Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies

This phase 1/2 study evaluated parsaclisib (INCB050465), a next-generation, highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies. Parsaclisib was administered as monotherapy or in combination with itacitinib (a Janus kinase 1 inhibitor) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy at doses ranging from 5 to 45 mg once daily, with expansion doses of 20 and 30 mg once daily. Intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was also explored. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached.

The most common nonhematologic treatment-emergent adverse events (TEAEs) included diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs affecting more than two patients included diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Elevations in aspartate and alanine transaminase levels were primarily grade 1, except for one grade 3 event each, both linked to sepsis. Two patients experienced three fatal TEAEs unrelated to parsaclisib (respiratory failure; respiratory failure and sepsis).

In non-Hodgkin lymphoma (NHL), parsaclisib monotherapy demonstrated promising efficacy, with objective response rates of 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma. Notably, 93% of responses were observed at the first assessment, approximately 9 weeks into treatment. These findings highlight parsaclisib’s antitumor activity in relapsed or refractory B-cell NHL and its potential to improve long-term patient outcomes. Phase 2 studies focusing on specific relapsed or refractory B-cell NHL subtypes are currently underway.