TRANSFORM-1 Phase 3 study: Efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis
Abstract
The Phase 3 TRANSFORM-1 study (NCT04472598) evaluated ruxolitinib (RUX) in combination with navitoclax (NAV) or placebo (PBO) in Janus-kinase-inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis and Eastern Cooperative Oncology Group performance status ≤2. Patients were randomized 1:1 to NAV (200 mg/day starting dose or 100 mg escalated to 200 mg/day) or PBO, with RUX dosed per label. The primary endpoint was ≥35% spleen volume reduction (SVR) at Week 24 (SVR35W24). Secondary endpoints included change from baseline in Total Symptom Score (TSS) at Week 24 and SVR35 at any time. A total of 252 patients (NAV+RUX, n=125; PBO+RUX, n=127; median follow-up 20.3 months) were randomized; >80% had intermediate-2 risk and nearly 50% were high-molecular risk (HMR). SVR35W24 was achieved by 63.2% with NAV+RUX versus 31.5% with PBO+RUX (P<0.0001). Mean change in TSS at Week 24 was not significantly different between NAV+RUX and PBO+RUX (−10.2 vs −11.6; P=0.2852). SVR35 at any time was achieved in 76.8% with NAV+RUX versus 44.1% with PBO+RUX (nominal P<0.0001). A ≥20% variant allele frequency reduction (exploratory endpoint) occurred in 58.5% (95% CI: 49.0-67.5) with NAV+RUX and 45.5% (95% CI: 36.4-54.8) with PBO+RUX. NAV+RUX showed higher hematologic toxicity versus PBO+RUX (Grade 3/4 thrombocytopenia: 54.0% vs 19.2%; Grade 3/4 neutropenia: 40.3% vs 8.8%); diarrhea (any grade: 41.9% vs 16.8%) was also more common. Cytopenias were generally manageable and reversible with dose adjustments.
Article Details
Authors (29)
Naveen Pemmaraju
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Adam J. Mead
Medical Research Council (MRC) Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR, Biomedical Research Centre, University of Oxford, Oxford, United Kingdom; Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
Tim C.P. Somervaille
Cancer Research UK Manchester Institute, The University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom
Francesca Palandri
2Seragnoli Hematology Institute, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Steffen Koschmieder
Robert Delage
Quebec CML-MPN Research Group, Montreal, Canada; Integrated Cancer Center, CHU de Québec, Laval University, Quebec, Canada
Jean-Jacques Kiladjian
Christopher B Benton
Rocky Mountain Cancer Centers, US Oncology Network, Denver, CO, United States
Srinivas K Tantravahi
Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, United States
Noa Lavi
Department of Hematology, Rambam Health Care Campus, Haifa 3109601, Israel
Su-Peng Yeh
China Medical University Hospital, Taichung, Taiwan
Maria Teresa Gomez Casares
Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain
Emanuele Ammatuna
Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Andrew Bruce McDonald
Netcare Pretoria East Hospital, Moreletapark, Pretoria, South Africa
Sung-Soo Yoon
From Tel Aviv Sourasky Medical Center (Y.C.C., I.A.), and the Faculty of Medical and Health Sciences, Tel Aviv University (Y.C.C., H.M., I.A.), Tel Aviv, Chaim Sheba Medical Center, Ramat Gan (H.M.), and Hadassah Hebrew University Medical Center, Jerusalem (M.G.) — all in Israel; McGill University and McGill University Health Centre, Montreal (M.S.), and Alberta Health Services, Edmonton (M.P.C.) — all in Canada; Samsung Medical Center, Sungkyunkwan University School of Medicine (K.K.), Seoul St. Mary’s Hospital, Catholic University of Korea (C.-K.M.), and Seoul National University College of Medicine (S.-S.Y.) — all in Seoul, South Korea; Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla, Universidad de Cantabria, Santander (E.M.O.), Cancer Center Clínica Universidad de Navarra, Center for Applied Medical Research, Pamplona (P.R.-O.), Institut Català d’Oncologia, Josep Carreras Leukemia Research Institute, and the Hospital Germans Trias i Pujol, Barcelona (A.O.)...
Keita Kirito
Timothy Devos
8Department of Hematology, University Hospitals Leuven and Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium
Andrew C Perkins
Australian Centre for Blood Diseases, Monash University and the Alfred Hospital, Melbourne, Victoria, Australia
Atanas Radinoff
Department of Clinical Hematology, University Hospital St. Ivan Rilski, Sofia, Bulgaria
Omur Gokmen Sevindik
Department of Hematology, Istanbul Medipol University Faculty of Medicine, Istanbul, Turkey
Andrija Bogdanovic
Clinic of Hematology, University Clinical Center of Serbia, and Faculty of Medicine, University of Belgrade, Serbia
Rastislav Moskal
AbbVie Inc., Prague, Czech Republic
Jason G. Harb
AbbVie Inc., North Chicago, IL, United States
Bryan C Murray
AbbVie, Inc., North Chicago, Illinois, United States
Qi Jiang
Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute
Avijeet S. Chopra
AbbVie, Inc., North Chicago, Illinois, United States
Elektra J. Papadopoulos
AbbVie, Inc., North Chicago, Illinois, United States
Jalaja Potluri
AbbVie Inc., North Chicago, IL, United States
Francesco Passamonti
University of Milan, Milan