Utomilumab in Patients With Immune Checkpoint Inhibitor-Refractory Melanoma and Non-Small-Cell Lung Cancer

Section Head: Clinical/translational cancer immunotherapy Background: The goal of this study was to estimate the objective response rate for utomilumab in adults with immune checkpoint inhibitor (ICI)-refractory melanoma and non–small-cell lung cancer (NSCLC). Methods: Utomilumab was dosed intravenously every 4 weeks (Q4W) and adverse events (AEs) monitored. Tumor responses by RECIST1.1 were assessed by baseline and on-treatment scans. Tumor biopsies were collected for detection of programmed cell death ligand 1, CD8, 4-1BB, perforin, and granzyme B, and gene expression analyzed by next-generation sequencing. CD8+ T cells from healthy donors were stimulated with anti-CD3 ± utomilumab and compared with control. Results: Patients with melanoma (n=43) and NSCLC (n=20) received utomilumab 0.24 mg/kg (n=36), 1.2 mg/kg (n=26), or 10 mg/kg (n=1). Treatment-emergent AEs (TEAEs) occurred in 55 (87.3%) patients and serious TEAEs in 18 (28.6%). Five (7.9%) patients discontinued owing to TEAEs. Thirty-two (50.8%) patients experienced treatment-related AEs, mostly grade 1–2. Objective response rate: 2.3% in patients with melanoma; no confirmed responses for patients with NSCLC. Ten patients each with melanoma (23.3%) or NSCLC (50%) had stable disease; respective median (95% confidence interval, CI) progression-free survival was 1.8 (1.7–1.9) and 3.6 (1.6–6.5) months. Utomilumab exposure increased with dose. The incidences of antidrug and neutralizing antibodies were 46.3% and 19.4%, respectively. Efficacy was associated with immune-active tumor microenvironments, and pharmacodynamic activity appeared to be blunted at higher doses. Conclusions: Utomilumab was well tolerated, but antitumor activity was low in patients who previously progressed on ICIs. The potential of 4-1BB agonists requires additional study to optimize efficacy while maintaining the tolerable safety profile.