Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

Abstract

Summary The B‐cell receptor and the phosphatidylinositol 3‐kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B‐cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP‐196) and ACP‐319 (AMG‐319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre‐clinical models. The two compounds showed activity in activated B‐cell‐like diffuse large B‐cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP‐319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on‐going current trials with acalabrutinib and ACP‐319 as single agents and provide the basis for the investigation of their combination as well.

A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies

“…Preclinical data suggest a need to cover the pathway for the entire duration of the dosing interval [34,35] to deliver efficacy in models of DLBCL. The data from this clinical trial assessing the combination of acalabrutinib and vistusertib suggest that greater target occupancy of the mTOR pathway is required to improve clinical responses.…”

Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma?

“…Preclinical studies indicate that a number of combinations with PI3K inhibitors show synergistic benefits in the B-cell lymphoma setting, including: idelalisib with obinutuzumab, roflumilast, bortezomib, tazemetostat, or pixantrone [55][56][57][58][59] ; copanlisib with ibrutinib (in certain situations) or venetoclax [60][61][62] ; duvelisib with ibrutinib, everolimus, or venetoclax 63 ; J o u r n a l P r e -p r o o f umbralisib with carfilzomib 64 ; ACP-319 with acalabrutinib 65 ; and dactolisib (BEZ235), a dual PI3K/mTOR inhibitor, with venetoclax, lenalidomide or oridonin. [66][67][68] In the clinical setting, a phase 1 combination study with idelalisib, lenalidomide, and rituximab in patients with relapsed indolent lymphoma, and a phase 2 study of idelalisib plus entospletinib in patients with relapsed or refractory CLL or NHL revealed unexpected serious toxicities leading to early terminations.…”

PI3K/Akt Pathway: The Indestructible Role of a Vintage Target as a Support to the Most Recent Immunotherapeutic Approaches

“…The Bruton tyrosine kinase (BTK) inhibitor ibrutinib was originally developed for treatment of chronic lymphocytic lymphoma (CLL). Both BTK and PI3K pathways are activated by the B cell receptor in CLL, and co-inhibition of BTK and PI3K delta (idelalisib) in preclinical model of aggressive lymphomas is reported to significantly improve the efficacy [24]. Ibrutinib has recently been shown to improve T cell function in CLL, resulting in the expansion of memory T cells, TH1 polarization reducing expression of inhibitory receptors, and improved immune synapse formation between T cells and CLL cells [25,26].…”