Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma

M Dreyling, F Morschhauser, K Bouabdallah, D Bron, D Cunningham, S E Assouline, G Verhoef, K Linton, C Thieblemont, U Vitolo, F Hiemeyer, M Giurescu, J Garcia-Vargas, I Gorbatchevsky, L Liu, K Koechert, C Peña, M Neves, B H Childs, P L Zinzani, M Dreyling, F Morschhauser, K Bouabdallah, D Bron, D Cunningham, S E Assouline, G Verhoef, K Linton, C Thieblemont, U Vitolo, F Hiemeyer, M Giurescu, J Garcia-Vargas, I Gorbatchevsky, L Liu, K Koechert, C Peña, M Neves, B H Childs, P L Zinzani

Abstract

Background: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms.

Patients and methods: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis.

Results: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively; median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression.

Conclusion: Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

Keywords: PI3K inhibitor; copanlisib; malignant lymphoma; treatment.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Percent best change in target lesion size from baseline (investigator assessment) in the indolent (A) and aggressive (B) cohorts with corresponding status of baseline upregulation of PI3K/PTEN pathway gene expression and tumor microenvironment (full analysis set). * indicates NOTCH1 mutation by next-generation sequencing. aUnfavorable tumor microenvironment gene-expression signature was defined as high (greater than the median value) weighted gene-expression scores combining genes expressed in stromal, inflammatory, and immune response pathways. bUpregulation of PI3K/PTEN pathway gene expression was defined as PTEN protein loss (0% of tumor cells stained positive for PTEN by IHC) or low PTEN protein expression (1%–4% of tumor cells stained positive), and/or a high PI3K/BCR gene-expression signature (defined by a weighted gene-expression score greater than the median value). cPositive PTEN protein expression was defined as ≥5% of cells staining positive for PTEN by IHC. dIncludes peripheral T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, and angio-immunoblastic T-cell lymphoma. BCR, B-cell receptor; CR, complete response; GEA, gene-expression analysis; IHC, immunohistochemistry; PD, progressive disease; PR, partial response; SD, stable disease; uCR, unconfirmed complete response.
Figure 2.
Figure 2.
Progression-free survival (full analysis set) (A), duration of response (per protocol set) (B), and overall survival (full analysis set) (C) in patients in the indolent or aggressive cohorts receiving copanlisib.

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