Safety and Efficacy of Bromodomain and Extra-Terminal Inhibitor INCB057643 in Patients with Relapsed or Refractory Myelofibrosis and Other Advanced Myeloid Neoplasms: A Phase 1 Study

Introduction: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of hematologic malignancies, including myelofibrosis (MF). In a previous phase 1/2 clinical trial, INCB057643 (an oral, small-molecule BET inhibitor) evaluated as monotherapy or combination (combo) with the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib (RUX) showed favorable tolerability and encouraging clinical activity in patients (pts) with advanced MF.

Methods: This ongoing phase 1, open-label 3+3 dose-escalation/expansion study (NCT04279847) is evaluating INCB057643 as monotherapy (part 1; 4 mg→12 mg once daily [qd]) in adults with relapsed/refractory MF, essential thrombocythemia (ET), myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes, or as combo therapy (part 2; 4 mg qd→part 1 maximum tolerated dose) with RUX in adults with MF who have suboptimal response to RUX. Primary endpoints are safety/tolerability, including dose-limiting toxicities (DLTs). Secondary endpoints include spleen volume (SV) response (≥35% reduction from baseline [BL] in SV [SVR35] at Week 24), symptom response (≥50% reduction from BL in MPN-Symptom Assessment Form total symptom score [TSS50] at Week 24), and anemia response (hemoglobin increase ≥1.5 g/dL from BL [if transfusion independent at BL] or achieving transfusion independence [if dependent at BL] for ≥12 weeks).

Results: Among pts treated with ≥1 dose of INCB057643 as of March 29, 2024, 18 were treated in part 1 monotherapy dose escalation (median [range] age, 71 [50-79] years), 10 in part 1 monotherapy dose expansion (68 [50-79] years), and 16 in part 2 combo therapy dose escalation (71 [50-76] years; median [range] RUX dose, 22.4 [10.0-47.2] mg/day). Overall, 37 (84.1%) pts had MF, 5 (11.4%) had MDS or MDS/MPN, and 2 (4.5%) had ET. Median (range) duration of INCB057643 exposure was 195.5 (15-654) days (d) in the monotherapy dose-escalation cohort, 139.0 (14-183) d in the monotherapy dose-expansion cohort, and 194.0 (85-402) d in the combo therapy dose-escalation cohort.

The most common treatment-emergent adverse events (TEAEs, >25.0%) overall were thrombocytopenia (59.1%), nausea (29.5%), and anemia (27.3%). Grade ≥3 TEAEs occurred in 61.4% overall, with thrombocytopenia or platelet count decrease (36.4%) and anemia (20.5%) the most common. Serious TEAEs occurred in 25.0% overall. There were 2 treatment-related serious TEAEs, 6 TEAEs leading to discontinuation, and no treatment-related fatal events. Two DLTs occurred with monotherapy (12 mg, thrombocytopenia, hyperbilirubinemia) and 1 with combo therapy (6 mg, thrombocytopenia). One pt with MDS/MPN experienced acute myeloid leukemia transformation. No clear/consistent clinically significant cardiotoxicity signals were identified.

Among evaluable monotherapy MF pts, Week 24 SVR35 was achieved by 3/16 pts treated with any dose (3/7 receiving ≥10 mg); improvements in SV at any time during the treatment period were observed in 13/19 pts treated with any dose. Among evaluable pts receiving combo therapy, Week 24 SVR35 was achieved by 3/12 pts treated with any combo dose; improvements in SV at any time during the treatment period were observed in 13/16 treated with any combo dose.

Of the evaluable pts receiving monotherapy, Week 24 TSS50 was achieved by 5/14 pts treated with any dose (5/7 receiving ≥10 mg); of 19 pts treated at any dose, 12 achieved best response of TSS50 during the treatment period. Among evaluable pts receiving combo therapy, Week 24 TSS50 was achieved by 6/11 pts treated with any combo dose; of 15 pts treated at any dose, 10 achieved best response of TSS50 during the treatment period.

Among 19 and 14 evaluable pts receiving monotherapy or combo therapy who were not transfusion dependent at BL, 3 each had anemia response. Lastly, 2/6 evaluable pts who were transfusion dependent at BL achieved transfusion independence (both received monotherapy).

Conclusions: Treatment with INCB057643 monotherapy or in combo with RUX was generally well tolerated, with no treatment-related fatal events. Improvements in anemia, spleen size, and symptom burden were observed in pts receiving monotherapy and combo therapy. Dose expansion is ongoing for 6 mg and 10 mg monotherapy; ongoing dose escalation for combo therapy is expected to be completed, with data presentation at ASH 2024.

