Copanlisib, a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against α and δ isoforms, shows immune stimulating effects and anti-tumor activity in combination with immune checkpoint blockers in tumor models. Here we explore tumor PI3K signaling and the effects of copanlisib on immune and tumor microenvironment modulation in subjects with NHL and solid tumors (ST) in a phase I pharmacodynamic study (NCT02155582).
Patients received 0.4 or 0.8 mg/kg (equivalent to a flat dose of 60 mg) copanlisib on an intermittent schedule (QW, IV, 3 wks on/1 wk off). Tumor biopsies were performed at baseline and Day 15. Tumor PI3K isoforms, PTEN, and CD3, CD4 and CD8 tumor infiltrating lymphocytes (TILs) were assessed by IHC. Plasma protein markers were measured using multiplexed immunoassay. Tumor and lymphoma responses were based on RECIST 1.1 and modified Cheson 2007 criteria, respectively.
A total of 61 patients were treated: 33 NHL (20 at 0.4 mg/kg and 13 at 0.8 mg/kg) and 28 ST (14 at 0.4 mg/kg and 14 at 0.8 mg/kg). Among patients treated at 0.8 mg/kg, 2 had CR (PTCL and DLBCL) and 5 had PR (MCL, FL, 2 DLBCL, and endometrial adenocarcinoma); 1 additional PR (DLBCL) occurred at 0.4 mg/kg. Tumor PI3K α was detected in most NHL (18/19) and ST (22/25) samples with comparable intensity. PI3K δ was predominantly present in NHL (18/19). PI3K ß and γ were present in a subset of NHL and ST. PTEN loss was more frequent in ST than NHL. CD3, CD4 and CD8 TIL numbers were higher in NHL than in ST. At 0.8 mg/kg copanlisib decreased tumor pAKT and pS6 in both NHL and ST, and reduced CD4 TILs in NHL (mean -81%, n = 7), with little effect on CD8 TILs in both NHL and ST. In plasma, copanlisib decreased cytokine/chemokines (e.g. CCL2, CCL5, CCL17), and factors associated with macrophages (e.g. CD163, CCL4, CCL22) and Treg cells (IL-2Ra). High baseline levels of CD27 and IL2Ra were associated with tumor reduction in NHL (p < 0.05, unadjusted).
The high prevalence of the PI3K isoforms – especially α in both NHL and ST and δ in NHL – is consistent with a role for PI3K signaling in immune suppression. The immune modulation profile for copanlisib supports combination studies with immunotherapy.
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I. Genvresse, K. Koechert, G. Cisternas, C. Granvil, C. Pena, L. Liu: Employee: Bayer. All other authors have declared no conflicts of interest.