Real-world data on immune checkpoint inhibitors in advanced sarcomas across multiple European institutions
DOI:
https://doi.org/10.2340/1651-226X.2025.43135Keywords:
immunotherapy, immune checkpoint inhibitor, programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), sarcomaAbstract
Background: Following the success of immune checkpoint inhibitors (ICI) in other cancer types, their role is being evaluated in sarcomas. They have been assessed as monotherapy, or in combination with other ICI, chemotherapeutic drugs and tyrosine kinase inhibitors (TKI) in several clinical trials. So far the results have been limited to non-selected sarcoma populations. Further work is required to select patients who will benefit from immunotherapy.
Patients and methods: We conducted a pooled retrospective analysis of the use of ICI in patients with advanced sarcomas in multiple European institutions. ICI-based treatments included ICI monotherapy
(n = 43, 59.7%), double ICI (n = 5, 6.9%), ICI plus TKI (n = 21, 29.2%) and ICI plus chemotherapy (n = 3, 4.2%).
Results: Seventy-two patients from 10 European institutions, with metastatic (87.5%) or locally advanced (12.5%) disease were included. The most common subtype was undifferentiated pleomorphic sarcoma (16.7%), followed by leiomyosarcoma (12%), liposarcoma (10%) and angiosarcoma (9.7%). The median number of prior lines of systemic therapy was 2 (0–8). The objective response rate was 34.4% and was higher in combination regimens versus ICI monotherapy. With a median follow-up of 20.7 months, median progression-free survival (PFS) was 4.6 and median overall survival (OS) 18.8 months. Line of therapy (1st/2nd vs. ≥ 3rd line) and best response to ICI was significantly associated with PFS and OS. Histological subtype was significantly associated with OS. Toxicity was in general manageable; only six (8.3%) patients discontinued therapy for AE.
Interpretation: Our study provided additional real-world data on the outcome of ICI in patients with advanced sarcomas.
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References
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711–23.
https://doi.org/10.1056/NEJMoa1003466 DOI: https://doi.org/10.1056/NEJMoa1003466
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540–50.
https://doi.org/10.1016/S0140-6736(15)01281-7 DOI: https://doi.org/10.1016/S0140-6736(15)01281-7
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803–13.
https://doi.org/10.1056/NEJMoa1510665 DOI: https://doi.org/10.1056/NEJMoa1510665
D’Angelo SP, Mahoney MR, Van Tine BA, Atkins J, Milhem MM, Jahagirdar BN, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018 Mar;19(3):416–26.
https://doi.org/10.1016/S1470-2045(18)30006-8 DOI: https://doi.org/10.1016/S1470-2045(18)30006-8
Tawbi HA, Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017 Nov;18(11):1493–501.
https://doi.org/10.1016/S1470-2045(17)30624-1 DOI: https://doi.org/10.1016/S1470-2045(17)30624-1
Somaiah N, Conley AP, Parra ER, Lin H, Amini B, Solis Soto L, et al. Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial. Lancet Oncol. 2022 Sep;23(9):1156–66.
https://doi.org/10.1016/S1470-2045(22)00392-8 DOI: https://doi.org/10.1016/S1470-2045(22)00392-8
Martin-Broto J, Hindi N, Grignani G, Martinez-Trufero J, Redondo A, Valverde C, et al. Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial. J Immunother Cancer. 2020 Nov;8(2):e001561.
https://doi.org/10.1136/jitc-2020-001561 DOI: https://doi.org/10.1136/jitc-2020-001561
Wilky BA, Trucco MM, Subhawong TK, Florou V, Park W, Kwon D, et al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial. Lancet Oncol. 2019 Jun;20(6):837–48.
https://doi.org/10.1016/S1470-2045(19)30153-6 DOI: https://doi.org/10.1016/S1470-2045(19)30153-6
Chen AP, Sharon E, O’Sullivan-Coyne G, Moore N, Foster JC, Hu JS, et al. Atezolizumab for advanced alveolar soft part sarcoma. N Engl J Med. 2023 Sep 7;389(10):911–21.
