Background: Janus kinase inhibitors (JAKis) provide symptom improvement and spleen volume reduction in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF). There remains a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival. The COMFORT-1 and -2 studies established JAKi monotherapy as standard-of-care with spleen volume reduction of ≥35% at Week 24 (SVR 35W24) of 42% and SVR 35W48 of 29%, respectively. In combination with the JAKi ruxolitinib, navitoclax, an orally available inhibitor of antiapoptotic B-cell lymphoma 2 proteins (BCL-X L, BCL-2, BCL-W), was shown to have pronounced antitumor activity in patients with MF in the phase 2 REFINE trial (NCT03222609). TRANSFORM-1 is an ongoing, phase 3, double-blind, placebo-controlled, multicenter, international study evaluating the safety and efficacy of navitoclax plus ruxolitinib (NAV + RUX) compared with placebo plus ruxolitinib (PBO + RUX) in JAK2i-naïve adults with MF.
Methods: TRANSFORM-1 (NCT04472598) enrolled adult patients with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior JAK2i treatment, and ECOG Performance Score ≤2. Patients were randomized 1:1 to receive NAV (starting dose of 200 mg [platelet {PLT} >150 × 10 9/L] or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days [PLT ≤150 × 10 9/L]) or PBO, plus RUX at label dose, based on stratification factors of intermediate-2 vs high-risk MF and PLT ≤200 × 10 9/L vs >200 × 10 9/L. The primary endpoint was SVR 35W24. Secondary endpoints included change in total symptom score at Week 24 (TSS W24) assessed using 7-item MFSAF v4.0 (scale 0-70), SVR 35 at any time, duration of SVR 35, anemia response (per International Working Group criteria), reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in PROMIS Fatigue scale, and improvement in EORTC QLQ-C30 physical functioning scale. Exploratory endpoints include progression-free survival.
Results: At data cutoff, April 13, 2023, 252 patients were enrolled with a median (range) follow-up of 14.9 (0.0-29.5) months; 125 patients were randomized to receive NAV + RUX and 127 to receive PBO + RUX. Most patients were male (57%), median (range) age was 69 (37-87) years, and patient demographics were similar between treatment arms ( Table 1). TRANSFORM-1 met its primary endpoint, with 79 patients (63.2%) in the NAV + RUX arm achieving SVR 35W24 compared with 40 patients (31.5%) in the PBO + RUX arm ( P<0.0001). Notably, SVR 35 at any time was achieved by 96 patients (77%) with NAV + RUX compared with 53 patients (42%) with PBO + RUX. Median (range) time to SVR 35 response was 12.3 (10.1-48.3) weeks with NAV + RUX versus 12.4 (11.3-72.3) weeks with PBO + RUX. Median duration of SVR 35 was not reached (NR) in the NAV + RUX arm compared with 19.4 months (95% CI 16.8, NR) in the PBO + RUX arm. At Week 24, the mean change in TSS from baseline was -9.7 (95% CI: -11.8, -7.6) with NAV + RUX compared with -11.1 (95% CI: -13.2, -9.1) with PBO + RUX arm ( P=0.2852). Grade ≥3 adverse events (AEs) were experienced by 85% of patients with NAV + RUX and 70% with PBO + RUX. The most common AEs (>30% of patients receiving NAV; Table 2) were thrombocytopenia, anemia, diarrhea, and neutropenia. Serious AEs were experienced by 26% of patients with NAV + RUX and 32% with PBO + RUX, including anemia (NAV + RUX: n=2; PBO + RUX: n=1), thrombocytopenia (NAV + RUX: n=2), and neutropenia (NAV + RUX: n=1). With NAV + RUX, AEs led to NAV dose reduction in 101 (81%) patients and NAV interruption in 87 (70%) patients of which 83 (67%) and 65 (52%) were due to thrombocytopenia, respectively. Of all enrolled patients, 83 (33%) discontinued study treatment; most common (>5% total patients) reason for NAV/PBO discontinuation were AEs (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). In each arm, 13 (10%) patients died; 6 with NAV + RUX and 5 with PBO + RUX died ≤30 days post-final dose.
Conclusions: This first randomized trial in JAKi-naïve MF with NAV + RUX combination led to an SVR 35W24 rate that was twice as high as PBO + RUX ( P<0.0001). The responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae. Additional evaluation is ongoing.
