OS07.3 Nivolumab in Combination With Radiotherapy With or Without Temozolomide in Patients With Newly Diagnosed Glioblastoma: Updated Results From CheckMate 143
Authors: A. Omuro, G. Vlahovic, J. Baehring, N. Butowski, D. Reardon, T. Cloughesy, S. Sahebjam, M. Lim, R. Zwirtes, J. Sampson
Journal: Neuro-Oncology (2017)

Background: Patients with glioblastoma (GBM) have a 5-year survival rate of approximately 5%, indicating that novel therapeutic options are critically needed. Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of the programmed death-1 receptor, has provided durable and clinically significant responses in multiple cancer types. In CheckMate 143 (NCT02017717), exploratory cohorts 1c and 1d evaluated the safety and tolerability of nivolumab in combination with radiotherapy (RT) ± temozolomide (TMZ) in patients with newly diagnosed GBM. Methods: In cohort 1c, patients with methylated, unmethylated, or indeterminate MGMT were treated with nivolumab 3 mg/kg every 2 weeks (Q2W) in combination with standard RT and concurrent TMZ (75 mg/m2 daily), followed by adjuvant TMZ (150–200 mg/m2 for 5 days per 28-day cycle for ≥ 6 cycles). I n cohort 1d, patients with unmethylated MGMT received nivolumab 3 mg/kg Q2W with standard RT without TMZ. Patients in both cohorts continued to receive nivolumab 3 mg/kg Q2W until confirmed disease progression or unacceptable toxicity. Results: Enrollment in the study has been completed (N = 110 patients); 57 patients with methylated (19%), unmethylated (68%), or indeterminate (12%) MGMT were treated in cohort 1c and 53 patients with unmethylated (96%) or indeterminate (4%) MGMT were treated in cohort 1d. Treatment discontinuations in cohorts 1c (39%) and 1d (51%) resulted from suspected radiographic progression (1c, 19%; 1d, 43%), patient decision (1c, 9%), study drug toxicity (1c, 5%; 1d, 4%), death (2% each), adverse event (AE) unrelated to study drug (1c, 2%), or unknown cause (2% each). Treatment-related AEs (TRAEs) occurred in 67% (1c) and 70% (1d) of patients, with the most common (≥ 15% in either cohort [1c, 1d]) being fatigue (28%, 26%), headache (21%, 13%), and increased ALT (16%, 9%). Grade 3–4 TRAEs reported in > 2 patients in either cohort (1c, 1d) included increased ALT (5%; 6%) and lipase (2%; 8%). AEs leading to discontinuation in cohort 1c were increased transaminases (5%) and asthenia, fatigue, and hypotension (2% each); in cohort 1d, AEs leading to discontinuation included increased ALT, increased lipase, herpes simplex virus encephalitis, and acute injury (2% each). No treatment-related deaths were reported. Signals of enhanced immune cell infiltration were observed in some patients who had surgery on study for suspected disease progression. Updated efficacy results will be presented. Conclusions: In this first prospective clinical trial of an immune checkpoint inhibitor in patients with newly diagnosed GBM, data suggest that nivolumab combined with RT ± TMZ was well tolerated, with no new safety signals. Rapid accrual in this study supports the feasibility of conducting a trial in patients with newly diagnosed unmethylated MGMT GBM without TMZ. Encouraging results warrant phase 2/3 studies, which have been initiated.