Subgroup Analysis from a Phase 2 Study of the Efficacy and Safety of Parsaclisib, a Selective PI3Kδ Inhibitor, in Combination with Ruxolitinib in Patients with Myelofibrosis (MF)
Authors: Yacoub Abdulraheem , Borate Uma , Rampal Raajit , Ali Haris , Wang Eunice S. , Gerds Aaron T. , Hobbs Gabriela , Kremyanskaya Marina , Winton Elliott , O'Connell Casey , Goel Swati , Oh Stephen , Schiller Gary J. , Assad Albert , Erickson-Viitanen Sue , Zhou Feng , Daver Naval 
Published: November 2021

Abstract

Background: Despite the demonstrated efficacy of ruxolitinib (potent and selective Janus kinase [JAK] 1 and JAK2 inhibitor) in patients with MF, inadequate responses or loss of response to ruxolitinib may occur, possibly due to persistent activation of the phosphatidylinositol 3-kinase (PI3K) pathway with chronic ruxolitinib therapy. Parsaclisib (INCB050465) is a potent and highly selective next-generation PI3Kδ inhibitor. We previously demonstrated preliminary efficacy in a phase 2 trial (INCB 50465-201, NCT02718300) of parsaclisib added to stable doses of ruxolitinib for patients with MF who experienced a suboptimal response to ruxolitinib. JAK inhibitors, including ruxolitinib, are associated with thrombocytopenia; therefore, patients with low platelet counts (PC) are traditionally more difficult to treat. We present the efficacy and safety subgroup analysis of this ongoing study in patients grouped by baseline PC.
Methods: Eligible adults had primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF with suboptimal response (palpable spleen &gt;10 cm below left subcostal margin, or palpable splenomegaly 5-10 cm below left subcostal margin and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 each using the Screening Symptom Form) after ≥6 months of ruxolitinib monotherapy (5-25 mg twice daily, stable dose for ≥8 weeks). Patients remained on their last stable ruxolitinib dose and received add-on parsaclisib 10 mg or 20 mg once-daily (QD) for 8 weeks and the same dose once-weekly thereafter (daily to weekly group), or parsaclisib 5 mg or 20 mg QD for 8 weeks and 5 mg QD thereafter (all daily group). For the subgroup analysis, patients were grouped by baseline PC (≥100×10 9/L, higher PC or 50-&lt;100×10 9/L, low PC). Key objectives were to evaluate the impact of baseline PC on spleen volume (SV) and total symptom score (TSS) as assessed by Myelofibrosis-Symptoms Assessment Form (MFSAF) v3.0 daily diary at week 12 and week 24, and safety.
Results: At data cutoff (Aug 27, 2020), 67 patients were enrolled, 21 with low PC and 46 with higher PC. Median age of both groups was 68 years, and median prior duration of ruxolitinib use was 34.7 months for low PC and 14.9 months for higher PC. Patients with low PC had higher baseline symptoms (MFSAF-TSS median [range], 21.4 [0.6-47]) than patients with higher PC (MFSAF-TSS, 10 [0-43]).
Responder analysis for SV reduction (SVR) is summarized in Table 1. At week 12, slightly more patients with low PC achieved ≥10% SVR compared with patients with higher PC, whereas, at week 24, responses were similar between the 2 groups. Of patients with at least 10% SVR at week 24, 4 of 6 with low PC and 9 of 13 with higher PC were receiving all daily dose regimens. Median (range) percentage change in MFSAF-TSS was −20.5 (−56.6 to +17.1) and −22.2 (−100 to +500) at week 12, and −26.1 (−54.7 to +2.4) and −23.1 (−91.3 to +222.5) at week 24, for patients with low PC and higher PC, respectively.
Overall for both baseline platelet groups, nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. Most common (≥20%) TEAEs were dyspnea (33%), falls (33%), peripheral edema (29%), and nasal congestion (24%) for patients in the low PC group, and diarrhea (28%), nausea (24%), abdominal pain (24%), cough (20%), and fatigue (20%) for patients with higher PC. Interruption of parsaclisib due to thrombocytopenia was observed in 9 of the 21 patients (43%) with low PC and 3 of the 46 patients (7%) with higher PC. One patient with low PC had thrombocytopenia leading to ruxolitinib interruption.
Conclusion: Add-on parsaclisib demonstrated promising preliminary efficacy in patients with MF experiencing suboptimal response to ruxolitinib monotherapy. In a subgroup analysis by baseline PC, responses for SV and MFSAF-TSS reduction were similar in both groups, indicating that patients with low PC can also tolerate and benefit from this treatment combination. Phase 3 trials in ruxolitinib-experienced and ruxolitinib-naive patients are underway to further assess the combination of JAK and PI3K inhibitors.
Figure 1 Figure 1.

