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

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

This randomized clinical trial examines the effect of programmed cell death 1 immune checkpoint inhibition with nivolumab on overall survival for patients with recurrent glioblastoma.

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