Disclosures
Pemmaraju:CancerNet: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmunoGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Curio Science: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; CareDx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medscape: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Aplastic Anemia & MDS International Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cimeio Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ClearView Healthcare Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pacylex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; United States Department of Defense (DOD): Research Funding; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Imedex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Harborside Press: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magdalen Medical Publishing: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; OncLive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Patient Power: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PeerView Institute for Medical Education: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Physician Education Resource (PER): Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASH Committee on Communications: Other: Leadership; ASCO Cancer.Net Editorial Board: Other: Leadership; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aptitude Health: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; HemOnc Times/Oncology Times: Other: Uncompensated; Bristol Myers Squibb Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mead:Sensyn: Consultancy, Speakers Bureau; Galecto: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; CTI: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; University of Oxford: Patents & Royalties: 2203947.3 ; Roche: Research Funding; Pfizer: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Sierra Oncology: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Relay Therapeutics: Consultancy, Speakers Bureau; Alethiomics Ltd: Consultancy, Current equity holder in private company, Other: Cofounder & equity holder, Research Funding; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Other: investigator for AbbVie sponsored trials, Speakers Bureau. Somervaille:Novartis: Consultancy; Abbvie: Consultancy; Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc.: Research Funding; Oryzon Genomics: Consultancy; CellCentric Ltd: Research Funding; Bristol Myers Squibb: Consultancy; Glaxo Smith Kline: Consultancy; Rain Oncology: Consultancy. McCloskey:Blueprint: Honoraria; Pharmaessentia: Honoraria; BMS: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria; Stemline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria. Palandri:Novartis, BMS, Celgene, GSK, Amgen, AbbVie, Karyopharm, AOP, Sierra Oncology, Janssen: Consultancy, Honoraria. Koschmieder:Pfizer, Incyte, Ariad, Novartis, AOP Pharma, Bristol Myers Squibb, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Protagonist, MPN Hub, Bedrock, PharmaEssentia: Consultancy; AOP Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support, Research Funding; Alexion, Novartis, Bristol Myers Squibb, Incyte, AOP Pharma, CTI BioPharma, Pfizer, Celgene, Janssen, Geron, Roche, AbbVie, GSK, Sierra Oncology, Kartos, Imago Biosciences, MSD, iOMEDICO: Other: Travel/accommodation support; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, AbbVie, Protagonist, PharmaEssentia: Other: Advisory board; PharmaEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RWTH Aachen University: Patents & Royalties: patent issued for a BET inhibitor; Squibb: Consultancy, Honoraria; CTI Biopharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Karthos: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; RWTH Aachen University: Patents & Royalties: BET inhibitor; Novartis, BMS/Celgene, Pfizer, Incyte, AOP Orphan, GSK, AbbVie, MPN Hub, Bedrock, iOMEDICO: Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support, Research Funding; Imago Bioscience: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Geron, Janssen, AOP Pharma, Novartis: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Protagonist: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support, Research Funding; Geron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation support, Research Funding. Lavie:Roche: Honoraria, Other: Advisory Board; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation expenses, lecture; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture; Medisson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board and Travel/Accommodation expenses; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture. Leber:Treadwell: Honoraria, Speakers Bureau; Gilead/KITE: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Otsuka: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Astex: Honoraria, Speakers Bureau; AMGEN: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Palladin Canada: Honoraria, Speakers Bureau; Jazz Canada: Honoraria, Speakers Bureau; Taiho Canada: Honoraria; Novartis Canada: Consultancy, Honoraria, Speakers Bureau; Janssen Canada: Honoraria, Speakers Bureau; Pfizer Canada: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb Canada: Honoraria, Speakers Bureau; Alexion Canada: Honoraria, Speakers Bureau; AbbVie Canada: Consultancy, Honoraria, Speakers Bureau. Yeh:AbbVie: Other: investigator for AbbVie sponsored trials. Gómez-Casares:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Gilead: Other: Training support; Janssen: Other: Training support; AstraZeneca: Other: Training support. Shin:AbbVie: Other: investigator for AbbVie sponsored trials. Kirito:Pharmaessentia: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Jourdan:GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Devos:AOP Pharma: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Chuah:Thermo Fisher Scientific: Research Funding; AbbVie: Honoraria. Radinoff:Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; SOBI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Swixx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Pfizer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses. Bogdanovic:AstraZeneca: Speakers Bureau; Takeda (local in Serbia): Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Membership on an entity's Board of Directors or advisory committees; AbbVie (local in Serbia): Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Moskal:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Jiang:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Chopra:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Papadopoulos:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Potluri:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: 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; Janssen: 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; AOP Orphan: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyiopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees; MEI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sumitomo: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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