Grilley-Olson JE, Allred JB, Schuetze S, Davis EJ, Wagner MJ, Poklepovic AS, et al. A multicenter phase II study of cabozantinib + nivolumab for patients (pts) with advanced angiosarcoma (AS) previously treated with a taxane (Alliance A091902). JCO. 2023 Jun;41(16_suppl):11503.
https://doi.org/10.1200/JCO.2023.41.16_suppl.11503 DOI: https://doi.org/10.1200/JCO.2023.41.16_suppl.11503
Wagner MJ, Zhang Y, Cranmer LD, Loggers ET, Black G, McDonnell S, et al. A phase 1/2 trial combining avelumab and trabectedin for advanced liposarcoma and leiomyosarcoma. Clin Cancer Res. 2022 Jun 1;28(11):2306–12.
https://doi.org/10.1158/1078-0432.CCR-22-0240 DOI: https://doi.org/10.1158/1078-0432.CCR-22-0240
Petitprez F, de Reyniès A, Keung EZ, Chen TWW, Sun CM, Calderaro J, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020 Jan;577(7791):556–60.
https://doi.org/10.1038/s41586-019-1906-8 DOI: https://doi.org/10.1038/s41586-019-1906-8
Iwai Y, Baldwin XL, Feeney T, Agala CB, Yanagihara TK, Stein JN, et al. Trends in the use of immunotherapy to treat soft tissue sarcoma. Am J Surg. 2024 Oct;236:115794.
https://doi.org/10.1016/j.amjsurg.2024.115794 DOI: https://doi.org/10.1016/j.amjsurg.2024.115794
Seligson ND, Chen JL, Goodrich AC, Van Tine BA, Campbell JD, Richards AL, et al. A multicenter, randomized, non-comparative, phase II study of nivolumab ± ipilimumab for patients with metastatic sarcoma (Alliance A091401): expansion cohorts and correlative analyses. J Immunother Cancer. 2024 Sep 28;12(9):e009472.
https://doi.org/10.1136/jitc-2024-009472 DOI: https://doi.org/10.1136/jitc-2024-009472
Cho HJ, Yun KH, Shin SJ, Lee YH, Kim SH, Baek W, et al. Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial. Nat Commun. 2024 Jan 23;15(1):685. DOI: https://doi.org/10.1038/s41467-024-44875-2
Monga V, Skubitz KM, Maliske S, Mott SL, Dietz H, Hirbe AC, et al. A retrospective analysis of the efficacy of immunotherapy in metastatic soft-tissue sarcomas. Cancers (Basel). 2020 Jul 11;12(7):1873.
https://doi.org/10.3390/cancers12071873 DOI: https://doi.org/10.3390/cancers12071873
Zhou M, Bui N, Bolleddu S, Lohman M, Becker HC, Ganjoo K. Nivolumab plus ipilimumab for soft tissue sarcoma: a single institution retrospective review. Immunotherapy. 2020 Dec;12(18):1303–12. DOI: https://doi.org/10.2217/imt-2020-0155
Miao R, Swank J, Melzer D, Ludlow S, Clark L, Finger M, et al. Anti-PD-1 therapy in advanced sarcomas: is cutaneous primary site a stronger predictor of response than histologic subtype? Cancer Immunol Immunother. 2023 Jul;72(7):2521–7.
https://doi.org/10.1007/s00262-023-03387-6 DOI: https://doi.org/10.1007/s00262-023-03387-6
You Y, Guo X, Zhuang R, Zhang C, Wang Z, Shen F, et al. Activity of PD-1 inhibitor combined with anti-angiogenic therapy in advanced sarcoma: a single-center retrospective analysis. Front Mol Biosci. 2021;8:747650.
https://doi.org/10.3389/fmolb.2021.747650 DOI: https://doi.org/10.3389/fmolb.2021.747650
Lee AQ, Hao C, Pan M, Ganjoo KN, Bui NQ. Histologic and immunologic factors associated with response to immune checkpoint inhibitors in advanced sarcoma. Clin Cancer Res. 2025 Feb 17;31(4):678–84. DOI: https://doi.org/10.1158/1078-0432.CCR-24-3485
Hindi N, Razak A, Rosenbaum E, Jonczak E, Hamacher R, Rutkowski P, et al. Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry. ESMO Open. 2023 Dec;8(6):102045.
