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

Although outcomes after first-line therapy for patients with indolent or aggressive non-Hodgkin lymphoma (NHL) are continually improving, relapse is still common. Current treatment options for patients with relapsed or refractory disease have limited efficacy, and various targeted therapies are under investigation to help improve outcomes in this patient population. The phosphatidylinositol 3-kinase (PI3K) pathway was identified as being involved in hematologic malignancies, leading to significant research for potential therapeutic agents. This has led to 3 PI3K inhibitors (idelalisib, copanlisib, and duvelisib) being approved for the treatment of patients with relapsed or refractory follicular lymphoma who have received at least 2 prior systemic therapies, with reported response rates of 40% to 59%. With potential class-specific and PI3K isoform-related toxicities that may limit clinical utility, the safety of the approved PI3K inhibitors has been carefully evaluated to weigh the risk/benefit ratio of therapy. Currently, there are no approved PI3K inhibitors for patients with aggressive NHL A number of newer PI3K inhibitors are in clinical development for the treatment of relapsed or refractory NHL, aiming to improve treatment benefit for patients. We discuss a number of attributes that are important to increase the therapeutic potential of newer PI3K inhibitors. More promising results may come from combination trials with these newer PI3K inhibitors, developed to limit toxicities (including long-term adverse events), and other antitumor agents. (C) 2020 The Authors. Published by Elsevier Inc.

Automated summary

Despite improvements in outcomes for patients with non-Hodgkin lymphoma, relapse remains common. Several PI3K inhibitors have been approved for certain types of relapsed or refractory lymphoma, but there are currently no approved PI3K inhibitors for patients with aggressive NHL. Clinical development of newer PI3K inhibitors aims to improve treatment benefit for patients, potentially through combination trials to limit toxicity and enhance efficacy.