methods to address the observed differential censoring, neither PFS nor OS remained statistically significant in CONFIRM, indicating that the originally reported survival benefit was not robust. In contrast, PROMISE-Meso showed less differential censoring and no evidence of post-progression censoring, yielding stable estimates and a consistent lack of benefit.\u003c/p\u003e \u003cp\u003eThe updated CONFIRM analysis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] further reinforces these concerns, failing to demonstrate an OS advantage and reporting a substantial incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 toxicity (20.4%). In second-line malignant mesothelioma, where prognosis is poor and most deaths occur shortly after progression, complete post-progression follow-up is essential to avoid overinterpreting survival. Early study termination or premature data lock can introduce post-progression censoring bias, favoring the investigational arm. In CONFIRM, both enrollment and follow-up were concluded ahead of schedule, with results released approximately one year early, raising concerns about the adequacy of follow-up and the reliability of the original survival estimates. Notably, when the updated CONFIRM results were subsequently reported, the OS advantage was no longer observed and the censoring pattern no longer demonstrated evidence of post-progression censoring. This alignment\u0026mdash;loss of the OS benefit together with resolution of the censoring imbalance\u0026mdash;supports our conclusion that the initial OS signal was driven, at least in part, by disproportionate censoring after progression rather than by a durable treatment effect. Taken together, these data reinforce the concern that truncated follow-up and premature analysis in the original release introduced bias into the survival estimates, overstating the apparent benefit of nivolumab.\u003c/p\u003e \u003cp\u003eBeyond statistical artifacts, the biological rationale for differential response remains uncertain. The updated CONFIRM report [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] included exploratory biomarker analyses suggesting a possible association between ICI response and a pre-existing inflamed tumor microenvironment. However, such immune signatures are known to be non-specific predictors in other solid tumors [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and the study lacked broader genomic profiling that could clarify mechanisms of resistance or sensitivity in MMe. In this context, other studies have reported that patients with somatic and/or germline BAP1 mutations treated with either ipilimumab/nivolumab or standard chemotherapy experienced improved survival compared with BAP1-wild-type cases [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], although additional real-world data found no such benefit. While BAP1-mutant tumors may occasionally display an inflamed microenvironment, there is no convincing evidence that this translates into immune-mediated sensitivity, as no significant differences in immune infiltration were observed between responders and non-responders in MMe patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Rather, the apparent advantage associated with BAP1 alterations likely reflects the prognostic nature of this mutation, which is linked to a more indolent disease course.\u003c/p\u003e \u003cp\u003eIn the exploratory analysis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], somatic BAP1 status was available for only 21 patients, with a numerically higher mutation rate among responders. Given the small sample size, no statistically reliable conclusions can be drawn; however, these exploratory findings are hypothesis-generating and raise the possibility of a genomic contribution to outcome. Importantly, germline BAP1 status was not assessed, despite substantial overlap between germline and somatic alterations. Germline BAP1 mutations, found in 9\u0026ndash;12% of MMe patients, have been associated with less aggressive disease and improved therapeutic response and may confer a more favorable prognosis than somatic variants [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, although the reported survival advantage in CONFIRM was small and not statistically significant, it remains possible that outcomes in BAP1-mutated patients contributed to this marginal signal. However, multiple limitations in the exploratory biomarker analysis, including the absence of germline data, preclude definitive interpretation.\u003c/p\u003e \u003cp\u003eMoreover, the epithelioid versus non-epithelioid histologic subtype is a well-recognized determinant of treatment outcomes in mesothelioma [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the CONFIRM update did not report a subgroup analysis comparing responders and non-responders by histologic subtype, limiting interpretation of differential treatment effects.\u003c/p\u003e \u003cp\u003eThe modest and inconsistent benefits of immune checkpoint inhibitors in MMe, combined with methodological flaws of the clinical trials, and limited mechanistic insights, underscore the need for a more cautious and evidence-based approach. Future researches should focus on identifying reliable predictive biomarkers employed to target therapy for MMe beyond immunotherapy, improving trial design and conduction, and ensuring robust translational analyses to guide therapy selection in this challenging disease.\u003c/p\u003e \u003cp\u003eIn conclusion, in second-line mesothelioma reanalysis indicates that excessive and post-progression censoring weakens the evidence for nivolumab benefit in MMe. Future trials should predefine censoring-sensitivity analyses, ensure comprehensive ascertainment of survival outcomes, and include adequately powered biomarker programs\u0026mdash;including histology and germline BAP1\u0026mdash;before adopting selection strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003e \u003cb\u003eDeclaration of interests\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eDr. Meirson, Mrs. Kugler, Dr. Moskovitz, Dr. Cerza and Dr. Belli have not conflict of interest to declare. Dr. Gray and Prof. Mutti disclose receiving funding for an investigator-initiated study from Portage Biotech\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eSupplementary Fig.\u0026nbsp;1.\u003c/h2\u003e \u003cp\u003eGraphs show reconstructed data from the CONFIRM 2025 progression-free survival (A) and CONFIRM 2025 overall survival (B) trials. The left, middle, and right panels depict reconstructed progression-free survival, excess censoring, and sensitivity analyses, respectively. Sensitivity analyses were adjusted for excess censoring in the control groups for the PFS (A) and OS (B) endpoints. HR\u0026thinsp;=\u0026thinsp;hazard ratio; RMST-D\u0026thinsp;=\u0026thinsp;restricted mean survival time difference.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSupplementary Fig.\u0026nbsp;2.