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

Abstract

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 CD79B mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, n = 19; GCB DLBCL, n = 30; unclassifiable, n = 3; missing, n = 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 CD79B mutations (wild type, n = 45; mutant, n = 9; missing, n = 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 BCL2 (53.7%) and MLL2 (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.

Phase 2 study of parsaclisib (INCB050465), a highly selective, next-generation PI3Kδ inhibitor, in relapsed or refractory diffuse large B-cell lymphoma (CITADEL-202)

“…The efficacy data reported herein are consistent with the findings of a phase 2 study of the pan-PI3K inhibitor, copanlisib (with preferential activity against the a and d isoforms), conducted in patients with relapsed or refractory DLBCL [22]. The ORR reported herein is 25.5% (N ¼ 55); the ORRs observed with copanlisib in the full cohort and per-protocol analysis sets were 19.4% (N ¼ 67) and 25.0% (N ¼ 40), respectively.…”

Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma?

“…[35][36][37]42 In studies with pan-PI3K inhibitors in patients with DLBCL (buparlisib, voxtalisib, copanlisib), reported ORR ranged from 5% to 19% (CR 0-7%), with median DOR of 2.2 months to 4.3 months and median PFS from 1.8 months to 7.1 months. 40,41,43 In studies with pan-PI3K inhibitors reporting outcomes in patients with MCL (buparlisib, voxtalisib), ORR J o u r n a l P r e -p r o o f ranged from 12% to 23% (CR 5-7%), and median PFS ranged from 2.0 months to 11.3 months. 40,41 There are currently no published manuscripts or ongoing clinical trials of duvelisib in aggressive B-cell NHL.…”

Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies

“…These features are sometimes cell type specific and may account in part for the different activity of the various BCR inhibitors in different B cell malignancies. For example, in addition to PI3Kδ, the related kinase PI3Kα has been implicated in signaling through the BCR in Activated B cell-like (ABC) DLBCL [ 16 , 17 ], providing a potential explanation for the greater clinical activity of the dual PI3Kα/δ inhibitor copanlisib compared to the PI3Kδ inhibitor idelalisib in patients with DLBCL [ 18 , 19 ]. Similarly, a recent study from our group showed that two pathways downstream of the BCR are involved in inactivation of the kinase GSK3 in chronic lymphocytic leukemia (CLL) cells, resulting in a different capacity of SYK, BTK, and PI3Kδ inhibitors to reduce the expression of the antiapoptotic protein Mcl-1, which is negatively regulated by GSK3 [ 20 ].…”

“…Copanlisib has also shown promising results in phase 2 trials of patients with R/R lymphoma, resulting in ORRs of 75% in SLL, of 59% in FL, of 70% in MZL, and of 64% in MCL [ 195 , 211 ]. More recently, copanlisib was tested in a phase 2 trial of patients with relapsed/refractory DLBCL, demonstrating ORRs of 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively [ 19 ].…”

“…Most of these data were obtained with the BTK inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib, which induce clinical responses in the vast majority of patients with CLL, MCL, and WM and in approximately half of the patients with FL and MZL ( Table 1 ). In addition, approximately one third of patients with ABC DLBCL initially respond to treatment with ibrutinib or the PI3Kα/δ inhibitor copanlisib, whereas responses are infrequent in patients with GCB DLBCL [ 19 , 105 ]. No clinical studies have been reported yet with BCR inhibitors in BL except for one case report [ 223 ].…”