Top

Published in:

Open Access 01-12-2024 | Glioblastoma | Research

Clinical activity and safety of sintilimab, bevacizumab, and TMZ in patients with recurrent glioblastoma

Authors: Yinghao Lu, Limin Liao, Kunpeng Du, Jianhua Mo, Xia Zou, Junxian Liang, Jiahui Chen, Wenwen Tang, Liwei Su, Jieping Wu, Junde Zhang, Yujing Tan

Published in: BMC Cancer | Issue 1/2024

Abstract

Purpose

There are limited and no standard therapies for recurrent glioblastoma. We herein report the antitumour activity and safety of sintilimab, bevacizumab and temozolomide (TMZ) in recurrent glioblastoma.

Methods

We retrospectively analysed eight patients with recurrent glioblastoma treated with sintilimab (200 mg) every three weeks + bevacizumab (10 mg/kg) every three weeks + TMZ (200 mg/m²orally) (5 days orally every 28 days for a total of four weeks). The primary objective was investigator-assessed median progression-free survival(mPFS). Secondary objectives were to assess the 6-month PFS, objective response rate (ORR) and duration of response (DOR) accroding to RANO criteria.

Results

The mPFS time for 8 patients was 3.340 months (95% CI: 2.217–4.463), The longest PFS was close to 9 months. Five patients were assessed to have achieved partial response (PR), with an overall remission rate of 62.5%, Four patients experienced a change in tumour volume at the best response time of greater than 60% shrinkage from baseline, and one patient remained progression free upon review, with a DOR of more than 6.57 months. The 6-month PFS was 25% (95% CI: 5.0–55.0%). Three patients had a treatment-related adverse events, though no grade 4 or 5 adverse events occurred.

Conclusion

In this small retrospective study, the combination regimen of sintilimab, bevacizumab and TMZ showed promising antitumour activity in treatment of recurrent glioblastoma, with a good objective remission rate.

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. 2005. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med (2005), 987–996. https://doi.org/10.1056/NEJMoa043330.

Clarke JL, Ennis MM, Yung WK, Chang SM, Wen PY, Cloughesy TF, Deangelis LM, Robins HI, Lieberman FS, Fine HA, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Lamborn KR, Prados MD. 2011. Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma? Neuro-Oncology (2011), 1118–1124. https://doi.org/10.1093/neuonc/nor110.

Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-Oncology (2008). 2008;162–170. https://doi.org/10.1215/15228517-2007-062.

Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. 2009. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol (2009), 740–745. https://doi.org/10.1200/JCO.2008.16.3055.

Desjardins A, Reardon DA, Coan A, Marcello J, Nd Herndon JE, Bailey L, Peters KB, Friedman HS, Vredenburgh JJ. 2012. Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer (2012), 1302–1312. https://doi.org/10.1002/cncr.26381.

Galanis E, Anderson SK, Lafky JM, Uhm JH, Giannini C, Kumar SK, Kimlinger TK, Northfelt DW, Flynn PJ, Jaeckle KA, Kaufmann TJ, Buckner JC. 2013. Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial. Clin. Cancer Res (2013), 4816–4823. https://doi.org/10.1158/1078-0432.CCR-13-0708.

Lassen U, Sorensen M, Gaziel TB, Hasselbalch B, Poulsen HS. Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme. Anticancer Res. 2013;33(4):1657–60.

Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE, Nd Herndon JE, Bulusu A, Threatt S, Friedman AH, Vredenburgh JJ, Friedman HS. 2012. Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naive, recurrent glioblastoma. J. Neuro-Oncol (2012), 155–164. https://doi.org/10.1007/s11060-011-0722-2.

Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Sampson JH, Sathornsumetee S, McLendon RE, Nd Herndon JE, Marcello JE, Norfleet J, Friedman AH, Bigner DD, Friedman HS. 2009. Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br. J. Cancer (2009), 1986–1994. https://doi.org/10.1038/sj.bjc.6605412.

10.

Sathornsumetee S, Desjardins A, Vredenburgh JJ, McLendon RE, Marcello J, Herndon JE, Mathe A, Hamilton M, Rich JN, Norfleet JA, Gururangan S, Friedman HS, Reardon DA. 2010. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro-Oncology (2010), 1300–1310. https://doi.org/10.1093/neuonc/noq099.

11.

Verhoeff JJC, Lavini C, van Linde ME, Stalpers LJA, Majoie CBLM, Reijneveld JC, van Furth WR, Richel DJ. 2010. Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann. Oncol (2010), 1723–1727. https://doi.org/10.1093/annonc/mdp591.