https://doi.org/10.1016/j.esmoop.2023.102045 DOI: https://doi.org/10.1016/j.esmoop.2023.102045
Bui N, Dietz H, Farag S, Hirbe AC, Wagner MJ, Van Tine BA, et al. A retrospective multi-institutional cohort analysis of clinical characteristics and outcomes in dedifferentiated chondrosarcoma. Cancers (Basel). 2023 Dec 5;15(9):2617.
https://doi.org/10.3390/cancers15092617 DOI: https://doi.org/10.3390/cancers15092617
Nasr LF, Zoghbi M, Lazcano R, Nakazawa M, Bishop AJ, Farooqi A, et al. High-grade pleomorphic sarcomas treated with immune checkpoint blockade: the MD Anderson Cancer Center Experience. Cancers (Basel). 2024 Dec 1;16(9):1763.
https://doi.org/10.3390/cancers16091763 DOI: https://doi.org/10.3390/cancers16091763
Liu Z, Wang X, Wang J, Zhang P, Li C, Wang B, et al. The efficacies and biomarker investigations of antiangiogenic agents and PD-1 inhibitors for metastatic soft tissue sarcoma: a multicenter retrospective study. Front Oncol. 2023;13:1124517.
https://doi.org/10.3389/fonc.2023.1124517 DOI: https://doi.org/10.3389/fonc.2023.1124517
Pollack SM, Redman MW, Baker KK, Wagner MJ, Schroeder BA, Loggers ET, et al. Assessment of doxorubicin and pembrolizumab in patients with advanced anthracycline-naive sarcoma: a phase 1/2 nonrandomized clinical trial. JAMA Oncol. 2020 Nov 1;6(11):1778–82.
https://doi.org/10.1001/jamaoncol.2020.3689 DOI: https://doi.org/10.1001/jamaoncol.2020.3689
Gordon EM, Chawla SP, Tellez WA, Younesi E, Thomas S, Chua-Alcala VS, et al. SAINT: a phase I/expanded phase II study using safe amounts of ipilimumab, nivolumab and trabectedin as first-line treatment of advanced soft tissue sarcoma. Cancers (Basel). 2023 Jan 31;15(3):906. DOI: https://doi.org/10.3390/cancers15030906
Rosenbaum E, Antonescu CR, Smith S, Bradic M, Kashani D, Richards AL, et al. Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center. J Immunother Cancer. 2022 Apr;10(4):e004149.
https://doi.org/10.1136/jitc-2021-004149 DOI: https://doi.org/10.1136/jitc-2021-004149
Wustrack RL, Shao E, Sheridan J, Zimel M, Cho SJ, Horvai AE, et al. Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma. Cancer Immunol Immunother. 2021 Oct;70(10):3031–40. DOI: https://doi.org/10.1007/s00262-021-02935-2
Rosenbaum E, Seier K, Bradic M, Kelly C, Movva S, Nacev BA, et al. Immune-related adverse events after immune checkpoint blockade-based therapy are associated with improved survival in advanced sarcomas. Cancer Res Commun. 2023 Oct 18;3(10):2118–25.
https://doi.org/10.1158/2767-9764.CRC-22-0140 DOI: https://doi.org/10.1158/2767-9764.CRC-22-0140
Pinato DJ, Marron TU, Mishra-Kalyani PS, Gong Y, Wei G, Szafron D, et al. Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice. Eur J Cancer. 2021 Nov;157:140–52.
https://doi.org/10.1016/j.ejca.2021.08.020 DOI: https://doi.org/10.1016/j.ejca.2021.08.020
Haddox CL, Nathenson MJ, Mazzola E, Lin JR, Baginska J, Nau A, et al. Phase II study of eribulin plus pembrolizumab in metastatic soft-tissue sarcomas: clinical outcomes and biological correlates. Clin Cancer Res. 2024 Apr 1;30(7):1281–92.
