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

Abstract

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. 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. 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. 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. 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. 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.