MPN-127: Add-On Parsaclisib (a PI3K5 Inhibitor) in Patients with Myelofibrosis and Suboptimal Response to Ruxolitinib: Interim Analysis from a Phase 2 Study

Context: Ruxolitinib is highly effective in myelofibrosis (MF), improving symptoms, reducing spleen size, and prolonging survival. However, suboptimal response may occur, potentially due to persistent PI3K/AKT pathway activation despite continued JAK inhibition. Objective: This phase 2 study (NCT02718300) evaluated optimal dosing, efficacy, and safety of add-on parsaclisib (INCB050465), a potent and highly selective next-generation PI3Kδ inhibitor, in patients with MF with a suboptimal response to ruxolitinib. Design: Patients had primary or secondary MF, ECOG performance status ≤2, and suboptimal response after ≥6 months of ruxolitinib (5–25 mg twice daily; stable dose ≥8 weeks). Patients remained on their stable ruxolitinib dose and were randomized to receive add-on parsaclisib 10 or 20 mg once daily (QD) for 8 weeks and the same dose once weekly (QW) thereafter (QD/QW group) or parsaclisib 5 or 20 mg QD for 8 weeks and 5 mg QD thereafter (all QD group). The primary endpoint was change in spleen volume from baseline to week 12. Results: At data cutoff (Aug 27, 2020) for this interim analysis, 32 patients had received parsaclisib QD/QW and 35 received parsaclisib all QD. Median percentage change in spleen volume at week 12 was –1.9 (n=29) in QD/QW and –13.0 (n=27) in QD and at week 24 was –3.5 (n=23) and –21.8 (n=17), respectively. Median percentage change in Myelofibrosis-Symptoms Assessment Form Total Symptom Score at week 12 was –14.0 (n=21) in QD/QW and –37.4 (n=17) in QD. Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. New-onset grade 3 and 4 thrombocytopenia were each observed in 6/32 (19%) patients in QD/QW and in 9/35 (26%) and 1/35 (3%) patients in QD, respectively. TEAEs of special interest included grade ≥2 diarrhea (n=4) and grade ≥2 rash (n=1) (all QD/QW). No colitis was reported. TEAEs led to parsaclisib discontinuation in 7/32 patients in QD/QW and 3/35 patients in QD and ruxolitinib discontinuation in 2/32 and 1/35 patients, respectively. Conclusions: Add-on parsaclisib showed preliminary efficacy in patients with MF experiencing suboptimal response to ruxolitinib; QD dosing appeared more efficacious than QD/QW dosing. Combination therapy was generally well tolerated with limited grade 3/4 AEs and TEAE-related discontinuations.