P1063: EFFICACY AND SAFETY OF PARSACLISIB-RUXOLITINIB COMBINATION THERAPY IN MYELOFIBROSIS PATIENTS WITH LOW VS HIGHER BASELINE PLATELET COUNT: A SUBGROUP ANALYSIS OF DATA FROM A PHASE 2 STUDY

Background: Despite the demonstrated efficacy of ruxolitinib (a potent and selective JAK1 and JAK2 inhibitor), patients with myelofibrosis (MF) often exhibit inadequate or loss of response to chronic ruxolitinib therapy, possibly due to persistent PI3K pathway activation. Parsaclisib (INCB50465) is a potent and highly selective next generation PI3Kδ inhibitor. In the ongoing phase 2 INCB 50465-201 trial (NCT02718300), add on parsaclisib has shown preliminary efficacy in patients with MF who experienced a suboptimal response to ruxolitinib. JAK inhibitors, including ruxolitinib, are associated with thrombocytopenia; therefore, patients with low platelet count (PC) are commonly more difficult to treat. Aims: Here we present a subgroup analysis of efficacy and safety data from the ongoing INCB 50465-201 study by baseline PC. Methods: Eligible adults had primary or secondary MF with suboptimal response (palpable spleen >10 cm below left subcostal margin [LSM]; or palpable spleen 5–10 cm below LSM and active symptoms) after ≥6 months of ruxolitinib monotherapy (5–25 mg BID; stable dose ≥8 weeks). Patients remained on their last stable ruxolitinib dose and received add on parsaclisib (10 or 20 mg QD for 8 weeks; same dose QW thereafter) or parsaclisib (5 or 20 mg QD for 8 weeks; 5 mg QD thereafter). For this analysis, spleen volume (SV), total symptom score (TSS) assessed by Myelofibrosis-Symptoms Assessment Form (MFSAF) v3.0 daily diary, and safety, were evaluated by baseline PC (low PC, 50 to <100×109/L; higher PC, ≥100×109/L). Results: At data cutoff (August 27, 2020), 67 patients were enrolled (low PC, n=21; higher PC, n=46; median age 68 years). Median prior duration of ruxolitinib use was 34.7 months for low PC compared with 14.9 months for higher PC; baseline symptoms were worse for patients with low PC than higher PC (median [range] MFSAF-TSS, 21.4 [0.6–47] vs 10 [0–43]). Table 1 summarizes the responder analysis for SV reduction (SVR) based on baseline PC. At week 12, slightly more patients with low PC achieved ≥10% SVR compared with patients with higher PC (50.0% vs 39.4%), whereas, at week 24, responses were similar between the 2 groups (35.2% vs 37.1%). Of patients with ≥10% SVR at week 24, 4/6 with low PC and 9/13 with higher PC were on all daily dosing regimens. Median (range) percentage change in MFSAF-TSS was −20.5 (−56.6 to +17.1) for patients with lower PC compared with −22.2 (−100 to +500) for patients with higher PC at week 12; and −26.1 (−54.7 to +2.4) compared to −23.1 (−91.3 to +222.5) at week 24, respectively. In both subgroups, nonhematologic treatment-emergent adverse events (TEAEs) were mostly grade 1 or 2. Most common (≥20%) TEAEs were dyspnea (33%), falls (33%), peripheral edema (29%), and nasal congestion (24%) for low PC; diarrhea (28%), nausea (24%), abdominal pain (24%), cough (20%), and fatigue (20%) for higher PC. For patients with low PC compared to higher PC, 9/21 (43%) compared to 3/46 (7%) patients had parsaclisib dose interruption due to thrombocytopenia. One patient with low PC had ruxolitinib interruption due to thrombocytopenia. Image:Summary/Conclusion: Add-on parsaclisib showed efficacy in patients from both low and higher baseline PC groups. Given the acceptable safety profile and efficacy of add-on parsaclisib, MF patients with both low and higher PC may be able to benefit from parsaclisib-ruxolitinib combination therapy. Phase 3 trials in ruxolitinib-treated and ruxolitinib-naive patients are underway to further assess the combination of JAK and PI3K inhibitors.