Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma

<jats:title>Abstract</jats:title><jats:p>Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have adverse outcomes. We evaluated the efficacy and safety of the phosphatidylinositol 3-kinase inhibitor copanlisib in patients with relapsed/refractory DLBCL and assessed the relationship between efficacy and DLBCL cell of origin (COO; activated B-cell like [ABC] and germinal center B-cell like [GCB]) and other biomarkers. The primary endpoint was objective response rate (ORR) in DLBCL COO subgroups (ABC, GCB, and unclassifiable) and by <jats:italic>CD79B</jats:italic> mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, <jats:italic>n</jats:italic> = 19; GCB DLBCL, <jats:italic>n</jats:italic> = 30; unclassifiable, <jats:italic>n</jats:italic> = 3; missing, <jats:italic>n</jats:italic> = 15). The ORR was 19.4%; 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively. ORR was 22.2%/20.0% for patients with/without <jats:italic>CD79B</jats:italic> mutations (wild type, <jats:italic>n</jats:italic> = 45; mutant, <jats:italic>n</jats:italic> = 9; missing, <jats:italic>n</jats:italic> = 13). Overall median progression-free survival and duration of response were 1.8 and 4.3 months, respectively. Adverse events included hypertension (40.3%), diarrhea (37.3%), and hyperglycemia (32.8%). Aberrations were detected in 338 genes, including <jats:italic>BCL2</jats:italic> (53.7%) and <jats:italic>MLL2</jats:italic> (53.7%). A 16-gene signature separating responders from nonresponders was identified. Copanlisib treatment demonstrated a manageable safety profile in patients with relapsed/refractory DLBCL and a numerically higher response rate in ABC vs. GCB DLBCL patients.</jats:p>