Abstract
A next-generation PI3Kδ inhibitor achieved objective responses and long-term tolerability in NHL.
Major finding: A next-generation PI3Kδ inhibitor achieved objective responses and long-term tolerability in NHL.
Concept: Parsaclisib potently and selectively inhibits PI3Kδ without inducing severe hepatoxicity.
Impact: Parsaclisib alone or with itacitinib or chemotherapy is safe in patients with refractory NHL.
Constitutive signaling of B-cell receptors (BCR) plays a critical role in the pathogenesis of many B-cell malignancies and leads to downstream activation of phosphatidylinositol 3 kinases (PI3K). The PI3Kδ isoform functions as a critical node in signaling networks that regulate B-cell growth and survival, and its aberrant activation is a key event in the malignant transformation of B cells. Many patients with relapsed non-Hodgkin lymphoma (NHL) suffer from poor prognosis, and although PI3K inhibitors have shown promise in treating patients with relapsed or refractory NHL, high hepatoxicity has limited their use in the clinic. To evaluate the safety and efficacy of parsaclisib, a structurally distinct and highly potent next-generation PI3Kδ inhibitor predicted to reduce off-target hepatotoxicity, Forero-Torres and colleagues conducted a phase I/II clinical trial in 72 patients with relapsed or refractory B-cell malignancies in which patients received parsaclisib alone or in combination with either the Janus kinase I inhibitor itacitinib or an immunochemotherapy combination comprised of rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE). Primary endpoints were safety and tolerability of parsaclisib monotherapy, parsaclisib plus itacitinib, or parsaclisib plus R-ICE, and secondary endpoints were efficacy and pharmacokinetics. Parsaclisib monotherapy resulted in no dose-limiting toxicities, and the maximum tolerated dose was not reached. Adverse events to either monotherapy or combination therapies included mild diarrhea/colitis, nausea, fatigue, and rash, and serious adverse events included diarrhea/colitis, pyrexia, hypotension, and sepsis. Two patients experienced fatal adverse events unrelated to parsaclisib. Objective response rates following parsaclisib monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma. Taken together, these data demonstrate that parsaclisib exhibits antitumor activity against B-cell malignancies and is well tolerated alone or in combination with standard-of-care agents, with no evidence of the severe toxicity associated with first-generation PI3Kδ inhibitors.
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