Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143

Abstract

Background: Immunotherapies have demonstrated efficacy across a diverse set of tumors supporting further evaluation in glioblastoma. The objective of this study was to evaluate the safety/tolerability and describe immune-mediated effects of nivolumab ± ipilimumab in patients with recurrent glioblastoma. Exploratory efficacy outcomes are also reported.

Methods: Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3). An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm.

Results: Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10; NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for ≥12 weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death ligand-1 expression ≥1%. Immune-mediated effects mimicking radiographic progression occurred in 2 patients.

Conclusions: Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma.

Fig. 1

Trial profile. ^aPatient died due to a stroke 39 days after the last dose of study treatment. ^bOne patient did not have a measurable target lesion at baseline and therefore was not evaluable for response; this patient was evaluable for PFS and OS.

Fig. 2

Kaplan–Meier estimates of (A) PFS and (B) OS for patients in the NIVO3, NIVO1+IPI3, and NIVO3+IPI1 treatment arms. Closed circles indicate patient censoring. Abbreviations: NE = not estimable.

Fig. 3

A patient case depicting immune-mediated effects of therapy is presented. (A) MRI scans from a 67-year-old patient treated with NIVO3 who had suspected disease progression, with an increase in lesion size from 12 mm at baseline (left) to 40 mm at day 73 (right). MRI scans were conducted using the same parameters for each scan. (B) Resected tumor at day 81 stained with hematoxylin and eosin indicating immune-mediated changes in lesion size consistent with large aggregates of immune cells (right) and extensive tumor necrosis (left). Scale bar denotes 100 μm. (C) Immunohistochemistry of resected tumor specimens depicts infiltrating immune cell aggregates, T cells, and macrophages. Scale bar denotes 50 μm. ^a12-mm temporal lobe lesion; no corticosteroid treatment. ^b40-mm temporal lobe lesion; patient received concomitant methylprednisolone 16 mg/day.