12.

Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, Lopez-Janeiro A, Porciuncula A, Idoate MA, Inoges S, de Andrea C, De Cerio A, Lopez-Diaz S, Tejada P, Berraondo F, Villarroel-Espindola J, Choi A, Gurpide M, Giraldez I, Goicoechea, Perez-Larraya J, Gallego MF, Sanmamed JL, Perez-Gracia, Melero I. 2019. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat. Med (2019), 470–476. https://doi.org/10.1038/s41591-018-0339-5.

13.

Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L. 2022. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ-British Medical Journal (2022), e68714. https://doi.org/10.1136/bmj-2021-068714.

14.

Lu S, Wu L, Jian H, Chen Y, Wang Q, Fang J, Wang Z, Hu Y, Sun M, Han L, Miao L, Ding C, Cui J, Li B, Pan Y, Li X, Ye F, Liu A, Wang K, Cang S, Zhou H, Sun X, Ferry D, Lin Y, Wang S, Zhang W, Zhang C. 2022. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol (2022), 1167–1179. https://doi.org/10.1016/S1470-2045(22)00382-5.

15.

Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, Li Q, Lu Y, Chen Y, Guo Y, Chen Z, Liu B, Jia W, Wu J, Wang J, Shao G, Zhang B, Shan Y, Meng Z, Wu J, Gu S, Yang W, Liu C, Shi X, Gao Z, Yin T, Cui J, Huang M, Xing B, Mao Y, Teng G, Qin Y, Wang J, Xia F, Yin G, Yang Y, Chen M, Wang Y, Zhou H, Fan J. 2021. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol (2021), 977–990. https://doi.org/10.1016/S1470-2045(21)00252-7.

16.

Nayak L, Molinaro AM, Peters K, Clarke JL, Jordan JT, de Groot J, Nghiemphu L, Kaley T, Colman H, McCluskey C, Gaffey S, Smith TR, Cote DJ, Severgnini M, Yearley JH, Zhao Q, Blumenschein WM, Duda DG, Muzikansky A, Jain RK, Wen PY, Reardon DA. 2021. Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. Clin. Cancer Res (2021), 1048–1057. https://doi.org/10.1158/1078-0432.CCR-20-2500.

17.

Lukas RV, Rodon J, Becker K, Wong ET, Shih K, Touat M, Fasso M, Osborne S, Molinero L, O’Hear C, Grossman W, Baehring J. 2018. Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. J. Neuro-Oncol (2018), 317–328. https://doi.org/10.1007/s11060-018-2955-9.

18.

Lakshmi Nayak AM, Molinaro K, Peters JL, Clarke, Justin T, Jordan Jde, Groot L, Nghiemphu T, Kaley H, Colman C, McCluskey S, Gaffey TR, Smith DJ, Cote M, Severgnini JH, Yearley Q, Zhao WM, Blumenschein DG, Duda A, Muzikansky RK, Jain PY, Wen, Reardon DA. 2021. Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. Clin. Cancer Res (2021), 1048–1057. https://doi.org/10.1158/1078-0432.CCR-20-2500.

19.

Wang S, Yao F, Lu X, Li Q, Su Z, Lee JH, Wang C, Du L. Temozolomide promotes immune escape of GBM cells via upregulating PD-L1. Am J Cancer Res. 2019;9(6):1161–71.

20.

Zeng J, Zhang XK, Chen HD, Zhong ZH, Wu QL, Lin SX. 2016. Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas. Oncotarget (2016), 8944–8955. https://doi.org/10.18632/oncotarget.6884.

21.

Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, Ling X, Zhou S, Ivan C, Chen JQ, Burks JK, Fuller GN, Calin GA, Conrad CA, Creasy C, Ritthipichai K, Radvanyi L, Heimberger AB. 2016. PD-L1 expression and prognostic impact in glioblastoma. Neuro-Oncology (2016), 195–205. https://doi.org/10.1093/neuonc/nov172.

22.

Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, Voloschin A, Ramkissoon SH, Ligon KL, Latek R, Zwirtes R, Strauss L, Paliwal P, Harbison CT, Reardon DA, Sampson JH. 2018. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro-Oncology (2018), 674–686. https://doi.org/10.1093/neuonc/nox208.

23.

