CLINICAL OUTCOMES AND MOLECULAR CHARACTERIZATION FROM a PHASE II STUDY OF COPANLISIB IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA

Abstract

Introduction: Relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) patients are characterized by poor prognosis. Copanlisib is a pan‐Class I phosphatidylinositol 3‐kinase (PI3K) inhibitor, with modest single‐agent activity in unselected DLBCL patients. Here we report the treatment effect of copanlisib in relapsed/refractory DLBCL patients with regards to cell of origin (COO) and molecular biomarker profiles (NCT02391116). Methods: Patients with relapsed/refractory DLBCL and >=1 prior lines of therapy were eligible. Copanlisib (60 mg IV infusion) was administered intermittently on days 1, 8 and 15 of a 28‐day cycle. Tumor samples were evaluated for COO, CD79B mutations and >400 genes by next generation sequencing (NGS). The primary endpoint was objective tumor response rate (ORR; per Lugano Classification, 2014) and response by COO and CD79B status. Results: The full‐analysis (FAS) and per‐protocol sets (PPS; >=3 doses, post‐baseline scans and COO/CD79B data) included 67 and 40 patients, respectively. Patients were 58% male, median age 69 (range 25‐93), ECOG status 0/1/2 22%/57%/21%, and heavily pretreated (median prior lines = 3, range 1‐13). In the PPS, COO (and mutant CD79B status) analysis identified 22 GCB DLBCL (2 mutant), 16 ABC DLBCL (6 mutant), and 2 unclassifiable. The ORR in the FAS was 19% (13 of 67). For patients in the PPS, the ORR was 25% (10 of 40), with 5 complete responses (CR) and 5 partial responses (PR); (Figure Presented) stable disease in 12 pts. The ORR was 13.6% with 1 CR in GCB pts and 37.5% with 4 CRs (25%) in ABC patient. Response to copanlisib was 25% in pts with (2/8) and without (8/32) CD79B mutations. Five of 10 ABC DLBCL‐wild‐typeCD79B patients and one GCB DLBCLmutantCD79B responded (ongoing >17 cycles). NGS analysis in 54 patients detected 348 mutations; BCL2 (54% of patients), TP53 (41%), BCL6 (30%), MYC (22%), CD79B (19%)/A (6%), MYD88 (19%), TNFAIP3 (17%), CARD11 (13%), and NFKBIA (9%). Response to copanlisib was not significantly different based on mutation status of BCL2 (ORR 17% [4/24] vs 35% [7/20] for mutant and wild‐type subsets, respectively), BCL6 (ORR 17% [2/12] vs 28% [9/32]), MYC (ORR 13% [1/8] vs 28% [10/36]), and MYD88 (ORR 25% [2/8] vs 25% [9/36]). With a median of 6 cycles (range 1‐29), the most common AEs (% all grade/gr3 + 4) were diarrhea (36/2), nausea (31/2), fatigue (31/3), fever (21/2) and transient hypertension (40/33) and hyperglycemia (34/31). There were 14 grade 5 AEs (none drug‐related). Conclusions: Copanlisib treatment of relapsed/refractory DLBCL patients resulted in encouraging responses, especially in the ABC subtype, with a manageable toxicity. Further study of copanlisib in treatment of DLBCL is warranted.