OS10.3 Randomized Phase 3 Study Evaluating the Efficacy and Safety of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: CheckMate 143

Abstract

Abstracts iii21NEURO-ONCOLOGY • MAY 2017 characterized, potential paracrine effects influencing antitumor immunity remain enigmatic. However, they are important to decipher, as immunotherapies targeting IDH1-mutant gliomas are emerging. AIM: This study aimed at characterizing a potential cell-specific modulatory role of the oncometabolite R-2-HG in shaping the immune microenvironment of IDH1-mutant gliomas. METHODS AND RESULTS: By means of expression dataset analyses, syngeneic murine tumor models and human glioma tissue, as well as a novel astrocyte-specific IDH1R132H-knock in model, we demonstrate that R-2-HG impairs endogenous and IDH1(R132H)-specific antitumor T cell immunity. This is underlined by functional and transcriptomic analyses of myeloid cells indicating a R-2-HG-driven induction of tolerogenicity and compromised antigen presentation. Metabolomic profiling was complemented by mitochondrial respiration assays, calcium measurements and pathway analyses in primary human and mouse immune cells to delineate key molecular mechanisms by which tumor-derived R-2-HG corrupts the glioma immunoenvironment. The functional relevance of R-2-HG-mediated impairment of antitumor immunity was demonstrated in vivo and potential pharmacological strategies abrogating its effects were assessed. CONCLU-SION: Glioma-derived R-2-HG impairs antitumor immunity by affecting both infiltrating T-cells and the associated myeloid compartment, thus contributing to tumorigenesis and resistance to therapy. Immunotherapeutic strategies against IDH-mutant gliomas may benefit from approaches to prevent excess R-2-HG production or its uptake by immune cells. BACKGROUND: Despite available treatment options for patients (pts) with recurrent glioblastoma (GBM), < 5% of pts survive 5 years beyond initial diagnosis, and no single-agent therapy has demonstrated a survival benefit in the second-line setting, including bevacizumab (bev), which is approved for the treatment of recurrent disease. Nivolumab (nivo), a fully human IgG4 monoclonal antibody that inhibits the programmed death 1 receptor, has provided clinical benefit in multiple cancer types. In cohort 2 of the open-label, phase 3 CheckMate 143 study (NCT02017717), the efficacy and safety of nivo was compared with that of bev in pts with GBM experiencing their first recurrence after prior radiotherapy (RT) and temozolomide (TMZ). METHODS: Pts with no prior VEGF therapy were randomized 1:1 to receive nivo 3 mg/kg Q2W or bev 10 mg/kg Q2W until confirmed disease progression; pts were stratified by the presence/absence of measurable disease. The primary endpoint was overall survival (OS); secondary endpoints were 12-mo OS rate and investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per Response Assessment in Neuro-Oncology criteria. RESULTS: At the time of final analyses (Jan 20, 2017), 369 pts were randomized to the nivo (n = 184) or bev (n = 185) treatment arms; of these pts, 182 received nivo and 165 received bev. At baseline, most pts in the nivo (...

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…The ECs lining HEVs are known to express ICAM1 and VCAM1, and thus facilitate homing and migration of immune cells to tumours 98 . These findings are of particular importance because anti-PD-1 treatment alone conferred a survival benefit for only a small fraction of patients with glioblastoma 99 and failed to improve the outcomes of patients with this disease in a randomized phase III trial 100 . Anti-PD-1 antibodies have also been shown to provide limited therapeutic benefit in a less immunogenic breast tumour model (MMTV-PyMT) 16 .…”

IDH mutational status and the immune system in gliomas: a tale of two tumors?

“…The results should also be considered in the context of the 2017 randomized CheckMate-143 Phase 3 trial (NCT02017717) for GBM, which unfortunately failed to demonstrate improved survival in patients treated with the PD-1 inhibitor nivolumab versus bevacizumab (2). Additional studies will be needed to investigate why this therapeutic approach, which has had proven benefit in several other tumor types, is meeting with less favorable efficacy for patients with GBM.…”

Improving diagnosis and management of primary brain tumors

“…Important efficacy in some systemic cancers (melanoma, nonsmall cell lung cancer), as well as the finding of expression of PD-L1 in gliomas, prompted their evaluation in GBM. On the contrary, results recently reported in the phase III study of recurrent GBM (CheckMate 143) did not show a benefit of Nivolumab as compared with Bevacizumab monotherapy [10]. In newly diagnosed GBM (with or without O(6)-Methylguanine-DNA methyltransferase promoter methylation), two randomized trials evaluating the addition of Nivolumab to conventional treatment are ongoing.…”