PHASE 2A STUDY OF THE PHOSPHATIDYLINOSITOL-3-KINASE (PI3K) INHIBITOR COPANLISIB IN PATIENTS WITH RELAPSED/REFRACTORY, INDOLENT OR AGGRESSIVE LYMPHOMA. P318, 2016: Non-Hodgkin & Hodgkin lymphoma - Novel agents

BackgroundCopanlisib (BAY 80-6946) is a potent and selective pan-class I PI3K inhibitor with preferential activity against the δ- and α-isoforms. In an expansion cohort of a phase I study, promising activity was seen in patients with non-Hodgkin lymphoma (NHL), with 6 of 6 responses in follicular lymphoma (FL) patients [2 of which were durable (>3 years) complete responses per post-hoc radiologic review (Patnaik et al, submitted)] and 1 of 3 diffuse large B-cell lymphoma (DLBCL) patients achieving a partial response (PR).AimsWe therefore investigated the efficacy and safety of copanlisib in subjects with relapsed/refractory indolent or aggressive NHL or chronic lymphocytic leukemia (CLL). (NCT01660451)MethodsPatients with histologically confirmed indolent or aggressive lymphoma or CLL, relapsed or refractory to ≥2 prior lines of treatment were enrolled. Copanlisib (0.8 mg/kg) was administered intravenously on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as assessed by independent radiology review according to the response criteria for lymphoma (Cheson et al, JCO 1999) or the guidelines for diagnosis and treatment of CLL (Hallek et al, Blood 2008). Secondary endpoints included progression-free survival (PFS) and duration of response (DOR), safety and tolerability.ResultsA total of 20 patients with indolent NHL (iNHL; 16 FL, 3 marginal zone lymphoma, 1 small lymphocytic lymphoma), 13 CLL and 48 with aggressive NHL [15 DLBCL, 14 peripheral T-cell lymphoma, 11 mantle cell lymphoma (MCL), 6 transformed, 1 mediastinal, and 1 Grade 3b FL] were treated; median age 67 years; 53% male; median 3 (range 1-10) number of previous lines of treatment and prior rituximab in 80% of patients. At the time of analysis, the ORR was 47% (90% CI 27-68) and stable disease (SD) was 47% (CI 27-68) in patients with iNHL, 38% (CI 17-65) and 46% (CI 22-71) in CLL, and 26% (CI 16-39) and 17% (CI 9-29) in aggressive NHL, respectively. For patients with FL, the ORR was 40% (CI 19-64), with 1 CR, 2 uCRs, and 3 PRs; SD in 53% (CI 30-76). The ORR in the MCL patients was 64% (CI 35-86; 2 uCR and 5 PRs). The median DOR was 390 days in the indolent group and 166 days in the aggressive group. The most common treatment-related adverse events (AEs) of all grades (G) were hyperglycemia (59%), hypertension (54%), diarrhea (33%), and fatigue (28%). G3-4 treatment-related AEs occurring in >10% of patients included hypertension (39%) and hyperglycemia (25%). Treatment-related AEs leading to dose reduction were observed in 4%, interruption in 36%, interruption and reduction in 7%, or permanent discontinuation in 17% of patients, respectively. There were 4 treatment-related grade 5 events: meningitis, respiratory failure and 2 lung infections.ConclusionCopanlisib is active as a single agent in heavily pretreated patients with a variety of relapsed/refractory indolent or aggressive lymphoma subtypes, with promising CR activity in FL and MCL. Copanlisib exhibited a manageable toxicity profile. Final results of survival rates will be presented. Based on these encouraging results, phase II studies in patients with FL, MCL, and DLBCL are ongoing.