Disclosures
Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Borate: Takeda: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Jazz Pharma: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Rampal: Blueprint: Consultancy; Jazz Pharmaceuticals: Consultancy; Disc Medicine: Consultancy; Constellation: Research Funding; Stemline: Consultancy, Research Funding; Kartos: Consultancy; BMS/Celgene: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Memorial Sloan Kettering: Current Employment; Incyte: Consultancy, Research Funding; Pharmaessentia: Consultancy. Ali: CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau. Wang: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Rafael Pharmaceuticals: Other: Data safety monitoring committee; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Gerds: CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Constellation: Consultancy; PharmaEssentia Corporation: Consultancy; Novartis: Consultancy. Hobbs: Incyte Corporation: Research Funding; AbbVie.: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Bayer: Research Funding. Kremyanskaya: Chimerix: Research Funding; Constellation: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Bristol Myers Squibb: Research Funding; Astellas: Research Funding; Astex: Research Funding. Winton: Samus Therapeutics: Research Funding; Incyte Corporation: Research Funding; Blueprint Medicines: Research Funding. O'Connell: Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Genentech: Research Funding; Astex Pharmaceuticals: Consultancy, Research Funding; Shionogi: Consultancy. Oh: Novartis: Consultancy; Kartos Therapeutics: Consultancy; Incyte Corporation: Consultancy; Geron: Consultancy; Disc Medicine: Consultancy; CTI BioPharma: Consultancy; Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Abbvie: Consultancy; PharmaEssentia: Consultancy; Sierra Oncology: Consultancy. Schiller: Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Evidera: Consultancy; NCI: Consultancy; UCSD: Research Funding; Eli Lilly: Research Funding; Onyx: Research Funding; UC Davis: Research Funding; Ambit: Research Funding; MedImmune: Research Funding; Bluebird Bio: Research Funding; ASH foundation: Other: Chair-unpaid; Ono-UK: Consultancy, Research Funding; Takeda: Research Funding; Leukemia & Lymphoma Society: Research Funding; Kaiser Permanente: Consultancy; Samus: Research Funding; Boehringer-Ingleheim: Research Funding; Millennium: Research Funding; Ariad: Research Funding; Cellerant: Research Funding; Janssen: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Trovagene: Research Funding; Bio: Research Funding; National Marrow Donor Program: Research Funding; Sellas: Research Funding; Ono: Consultancy; Cyclacel: Research Funding; CTI Biopharma: Research Funding; Tolero: Research Funding; Pharma: Consultancy; AstraZeneca: Consultancy; NIH: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Sangamo: Research Funding; Biomed Valley Discoveries: Research Funding; Incyte: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; Pharmamar: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; PrECOG: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Mateon: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Abbvie: Research Funding; Novartis: Speakers Bureau. Assad: Incyte: Current Employment, Current equity holder in publicly-traded company. Erickson-Viitanen: Incyte: Current Employment, Current equity holder in publicly-traded company. Zhou: Incyte: Current Employment, Current equity holder in publicly-traded company. Daver: Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Novartis: Consultancy; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Syndax: Consultancy; Agios: Consultancy; Dava Oncology (Arog): Consultancy; FATE Therapeutics: Research Funding; Novimmune: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Shattuck Labs: Consultancy; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding.