Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial | Neuro-oncology | JAMA Oncology | JAMA Network
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    Possibility of combination therapy with antitumor agents and agents for epigenetic changes in the treatment of glioblastoma
    takuma hayashi, MBBS, D.M.Sci., GMRC, PhD | National Hospital Organization Kyoto Medical Center
    Glioblastoma is an almost incurable disease with a median survival of 14.6 months, even in patients who can receive standard treatment. For a long time, postoperative radiation therapy has been the only treatment that significantly prolongs survival. Chemotherapy has been shown to not contribute to or only slightly prolong survival.

    In a randomized controlled trial published in 2005, the effectiveness of the combination of temozolomide with radiation therapy and subsequent maintenance therapy for glioblastoma was confirmed. Temozolomide chemotherapy has become widespread. However, the life-prolonging effect of temozolomide chemotherapy is limited.

    MGMT promoter methylation status is a widely accepted
    biomarker in glioblastoma in the Japan Society of Neuro-Oncology. Therefore methylation of the O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter is predictive for treatment response in glioblastoma patients. However, precise predictive cutoff values to distinguish “MGMT methylated” from “MGMT unmethylated” patients remain highly debated in terms of pyrosequencing (PSQ) analysis.

    The CheckMate 143 Phase 3 Randomized Clinical Trial of 369 patients diagnosed with recurrent glioblastoma treated with nivolumab, an improved survival benefit was not observed in patients who received nivolumab compared with bevacizumab-treated control patients.

    In Japan cancer genomic medicine, even if a therapeutic agent for the pathogenic variant is detected in patients with glioblastoma, in particular, chemotherapy does not have a life-prolonging effect in patients with MGMT methylated glioblastoma.

    Epigenetic changes are known as a factor of resistance to antitumor agents. For example, various epigenetic changes have been observed in advanced and recurrent ovarian cancer. For cancers with epigenetic changes, the therapeutic effect of chemotherapy is not expected. Therefore, as a treatment for antitumor agents-resistant cancers in which epigenetic changes have been observed, combination treatments of epigenetic agents (for example, HDAC inhibitors) and antitumor agents are being investigated.

    It is reported that currently a study of nivolumab in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma with methylated MGMT promoter is ongoing. Nevertheless, a combination treatment of antitumor agents and agents for epigenetic changes such as MGMT methylation should be considered for patients with glioblastoma.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    May 21, 2020

    Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial

    Author Affiliations
    • 1Dana-Farber/Harvard Cancer Center, Boston, Massachusetts
    • 2AUSL–IRCCS Institute of Neurological Sciences, Bologna, Italy
    • 3Department of Neurology and Yale Cancer Center, Yale University, New Haven, Connecticut
    • 4University College London Hospitals, London, United Kingdom
    • 5The Johns Hopkins Hospital, Baltimore, Maryland
    • 6Neurology Clinic, University of Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany
    • 7Yale School of Medicine, New Haven, Connecticut
    • 8Cleveland Clinic, Cleveland, Ohio
    • 9Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland
    • 10Dr Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany
    • 11Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • 12Hospital Universitario 12 de Octubre, Madrid, Spain
    • 13University of Wollongong School of Medicine, Wollongong, NSW, Australia
    • 14Moffitt Cancer Center, University of South Florida, Tampa, Florida
    • 15Bristol Myers Squibb, Princeton, New Jersey
    • 16Duke University Hospital, Durham, North Carolina
    JAMA Oncol. 2020;6(7):1003-1010. doi:10.1001/jamaoncol.2020.1024
    Key Points

    Question  Does programmed cell death 1 immune checkpoint inhibition with nivolumab improve overall survival compared with bevacizumab treatment for patients with recurrent glioblastoma?

    Findings  In this randomized phase 3 clinical trial of 369 patients diagnosed with recurrent glioblastoma treated with nivolumab, an improved survival benefit was not observed in patients who received nivolumab compared with bevacizumab-treated control patients.

    Meaning  Additional research is needed; nivolumab monotherapy did not improve overall survival compared with bevacizumab in the treatment of recurrent glioblastoma. A study of nivolumab in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma with methylated MGMT promoter is ongoing.

    Abstract

    Importance  Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported.

    Objective  To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab.

    Design, Setting, and Participants  In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites.

    Interventions  Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death.

    Main Outcomes and Measures  The primary end point was overall survival (OS).

    Results  A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs.

    Conclusions and Relevance  Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types.

    Trial Registration  ClinicalTrials.gov Identifier: NCT02017717

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