Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143

Antonio Omuro; David A Reardon; John H Sampson; Joachim Baehring; Solmaz Sahebjam; Timothy F Cloughesy; Alexandros-Georgios Chalamandaris; Von Potter; Nicholas Butowski; Michael Lim

doi:10.1093/noajnl/vdac025

journal article Open Access Jan 01, 2022

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143

Antonio Omuro David A Reardon John H Sampson Joachim Baehring Solmaz Sahebjam Timothy F Cloughesy Alexandros-Georgios Chalamandaris Von Potter Nicholas Butowski Michael Lim

Neuro-Oncology Advances Vol. 4 No. 1 · Oxford University Press (OUP)

View at Publisher Save 10.1093/noajnl/vdac025

Abstract

AbstractBackgroundThe phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma.MethodsIn total, 136 patients were enrolled. In part A (safety lead-in), 31 patients (n = 15, methylated/unknown MGMT promoter; n = 16, unmethylated MGMT promoter) received nivolumab and RT+TMZ (NIVO+RT+TMZ) and 30 patients with unmethylated MGMT promoter received NIVO+RT. In part B (expansion), patients with unmethylated MGMT promoter were randomized to NIVO+RT+TMZ (n = 29) or NIVO+RT (n = 30). Primary endpoint was safety/tolerability; secondary endpoint was overall survival (OS).ResultsNIVO+RT±TMZ was tolerable; grade 3/4 treatment-related adverse events occurred in 51.6% (NIVO+RT+TMZ) and 30.0% (NIVO+RT) of patients in part A and 46.4% (NIVO+RT+TMZ) and 28.6% (NIVO+RT) in part B. No new safety signals were detected. In part A, median OS (mOS) with NIVO+RT+TMZ was 33.38 months (95% CI, 16.2 to not estimable) in patients with methylated MGMT promoter. In patients with unmethylated MGMT promoter, mOS was 16.49 months (12.94–22.08) with NIVO+RT+TMZ and 14.41 months (12.55–17.31) with NIVO+RT. In part B, mOS was 14.75 months (10.01–18.6) with NIVO+RT+TMZ and 13.96 months (10.81–18.14) with NIVO+RT in patients with unmethylated MGMT promoter.ConclusionsCheckMate 143 was the first trial evaluating immune checkpoint inhibition with first-line treatment of glioblastoma. Results showed that NIVO can be safely combined with RT±TMZ, with no new safety signals. Toxicities, including lymphopenia, were more frequent with NIVO+RT+TMZ. OS was similar with or without TMZ in patients with unmethylated MGMT promoter, and differences by MGMT methylation status were observed.

Topics

No keywords indexed for this article. Browse by subject →

References

34

[1]

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

Roger Stupp, Monika E Hegi, Warren P Mason et al.

The Lancet Oncology 2009 10.1016/s1470-2045(09)70025-7

[2]

CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015

Quinn T Ostrom, Haley Gittleman, Gabrielle Truitt et al.

Neuro-Oncology 2018 10.1093/neuonc/noy131

[3]

Preusser "Prospects of immune checkpoint modulators in the treatment of glioblastoma" Nat Rev Neurol. (2015) 10.1038/nrneurol.2015.139

[4]

Wen "Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions" Neuro Oncol. (2020) 10.1093/neuonc/noaa106

[5]

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Roger Stupp, Warren P. Mason, Martin J. van den Bent et al.

New England Journal of Medicine 2005 10.1056/nejmoa043330

[6]

Weller "European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas" Lancet Oncol. (2017) 10.1016/s1470-2045(17)30194-8

[7]

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma

Roger Stupp, Sophie Taillibert, Andrew Kanner et al.

JAMA 2017 10.1001/jama.2017.18718

[8]

Omuro "Glioblastoma and other malignant gliomas: a clinical review" JAMA. (2013) 10.1001/jama.2013.280319

[9]

Weller "Standards of care for treatment of recurrent glioblastoma—are we there yet?" Neuro Oncol. (2013) 10.1093/neuonc/nos273

[10]

Weller "MGMT promoter methylation in malignant gliomas: ready for personalized medicine?" Nat Rev Neurol. (2010) 10.1038/nrneurol.2009.197

[11]

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Monika E. Hegi, Annie-Claire Diserens, Thierry Gorlia et al.

