Selinexor Plus Ruxolitinib in Janus Kinase Inhibitor–Naïve Myelofibrosis: Phase III SENTRY Trial

Author(s): Prithviraj Bose, MD1; Haris Ali, MD2; Haifa Kathrin Al-Ali, MD, PhD3; Valentin Garcia-Gutierrez, MD, PhD4; Sebastian Grosicki, MD, PhD5; Zhanet Grudeva-Popova, MD, PhD, MHM6; Claire Harrison, DM, FRCP, PRCPath7; Junshik Hong, MD, PhD8; Hsin-An Hou, MD, PhD9; Michal Kwiatek, MD, PhD10; Michael Loschi, MD, PhD11; Francesco Passamonti, MD12,13; Andrea Patriarca, MD, PhD14; Nikolai Podoltsev, MD, PhD15; Raajit Rampal, MD, PhD16; Srinivas Tantravahi, MBBS, MRCP17; Laura Gabriela Urian, MD18; Yi Chai, MS19; Pietro Taverna, PhD19; Tomer Mark, MD, MSc19; Amama Sadiq, MD, MPH19; Reshma Rangwala, MD, PhD19; Pankit Vachhani, MD20; John Mascarenhas, MD21; for the SENTRY Trial Investigators;
Source: DOI: 10.1200/JCO-26-01080
Original Article
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Patients were randomized to Rux placebo vs Rux and selinexor. At week 24, spleen volume reduction ≥35% (SVR35) was achieved in 49.8% of the selinexor plus ruxolitinib group vs 28.0% of the placebo plus ruxolitinib group. Symptom scores improved from baseline in both groups (−9.9 selinexor plus ruxolitinib, −10.9 placebo plus ruxolitinib), with no significant between-group difference will need long term follow up to assess the symptoms relief and the clonal regression.

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. 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. 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.

Author Affiliations

1University of Texas MD Anderson Cancer Center, Houston, TX; 2City of Hope, Duarte, CA; 3Krukenberg Cancer Center Halle, University Hospital Halle (Saale), Halle, Germany; 4Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; 5Department of Cancer Prevention, Medical University of Silesia, Katowice, Poland; 6Medical University of Plovdiv, Plovdiv, Bulgaria; 7Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; 8Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 9National Taiwan University Hospital, Taipei, Taiwan; 10Aidport Clinical Trials Hospital, Skorzewo, Poznan, Poland; 11Centre Hospitalier Universitaire de Nice, Nice, France; 12Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 13Dipartimento di Oncologia ed Onco-Ematologia, Università degli Studi di Milano, Milan, Italy; 14Hematology Unit, AOU Maggiore della Carità and department of translational medicine, University of Eastern Piedmont, Novara, Italy; 15Department of Internal Medicine, Yale School of Medicine, New Haven, CT; 16Memorial Sloan Kettering Cancer Center, New York, NY; 17Huntsman Cancer Institute, Salt Lake City, UT; 18Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 19Karyopharm Therapeutics, Newton, MA; 20University of Alabama Birmingham, Birmingham, AL; 21Tisch Cancer Institute, Icahn School of Medicine Mount Sinai, New York, NY

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