Watts:Incyte: Research Funding; Rafael Pharma: Consultancy; Reven Pharma: Consultancy; Daiichi Sankyo: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Systems Key: Research Funding; Takeda: Research Funding; Celgene/BMS: Consultancy; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Other: safety monitoring or advisory boards, Research Funding. Hunter:GSK: Consultancy, Honoraria; PharmaEssentia: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Sobi​ (formerly CTI biopharma): Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Cogent Biosciences: Research Funding; Ascentage Pharma: Research Funding; Syntrix Biosystems: Research Funding; Novartis: Research Funding; PharmaEssentia: Research Funding. Vannuchhi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphans Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Gupta:Incyte: Consultancy, Other: Participation on a data safety or advisory board; Pfizer: Consultancy, Other: Participation on a data safety or advisory board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Other: support for attending meetings and/or travel; BMS/Celgene: Consultancy, Other: Participation on a data safety or advisory board; Constellation: Consultancy; CTI Biopharma: Consultancy, Other: Participation on a data safety or advisory board; Daiichi Sankyo: Consultancy, Other: Participation on a data safety or advisory board; Sierra Oncology: Consultancy, Other: Participation on a data safety or advisory board; Novartis: Consultancy; Sumitomo Pharm: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Tantravahi:Morphosys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria, Research Funding; Partnership for Health Analytic Research LLC: Consultancy, Honoraria; CTI Biopharma: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Iurlo:BMS: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; AOP: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. McMahon:Incyte: Research Funding; GSK: Consultancy; PharmaEssentia: Consultancy. Palandri:Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria; Constellation-Morphosys: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Telios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI: Consultancy, Honoraria; AOP: Consultancy, Honoraria; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yuda:AbbVie: Research Funding; Daiichi Sankyo: Research Funding; Chugai: Research Funding; Genmab: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Takeda: Research Funding; BMS: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Sumitomo: Research Funding; MSD: Research Funding; Mitsubishi Tanabe: Research Funding. Searle:AbbVie: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Research Funding; Beigene: Honoraria; Nurix: Honoraria; Jazz: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; DarkBlue Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Halpern:Jazz: Research Funding; Gilead: Research Funding; Bayer: Research Funding; Karyopharm Therapeutics: Research Funding; Imago Biosciences: Research Funding; Incyte Corporation: Research Funding; Agios: Consultancy; Disc Medicine: Research Funding; AbbVie: Consultancy; Notable Lab: Consultancy. Ayala:Astellas: Speakers Bureau; Incyte: Consultancy; BMS: Speakers Bureau; Altum Sequencing: Current equity holder in private company; Novartis: Consultancy, Speakers Bureau. Tomita:Chugai Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Otsuka Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Shionogi: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Taiho Pharmaceutical: Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Teijin: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Nihon Pharmaceutical: Research Funding; Pfizer Japan: Research Funding; Mochida Pharmaceutical: Research Funding; Yakult Honsha: Research Funding; Perseus Proteomics: Research Funding; AstraZeneca: Honoraria; AbbVie GK: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; Bristol-Myers Squibb: Honoraria; SymBio Pharmaceutical: Honoraria. Xicoy:BMS: Honoraria. Bose:BMS: Honoraria, Research Funding; Cogent: Honoraria, Research Funding; CTI Biopharma Corp: Honoraria, Research Funding; Astellas: Research Funding; Telios: Research Funding; PharmaEssentia: Honoraria; Kartos: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Ionis Pharmaceuticals: Research Funding; Novartis: Honoraria; AbbVie: Honoraria; Blueprint: Honoraria, Research Funding; GSK: Honoraria; Disc Medicine: Research Funding; Karyopharm: Honoraria; MorphSys: Honoraria, Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Reeves:Incyte: Honoraria; BMS: Honoraria; PharmaEssentia: Honoraria. Chen:Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. Burke:Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. Zhou:Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. Zheng:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Vachhani:Amgen: Consultancy, Research Funding; GenenTech: Consultancy; MorphoSys: Consultancy; Takeda: Research Funding; GlaxoSmith Kline: Consultancy; Kartos Therapeutics: Research Funding; Pfizer: Consultancy; Abbvie: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Daiichi Sankyo: Consultancy; Gilead/Forty Seven: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma Corp (now Sobi): Consultancy, Research Funding; Stemline: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Blueprint Medicines: Consultancy, Research Funding; Cogent Biosciences: Consultancy.

INCB057643 is a small-molecule oral BET inhibitor being evaluated in myelofibrosis and other hematologic malignancies