New England Journal of Medicine 2005 10.1056/nejmoa043331

[12]

Esteller "Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents" N Engl J Med. (2000) 10.1056/nejm200011093431901

[13]

Hegi "Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide" Clin Cancer Res. (2004) 10.1158/1078-0432.ccr-03-0384

[14]

Berghoff "Clinical neuropathology practice guide 06-2012: MGMT testing in elderly glioblastoma patients—yes, but how?" Clin Neuropathol. (2012) 10.5414/np300576

[15]

Weller "Where does O6-methylguanine DNA methyltransferase promoter methylation assessment place temozolomide in the future standards of care for glioblastoma?" Cancer. (2018) 10.1002/cncr.31244

[16]

Reardon "Immunotherapy advances for glioblastoma" Neuro Oncol. (2014) 10.1093/neuonc/nou212

[17]

T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma

Karolina Woroniecka, Pakawat Chongsathidkiet, Kristen Rhodin et al.

Clinical Cancer Research 2018 10.1158/1078-0432.ccr-17-1846

[18]

Park "Immune checkpoint inhibitor-induced reinvigoration of tumor-infiltrating CD8(+) T cells is determined by their differentiation status in glioblastoma" Clin Cancer Res. (2019) 10.1158/1078-0432.ccr-18-2564

[19]

Tang "Combining radiation and immunotherapy: a new systemic therapy for solid tumors?" Cancer Immunol Res. (2014) 10.1158/2326-6066.cir-14-0069

[20]

Nduom "PD-L1 expression and prognostic impact in glioblastoma" Neuro Oncol. (2016) 10.1093/neuonc/nov172

[21]

Hao "PD-L1 expression in glioblastoma, the clinical and prognostic significance: a systematic literature review and meta-analysis" Front Oncol. (2020) 10.3389/fonc.2020.01015

[22]

Reardon "Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model" Cancer Immunol Res. (2016) 10.1158/2326-6066.cir-15-0151

[23]

Zeng "Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas" Int J Radiat Oncol Biol Phys. (2013) 10.1016/j.ijrobp.2012.12.025

[24]

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

Timothy F. Cloughesy, Aaron Y. Mochizuki, Joey R. Orpilla et al.

Nature Medicine 2019 10.1038/s41591-018-0337-7

[25]

(2020)

[26]

Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma

David A. Reardon, Alba A. Brandes, Antonio Omuro et al.

JAMA Oncology 2020 10.1001/jamaoncol.2020.1024

[27]

Omuro "Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143" Neuro Oncol. (2018) 10.1093/neuonc/nox208

[28]

US Department of Health and Human Services (2009)

[29]

Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Patrick Y. Wen, David R. Macdonald, David A. Reardon et al.

Journal of Clinical Oncology 2010 10.1200/jco.2009.26.3541

[30]

Gustafson "Systemic immune suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone" Neuro Oncol. (2010) 10.1093/neuonc/noq001

[31]

[32]

[33]

Schalper "Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma" Nat Med. (2019) 10.1038/s41591-018-0339-5

[34]

Zhao "Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma" Nat Med. (2019) 10.1038/s41591-019-0349-y

Cited By

37

Immunotherapy approaches for adult glioma: knowledge gained from recent clinical trials

Brian M. Andersen, David A. Reardon · 2022

Current Opinion in Neurology

Metrics

37

Citations

34

References

Details

Published: Jan 01, 2022
Vol/Issue: 4(1)
License: View

Authors

A

Antonio Omuro

Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA

D

David A Reardon

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

J

John H Sampson

Department of Neurosurgery, Duke University Hospital, Durham, North Carolina, USA

J

Joachim Baehring

Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA

S

Solmaz Sahebjam

Moffitt Cancer Center, University of South Florida, Tampa, Florida, USA

T

Timothy F Cloughesy

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA

A

Alexandros-Georgios Chalamandaris

Biostatistics, Bristol Myers Squibb, Braine-L’Alleud, Belgium

V

Von Potter

Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA

N

Nicholas Butowski

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA

M

Michael Lim

Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA

Funding

Bristol Myers Squibb

Cite This Article

Antonio Omuro, David A Reardon, John H Sampson, et al. (2022). Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro-Oncology Advances, 4(1). https://doi.org/10.1093/noajnl/vdac025

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143

You May Also Like