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Clinical Trial
. 2020 Jul 1;6(7):1003-1010.
doi: 10.1001/jamaoncol.2020.1024.

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

David A Reardon  1 , Alba A Brandes  2 , Antonio Omuro  3 , Paul Mulholland  4 , Michael Lim  5 , Antje Wick  6 , Joachim Baehring  7 , Manmeet S Ahluwalia  8 , Patrick Roth  9 , Oliver Bähr  10 , Surasak Phuphanich  11 , Juan Manuel Sepulveda  12 , Paul De Souza  13 , Solmaz Sahebjam  14 , Michael Carleton  15 , Kay Tatsuoka  15 , Corina Taitt  15 , Ricardo Zwirtes  15 , John Sampson  16 , Michael Weller  9
Affiliations
Clinical Trial

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

David A Reardon et al. JAMA Oncol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Reardon has received grant funding from Acerta Pharmaceuticals, Incyte, Midatech, Omniox, and Tragara; grant funding and personal fees from Agenus, Celldex, EMD Serono, and Inovio; and personal fees from Advantagene, Genentech/Roche, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline Therapeutics, and Taiho Oncology. Dr Brandes has received travel grants from Roche and Celgene. Dr Omuro has received personal fees from Bristol Myers Squibb, BTG, AstraZeneca, Inovio, Merck, Stemline, Novocure, and Alexion. Dr Mulholland has received grant funding, travel support, and nonfinancial support (to forward plan immuno-oncology use at Mount Vernon) from Bristol Myers Squibb. Dr Lim has received grant funding from Bristol Myers Squibb, Kryin-Kwoya, Biohaven, Accuary, and Arbor; personal fees for an advisory board from SQZ Biotechnologies, VBI Technologies, and Tocagen; consultancy fees from Stryker and Baxter; and grant funding for laboratory research from DNATrix; and has a patent combining local chemotherapy with immunotherapy pending to Arbor and a patent combining stereotactic radiosurgery with immunotherapy that has been issued. Dr Baehring has served as a consultant to Bristol Myers Squibb. Dr Ahluwalia has received research funding from Bristol Myers Squibb; grants and consultancy fees from Incyte, Bristol Myers Squibb, AstraZeneca, Novocure, and AbbVie; grant funding from Tracon, Novartis, Pharmacyclics, Merck, and Bayer; consultancy fees from Monteris Medical, Caris Life Sciences, MRI Solutions, CBT Pharmaceuticals, Flatiron, Karyopharm, Tocagen, Bayer, and Varian Medical Systems; personal fees from Kadman and VBI vaccines; stock options from MimiVax and Doctible; and personal fees from Forma Therapeutics outside the submitted work. Dr Roth has received personal fees from Bristol Myers Squibb, Covagen, Medac, Novocure, Roche, Debiopharm, and Virometix; grants from MSD outside the submitted work. Dr Bähr has received research funding and personal fees from Bristol Myers Squibb and personal fees from Novocure and Medac. Dr Phuphanich reported grants from Bristol Myers during the conduct of the study. Dr Sepulveda has received personal fees from Bayer, AbbVie, Novartis, GW Pharma, Celgene, and Pierre Fabre; and grant funding and personal fees from Pfizer and Catalysis Pharma. Dr De Souza reported other from BioSceptre outside the submitted work. Dr Sahebjam has received grant funding from Merck and Bristol Myers Squibb and funding from Bristol Myers Squibb, Merck, Brooklyn ImmunoTherapeutics, Lilly Pharmaceuticals, Cortice Bioscience, Merck, and Bristol Myers Squibb outside the submitted work. Drs Carleton, Tatsuoka, and Taitt are employed by Bristol Myers Squibb. Dr Zwirtes is employed by and owns stock in Bristol Myers Squibb. Dr Sampson has served as a consultant/advisory board member for Bristol Myers Squibb and Brainlab; has received grant funding and personal fees from and is a patent holder for Celldex Therapeutics; has received grant funding and personal fees from, owns equity/stock in, and is a patent holder for Annias Immunotherapeutics; and owns stock in Istari. Dr Weller has received fees for patient enrollment per study contract from Bristol Myers Squibb; grant funding and personal fees from AbbVie, MSD, Novocure, Merck (EMD Serono), and Roche; grant funding from Actelion, Acceleron, Bayer, Tragara, OGD Pharma, Piqur, and Dracen; and personal fees from Basilea, Celgene, Celldex, Progenics, Tocagen, and Orbus.

Figures

Figure 1.
Figure 1.. Study Profile
CONSORT diagram showing the number of patients in CheckMate 143 cohort 2 who were enrolled, treated with nivolumab or bevacizumab, discontinued treatment, and analyzed for efficacy and safety. Q2W indicates every 2 weeks.
Figure 2.
Figure 2.. Overall Survival (OS) and Progression-Free Survival (PFS) in All Patients
A, The number of events; median OS; OS rates at 6, 12, and 18 months; and the Kaplan-Meier curve for OS in all patients treated with nivolumab or bevacizumab. B, The number of events; median PFS; PFS rates at 6, 12, and 18 months; and the Kaplan-Meier curve for PFS per investigator assessment in patients treated with nivolumab or bevacizumab. Symbols indicate censored observations. Hazard ratios (HRs) and CIs were estimated using a Cox proportional hazards model.
Figure 3.
Figure 3.. Overall Survival (OS) in Prespecified Patient Subgroups Defined by Baseline Clinical Characteristics
A, Forest plot of unstratified hazard ratios (HRs) for death in the analysis of treatment effect in prespecified patient subgroups according to baseline characteristics. B, Exploratory post hoc analyses of the number of events, median OS, and Kaplan-Meier curves for OS in prespecified patient subgroups treated with nivolumab. C, Exploratory post hoc analyses for bevacizumab. Subgroups include patients with methylated tumors who did not receive corticosteroids at baseline, patients with methylated tumors who received corticosteroids at baseline, patients with unmethylated tumors who did not receive corticosteroids at baseline, and patients with unmethylated tumors who received corticosteroids at baseline. Symbols indicate censored observations; HRs and CIs were estimated using a Cox proportional hazards model.
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Comment in

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