Nassiri F, Patil V, Yefet LS, Singh O, Liu J, Dang RMA, Yamaguchi TN, Daras M, Cloughesy TF, Colman H, Kumthekar PU, Chen CC, Aiken R, Groves MD, Ong SS, Ramakrishna R, Vogelbaum MA, Khagi S, Kaley T, Melear JM, Peereboom DM, Rodriguez A, Yankelevich M, Nair SG, Puduvalli VK, Aldape K, Gao A, Lopez-Janeiro A, de Andrea CE, Alonso MM, Boutros P, Robbins J, Mason WP, Sonabend AM, Stupp R, Fueyo J, Gomez-Manzano C, Lang FF, Zadeh G. 2023. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. Nat. Med (2023), 1370–1378. https://doi.org/10.1038/s41591-023-02347-y.

24.

Jiang H, Yu K, Cui Y, Ren X, Li M, Yang C, Zhao X, Zhu Q, Lin S. 2021. Combination of Immunotherapy and Radiotherapy for Recurrent Malignant Gliomas: Results From a Prospective Study. Front. Immunol (2021), 632547. https://doi.org/10.3389/fimmu.2021.632547.

25.

Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh JJ, Bigner DD, Heimberger AB. 2011. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-Oncology (2011), 324–333. https://doi.org/10.1093/neuonc/noq157.

26.

Karachi A, Dastmalchi F, Mitchell DA, Rahman M. 2018. Temozolomide for immunomodulation in the treatment of glioblastoma. Neuro-Oncology (2018), 1566–1572. https://doi.org/10.1093/neuonc/noy072.

27.

Chaudhry IH, O’Donovan DG, Brenchley PE, Reid H, Roberts IS. 2001. Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas. Histopathology (2001), 409–415. https://doi.org/10.1046/j.1365-2559.2001.01230.x.

28.

Rahma OE, Hodi FS. 2019. The Intersection between Tumor Angiogenesis and Immune Suppression. Clin. Cancer Res (2019), 5449–5457. DOI https://doi.org/10.1158/1078-0432.CCR-18-1543.

29.

Pellerino A, Bruno F, Soffietti R, Ruda R. 2023. Antiangiogenic Therapy for Malignant Brain Tumors: Does It Still Matter? Curr. Oncol. Rep (2023), 777–785. https://doi.org/10.1007/s11912-023-01417-1.

30.

Lee J, Koh J, Kim HK, Hong S, Kim K, Park S, Jung HA, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. 2022. Bevacizumab Plus Atezolizumab After Progression on Atezolizumab Monotherapy in Pretreated Patients With NSCLC: An Open-Label, Two-Stage, Phase 2 Trial. J. Thorac. Oncol (2022), 900–908. https://doi.org/10.1016/j.jtho.2022.04.001.

31.

Sepulveda JM, Belda-Iniesta C, Gil-Gil M, Perez-Segura P, Berrocal A, Reynes G, Gallego O, Capellades J, Ordonez JM, La Orden B, Balana C. 2015. A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma. Clin. Transl. Oncol (2015), 743–750. https://doi.org/10.1007/s12094-015-1304-0.

32.

Gilbert MR, Pugh SL, Aldape K, Sorensen AG, Mikkelsen T, Penas-Prado M, Bokstein F, Kwok Y, Lee RJ, Mehta M. 2017. NRG oncology RTOG 0625: a randomized phase II trial of bevacizumab with either irinotecan or dose-dense temozolomide in recurrent glioblastoma. J. Neuro-Oncol (2017), 193–199. https://doi.org/10.1007/s11060-016-2288-5.

Title: Clinical activity and safety of sintilimab, bevacizumab, and TMZ in patients with recurrent glioblastoma
Authors: Yinghao Lu
Limin Liao
Kunpeng Du
Jianhua Mo
Xia Zou
Junxian Liang
Jiahui Chen
Wenwen Tang
Liwei Su
Jieping Wu
Junde Zhang
Yujing Tan
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Bevacizumab
Glioma
Glioma
Glioma
Published in: BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-024-11848-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2024

Mechanism of intestinal microbiota disturbance promoting the occurrence and development of esophageal squamous cell carcinoma——based on microbiomics and metabolomics

The role of adenocarcinoma subtypes and immunohistochemistry in predicting lymph node metastasis in early invasive lung adenocarcinoma

G6PD and machine learning algorithms as prognostic and diagnostic indicators of liver hepatocellular carcinoma

Positivity rates, trends and experiences of health workers on human papillomavirus screened using genexpert in Uganda: a three-year retrospective cohort study

Effects of educational interventions based on the theory of planned behavior on oral cancer-related knowledge and tobacco smoking in adults: a cluster randomized controlled trial

Anus preservation in low rectal adenocarcinoma based on MMR/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial

Keynote webinar | Spotlight on antibody–drug conjugates in cancer