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Immune checkpoint blockers in patients with unresectable or metastatic thymic epithelial tumours: A meta-analysis

Published:December 31, 2022DOI:https://doi.org/10.1016/j.ejca.2022.12.005

      Highlights

      • Immune checkpoint blockers strategy is feasible in pre-treated thymic carcinomas.
      • In this population, ICB achieve a RR of 18% and one-year OS of 67%.
      • Close monitoring of patients is strongly advised to detect severe immune-toxicity.

      Abstract

      Background

      For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice.

      Methods

      We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy.

      Results

      Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3–26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6–34.6) and 66.9% (95% CI: 59.6–75.2%), respectively. The incidence of grade 3–5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma.

      Conclusions

      Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity.

      Keywords

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      References

        • Marx A.
        • Chan J.K.C.
        • Chalabreysse L.
        • Dacic S.
        • Detterbeck F.
        • French C.A.
        • et al.
        The 2021 WHO classification of tumors of the thymus and mediastinum: what is new in thymic epithelial, germ cell, and mesenchymal tumors?.
        J Thorac Oncol. 2022; 17: 200-213https://doi.org/10.1016/j.jtho.2021.10.010
        • Shin D.W.
        • Cho J.H.
        • Ha J.
        • Jung K.-W.
        Trends in incidence and survival of patients with thymic epithelial tumor in a high-incidence Asian Country: analysis of the Korean Central Cancer Registry 1999 to 2017.
        J Thorac Oncol. 2022; 17: 827-837https://doi.org/10.1016/j.jtho.2022.02.001
        • Montanez J.C.B.
        • Boucher M.-É.
        • Dansin E.
        • Kerjouan M.
        • Mazieres J.
        • Pichon E.
        • et al.
        Autoimmune diseases in centrally reviewed thymic epithelial tumours (TET).
        Ann Oncol. 2020; 31: S1078https://doi.org/10.1016/j.annonc.2020.08.1442
        • Giaccone G.
        • Rajan A.
        • Ruijter R.
        • Smit E.
        • van Groeningen C.
        • Hogendoorn P.C.W.
        Imatinib mesylate in patients with WHO B3 thymomas and thymic carcinomas.
        J Thorac Oncol. 2009; 4: 1270-1273https://doi.org/10.1097/JTO.0b013e3181b6be57
        • Girard N.
        • Ruffini E.
        • Marx A.
        • Faivre-Finn C.
        • Peters S.
        • ESMO Guidelines Committee
        Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2015; 26: v40-v55https://doi.org/10.1093/annonc/mdv277
        • Conforti F.
        • Pala L.
        • Giaccone G.
        • De Pas T.
        Thymic epithelial tumors: from biology to treatment.
        Cancer Treat Rev. 2020; 86102014https://doi.org/10.1016/j.ctrv.2020.102014
        • Merveilleux du Vignaux C.
        • Dansin E.
        • Mhanna L.
        • Greillier L.
        • Pichon E.
        • Kerjouan M.
        • et al.
        Systemic therapy in advanced thymic epithelial tumors: insights from the RYTHMIC prospective cohort.
        J Thorac Oncol. 2018; 13: 1762-1770https://doi.org/10.1016/j.jtho.2018.08.005
        • Petat A.
        • Dansin E.
        • Calcagno F.
        • Greillier L.
        • Pichon E.
        • Kerjouan M.
        • et al.
        Treatment strategies for thymic carcinoma in a real-life setting. Insights from the RYTHMIC network.
        Eur J Cancer. 2022; 162: 118-127https://doi.org/10.1016/j.ejca.2021.11.028
        • Song X.
        • Fan J.
        • Zhu L.
        • Wang Z.
        • He Y.
        • Zhou C.
        The efficacy and safety of immunotherapy in thymic epithelial tumors: more effective, more risky: a systematic review.
        J Thorac Dis. 2021; 13: 5093-5103https://doi.org/10.21037/jtd-21-290
        • Chen Y.
        • Zhang Y.
        • Chai X.
        • Gao J.
        • Chen G.
        • Zhang W.
        • et al.
        Correlation between the expression of PD-L1 and clinicopathological features in patients with thymic epithelial tumors.
        BioMed Res Int. 2018; 20185830547https://doi.org/10.1155/2018/5830547
        • Girard N.
        Immune checkpoints in thymic epithelial tumors: challenges and opportunities.
        Immuno-Oncol Technol. 2019; 3: 8-14https://doi.org/10.1016/j.iotech.2019.09.002
        • Giaccone G.
        • Kim C.
        • Thompson J.
        • McGuire C.
        • Kallakury B.
        • Chahine J.J.
        • et al.
        Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study.
        Lancet Oncol. 2018; 19: 347-355https://doi.org/10.1016/S1470-2045(18)30062-7
        • Giaccone G.
        • Kim C.
        Durable response in patients with thymic carcinoma treated with pembrolizumab after prolonged follow-up.
        J Thorac Oncol. 2021; 16: 483-485https://doi.org/10.1016/j.jtho.2020.11.003
        • Cho J.
        • Kim H.S.
        • Ku B.M.
        • Choi Y.-L.
        • Cristescu R.
        • Han J.
        • et al.
        Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial.
        J Clin Oncol. 2019; 37: 2162-2170https://doi.org/10.1200/JCO.2017.77.3184
        • Katsuya Y.
        • Horinouchi H.
        • Seto T.
