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

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.

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.

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.