\u003c/strong\u003e \u003cp\u003eGraphs show reconstructed data from the CONFIRM 2025 trial. The left, middle, and right panels depict reconstructed overall survival and progression-free survival, reverse Kaplan-Meier, and excess censoring, respectively. Proportions of excess censoring in OS and PFS, defined as % censored (OS) \u0026minus; % censored (PFS), were estimated using the reverse Kaplan\u0026ndash;Meier method.\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFennel DA, Ewings S, Ottensmeier C et al (2021) Nivolumab versus placebo in patients with relapsed malignant Mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 22:1530\u0026ndash;1540\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePopat S, Curioni-Fontecedro A, Dafni U et al (2020) A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural Mesothelioma: the European Thoracic Oncology Platform (ETOP 9\u0026ndash;15) PROMISE-meso trial. Ann Oncol 31:1734\u0026ndash;1745\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu EJ, Lin TA, Dabush DR et al (2024) Association of differential censoring with survival and suboptimal control arms among oncology clinical trials. J Natl Cancer Inst 116:990\u0026ndash;994\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFennell DA, Hill K, Zhang M et al (2025) Constitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomized phase III trial. Nat Commun 16:6688\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeirson T, Ofer J, Zimhony-Nissim N et al (2025) Reanalysis of Urothelial Cancer Chemoimmunotherapy Trials With Differential Censoring. JAMA Netw Open 8:e2455630\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKindler HL, Hismaila N, Bazhenova L et al (2025) Treatment of Pleural Mesothelioma: ASCO Guideline Update. J Clin Oncol 43:1006\u0026ndash;10382025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeong H, Koh J, Kim S et al (2024) Epithelial\u0026thinsp;\u0026ndash;\u0026thinsp;mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer. Br J Cancer 131:23\u0026ndash;36\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCabria R et al (2019) Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 19:307\u0026ndash;325\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLitchfield K et al (2021) Meta-analysis of tumor and T cell-intrinsic mechanism of sensitization to checkpoint inhibition. Cell 184:596\u0026ndash;614 e514\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLouw A, Panou V, Szejniuk WM et al (2022) BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study. J Thorac Oncol 17:921\u0026ndash;930\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu X, Hernandez FV, Wang H et al Prospective Analysis of Mesotheliomas in Subjects With BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease. J Thorac Oncol 2025 Aug 6:S1556-0864(25)0098\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDagogo-Jack I, Mitchell O, Codd E et al (2025) Immune Composition and Immunotherapy Outcomes of Mesothelioma with BAP1, CDKN2A, MTAP, and NF2 Alteration. J Thorac Oncol ;S1556-0864(25)00806-8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarbone M, Minaai M, Kittaneh M et al (2025) Clinical and pathological phenotyping of mesothelioma developing in carriers of germline BAP1 mutations. J Thorac Oncol ;S1556-0864(25)00808-1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDudnik E, Bar J, Moore A et al (2021) BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors. Front Oncol 11:603223\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrcic L, Kern L (2020) Clinical significance of histologic subtyping of malignant pleural mesothelioma. Transl Lung Cancer Res 9:924\u0026ndash;933\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Italian Group for Study and Therapy of Mesothelioma and Environmental Oncology","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"malignant mesothelioma, immunotherapy, censoring analysis, biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-8327625/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8327625/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 have shown inconsistent benefit in second-line malignant pleural mesothelioma. Although histology and several molecular biomarkers, such as BAP1 and others, reveal substantial heterogeneity, their contribution to treatment selection remains uncertain. Because informative censoring may bias time-to-event analyses, we re-evaluated key second-line trials to determine whether censoring patterns contributed to discordant efficacy results.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePublished Kaplan\u0026ndash;Meier curves from CONFIRM (nivolumab vs placebo), the CONFIRM update, and PROMISE-Meso (pembrolizumab vs chemotherapy) were reconstructed. Censoring distributions were quantified using reverse-KM, and differential censoring between arms and across endpoints (overall survival [OS] vs progression-free survival [PFS]) was evaluated over time. Sensitivity analyses were applied to address excessive censoring, and hazard ratios and restricted mean survival time differences were calculated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn CONFIRM, the initially reported OS advantage coincided with short follow-up and a differential censoring pattern consistent with post-progression censoring. The updated CONFIRM dataset, with longer follow-up, demonstrated no OS benefit and no evidence of post-progression censoring. In contrast, PROMISE-Meso showed no evidence of post-progression censoring at any time and remained negative throughout. When general differential censoring was addressed using sensitivity analyses, both the PFS effect and the OS advantage in CONFIRM lost statistical significance.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePost-progression censoring is an under-recognized source of bias that can generate misleading survival signals and may have contributed to the initial CONFIRM findings that were based on a premature early data lock. Although a modest treatment effect in a biologically defined subgroup cannot be excluded, current evidence remains inconclusive. Future studies should ensure comprehensive ascertainment of survival outcomes and include adequately powered biomarker programs, including histology and BAP1 status.\u003c/p\u003e","manuscriptTitle":"Second-Line Immune Checkpoint Trials in Mesothelioma: The Impact of Censoring and Predictive Biological Factors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 14:07:30","doi":"10.21203/rs.3.rs-8327625/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f11a1063-6889-43c6-9ba0-7d328e5e2fe7","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59423385,"name":"Oncology"}],"tags":[],"updatedAt":"2025-12-16T14:07:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-16 14:07:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8327625","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8327625","identity":"rs-8327625","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}