        • Umemura S.
        • Hosomi Y.
        • Satouchi M.
        • et al.
        Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study.
        Eur J Cancer. 2019; 113: 78-86https://doi.org/10.1016/j.ejca.2019.03.012
        • Girard N.
        • Ponce Aix S.
        • Cedres S.
        • Berghmans T.
        • Burgers S.
        • Toffart A.C.
        • et al.
        Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial.
        Ann Oncol. 2021; 32: S1342https://doi.org/10.1016/j.annonc.2021.08.2147
        • Rajan A.
        • Heery C.R.
        • Thomas A.
        • Mammen A.L.
        • Perry S.
        • O'Sullivan Coyne G.
        • et al.
        Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma.
        J Immunother Cancer. 2019; 7: 269https://doi.org/10.1186/s40425-019-0723-9
        • Tabernero J.
        • Andre F.
        • Blay J.-Y.
        • Bustillos A.
        • Fear S.
        • Ganta S.
        • et al.
        Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers.
        ESMO Open. 2022; 7100419https://doi.org/10.1016/j.esmoop.2022.100419
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6e1000097https://doi.org/10.1371/journal.pmed.1000097
        • Liu N.
        • Zhou Y.
        • Lee J.J.
        IPDfromKM: reconstruct individual patient data from published Kaplan-Meier survival curves.
        BMC Med Res Methodol. 2021; 21: 111https://doi.org/10.1186/s12874-021-01308-8
        • Hunter J.P.
        • Saratzis A.
        • Sutton A.J.
        • Boucher R.H.
        • Sayers R.D.
        • Bown M.J.
        In meta-analyses of proportion studies, funnel plots were found to be an inaccurate method of assessing publication bias.
        J Clin Epidemiol. 2014; 67: 897-903https://doi.org/10.1016/j.jclinepi.2014.03.003
        • Ritchie G.
        • Gasper H.
        • Man J.
        • Lord S.
        • Marschner I.
        • Friedlander M.
        • et al.
        Defining the most appropriate primary end point in phase 2 trials of immune checkpoint inhibitors for advanced solid cancers: a systematic review and meta-analysis.
        JAMA Oncol. 2018; 4: 522-528https://doi.org/10.1001/jamaoncol.2017.5236
        • Antonarelli G.
        • Corti C.
        • Zucali P.A.
        • Perrino M.
        • Manglaviti S.
        • Lo Russo G.
        • et al.
        Continuous sunitinib schedule in advanced platinum refractory thymic epithelial neoplasms: a retrospective analysis from the ThYmic MalignanciEs (TYME) Italian collaborative group.
        Eur J Cancer. 2022; 174: 31-36https://doi.org/10.1016/j.ejca.2022.07.009
        • Sato J.
        • Satouchi M.
        • Itoh S.
        • Okuma Y.
        • Niho S.
        • Mizugaki H.
        • et al.
        Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial.
        Lancet Oncol. 2020; 21: 843-850https://doi.org/10.1016/S1470-2045(20)30162-5
        • Benitez J.C.
        • Florez-Arango J.
        • Dansin E.
        • Giaccone G.
        • Basse C.
        • Mazieres J.
        • et al.
        Lenvatinib for the treatment of thymic epithelial tumors (TETs): a real-life multicenter experience.
        J Clin Orthod. 2022; 40 (8585–8585)https://doi.org/10.1200/JCO.2022.40.16_suppl.8585
        • He Y.
        • Ramesh A.
        • Gusev Y.
        • Bhuvaneshwar K.
        • Giaccone G.
        Molecular predictors of response to pembrolizumab in thymic carcinoma.
        Cell Rep Med. 2021; 2100392https://doi.org/10.1016/j.xcrm.2021.100392
        • Radovich M.
        • Pickering C.R.
        • Felau I.
        • Ha G.
        • Zhang H.
        • Jo H.
        • et al.
        The integrated genomic landscape of thymic epithelial tumors.
        Cancer Cell. 2018; 33: 244-258.e10https://doi.org/10.1016/j.ccell.2018.01.003
        • Bonneville R.
        • Krook M.A.
        • Kautto E.A.
        • Miya J.
        • Wing M.R.
        • Chen H.-Z.
        • et al.
        Landscape of microsatellite instability across 39 cancer types.
        JCO Precis Oncol. 2017; 2017https://doi.org/10.1200/PO.17.00073
        • Yamamoto Y.
        • Iwahori K.
        • Funaki S.
        • Matsumoto M.
        • Hirata M.
        • Yoshida T.
        • et al.
        Immunotherapeutic potential of CD4 and CD8 single-positive T cells in thymic epithelial tumors.
        Sci Rep. 2020; 10: 4064https://doi.org/10.1038/s41598-020-61053-8
        • Xie W.
        • Huang H.
        • Xiao S.
        • Fan Y.
        • Deng X.
        • Zhang Z.
        Immune checkpoint inhibitors therapies in patients with cancer and preexisting autoimmune diseases: a meta-analysis of observational studies.
        Autoimmun Rev. 2020; 19102687https://doi.org/10.1016/j.autrev.2020.102687
      1. https://www.nccn.org/professionals/physician_gls/pdf/thymic.pdf n.d.

        • Grant M.J.
        • Herbst R.S.
        • Goldberg S.B.
        Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC.
        Nat Rev Clin Oncol. 2021; 18: 625-644https://doi.org/10.1038/s41571-021-00520-1
        • Conforti F.
        • Zucali P.A.
        • Pala L.
        • Catania C.
        • Bagnardi V.
        • Sala I.
        • et al.
        Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial.
        Lancet Oncol. 2022; (S1470-2045(22)00542-3. https://doi.org/10.1016/S1470-2045(22)00542-3)