Prithviraj Bose, Haris Ali, Haifa Kathrin Al-Ali, Valentín García‐Gutiérrez, Sebastian Grosicki, Жанет Грудева-Попова, Claire Harrison, Junshik Hong, Hsin-An Hou, Michal Kwiatek, Michael Loschi, Francesco Passamonti, Andrea Patriarca, Nikolai Podoltsev, Raajit Rampal, Srinivas Tantravahi, Laura Urian, Yi Chai, Pietro Taverna, Tomer Mark, Amama Sadiq, Reshma Rangwala, Pankit Vachhani, John Mascarenhas, for the SENTRY Trial Investigators, Aitor Abuín Blanco, Haris Ali, Seo-Yeon Ahn, Haifa Kathrin Al-Ali, Alberto Alvarez-Larran, Anna Angona, Emanuele Ammatuna, Rosa Ayala, Soo-Mee Bang, Fiorenza Barraco, Sabrina Barriere, Aart Beeker, Eloise Beggiato, Petra Belohlavkova, Christopher Benton, Bhavana Bhatnagar, Massimiliano Bonifacio, Gabriela Borsaru, Prithviraj Bose, Françoise Boyer‐Perrard, Joseph Brandwein, Massimo Breccia, Celeste Bremer, Aleksandra Butrym, Nauman Butt, Marianna Caramella, Yariv Carasso, Hung Chang, June‐Won Cheong, Ling‐Jung Chiu, Dominik Chraniuk, Daniela Cilloni, Blanca Xicoy Cirici, Carl Crodel, Julia Cunningham, Catalin Doru DANAILA, Ruchi Desai, Valerio De Stefano, Timothy Devos, M. Donchev, Jan Van Droogenbroeck, Жанет Грудева-Попова, Gabriel Etienne, Maria Angeles Fernandez Rodriguez, Fiona Fernando, María Laura Fox, Mitul Gandhi, Regina García Delgado, Elena Maria Elli, Jose Valentín García-Gutiérrez, Nicolas Gauthier, Daniela Georgescu, Bartlomiej Getta, Federica Gigli, Maria Pilar Giraldo Castellano, Krzysztof Giannopoulos, Nikki Granacher, Stefanie Gröpper, Жанет Грудева-Попова, Sebastian Grosicki, Evgueniy Hadjiev, Anna Halpern, Claire Harrison, Eleftheria Hatzimichael, Victor Higuero Saavedra, Holger Hebart, Jesús María Hernández Rivas, Antonín Hluší, Junshik Hong, Hsin-An Hou, Jonathan How, Hui-Hua Hsiao, Jean‐Christophe Ianotto, Ian Irving, Alessandra Iurlo
PURPOSE Ruxolitinib improves splenomegaly and symptoms in myelofibrosis (MF) but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in MF. We evaluated selinexor plus ruxolitinib versus ruxolitinib alone in Janus kinase inhibitor–naïve MF. METHODS In this double-blind, phase III trial, patients were randomly assigned (2:1) to receive selinexor plus ruxolitinib or placebo plus ruxolitinib. Coprimary end points were spleen volume reduction ≥35% (SVR35) and absolute mean change in total symptom score (AbsTSS; excluding fatigue) from baseline to week 24. RESULTS A total of 353 patients were randomly assigned. At week 24, SVR35 was achieved in 49.8% of the selinexor plus ruxolitinib group versus 28.0% of the placebo plus ruxolitinib group (difference, 21.8 percentage points; odds ratio, 2.58 [95% CI, 1.60 to 4.17]; P < .0001). Differences were evident by week 12 and through week 36. The AbsTSS coprimary end point was not met; however, symptom scores improved from baseline in both groups (−9.9 selinexor plus ruxolitinib, −10.9 placebo plus ruxolitinib), with no significant between-group difference. At a median follow-up of approximately 12 months, the overall survival (OS) hazard ratio was 0.43 ([95% CI, 0.19 to 1.00]; nominal P = .022). Grade ≥3 adverse events (AEs) occurred in 70.1% and 50.0% of patients in the selinexor plus ruxolitinib or placebo plus ruxolitinib groups, respectively, most commonly anemia, thrombocytopenia, and neutropenia. Nausea was more frequent with selinexor but predominantly low-grade and early. CONCLUSION In patients with JAK inhibitor–naïve MF, selinexor plus ruxolitinib met its coprimary end point of improved SVR35 but did not meet the AbsTSS coprimary end point, compared with placebo plus ruxolitinib. An early OS difference was observed. The safety profile was consistent with known AE profiles of the individual agents.