https://doi.org/10.1158/1078-0432.CCR-23-2250 DOI: https://doi.org/10.1158/1078-0432.CCR-23-2250
Liu J, Gao T, Tan Z, Li S, Xu J, Bai C, et al. Phase II study of TQB2450, a novel PD-L1 antibody, in combination with anlotinib in patients with locally advanced or metastatic soft tissue sarcoma. Clin Cancer Res. 2022 Aug 15;28(16):3473–9. DOI: https://doi.org/10.1158/1078-0432.c.6532382
Tian Z, Dong S, Zuo W, Li P, Zhang F, Gao S, et al. Efficacy and safety of sintilimab plus doxorubicin in advanced soft tissue sarcoma: a single-arm, phase II trial. Front Pharmacol. 2022;13:987569. DOI: https://doi.org/10.3389/fphar.2022.987569
Pollack SM, He Q, Yearley JH, Emerson R, Vignali M, Zhang Y, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer. 2017 Sep 1;123(17):3291–304.
https://doi.org/10.1002/cncr.30726 DOI: https://doi.org/10.1002/cncr.30726
D’Angelo SP, Shoushtari AN, Agaram NP, Kuk D, Qin LX, Carvajal RD, et al. Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol. 2015 Mar;46(3):357–65.
https://doi.org/10.1016/j.humpath.2014.11.001 DOI: https://doi.org/10.1016/j.humpath.2014.11.001
Vanhersecke L, Bougouin A, Crombé A, Brunet M, Sofeu C, Parrens M, et al. Standardized pathology screening of mature tertiary lymphoid structures in cancers. Lab Invest. 2023 Dec;103(5):100063.
https://doi.org/10.1016/j.labinv.2023.100063 DOI: https://doi.org/10.1016/j.labinv.2023.100063
Painter CA, Jain E, Tomson BN, Dunphy M, Stoddard RE, Thomas BS, et al. The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research. Nat Med. 2020 Feb;26(2):181–7.
https://doi.org/10.1038/s41591-019-0749-z DOI: https://doi.org/10.1038/s41591-019-0749-z
Subramanian A, Nemat-Gorgani N, Ellis-Caleo TJ, van IJzendoorn DGP, Sears TJ, Somani A, et al. Sarcoma microenvironment cell states and ecosystems are associated with prognosis and predict response to immunotherapy. Nat Cancer. 2024 Apr;5(4):642–58.
https://doi.org/10.1038/s43018-024-00743-y DOI: https://doi.org/10.1038/s43018-024-00743-y
Wilky B, Trent JC, Gordon M, El-Khoueiry AB, Bullock A, Henick BS, et al. 1919MO Efficacy and safety of botensilimab (BOT) plus balstilimab (BAL) in patients (pts) with refractory metastatic sarcoma. Ann Oncol. 2023 Oct 1;34:S1032–3.
https://doi.org/10.1016/j.annonc.2023.09.1148 DOI: https://doi.org/10.1016/j.annonc.2023.09.1148
Keung EZ, Lazar AJ, Torres KE, Wang WL, Cormier JN, Ashleigh Guadagnolo B, et al. Phase II study of neoadjuvant checkpoint blockade in patients with surgically resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. BMC Cancer. 2018 Sep 24;18(1):913.
https://doi.org/10.1186/s12885-018-4829-0 DOI: https://doi.org/10.1186/s12885-018-4829-0
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Copyright (c) 2025 Stefania Kokkali, Ana Dolcan, Kjetil Boye, Anastasios Kyriazoglou, Ioannis Boukovinas, Foteini Kalofonou, Anna Koumarianou, Natalia Asimakopoulou, Eleftherios Vorrias, Konstantinos Tsapakidis, Eleni Georgaki, Anna Boulouta, Leonidas Mavroeidis, Magnus Harneshaug, Stamatios Theocharis, Robin L. Jones, Antonia Digklia
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