Dr Mascarenhas on the Potential Utility of Selinexor Plus Ruxolitinib in Myelofibrosis

John Mascarenhas, MD, professor of medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, Mount Sinai, discusses the potential advantages of utilizing selinexor (Xpovio) with ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis.

The rationale behind combining the investigational oral XPO1 inhibitor selinexor with the JAK inhibitor ruxolitinib lies in the potential synergy between the 2 drugs, which is achieved through leveraging their overlapping pathways, Mascarenhas begins.

Preclinical data have indicated the potential synergy between selinexor and ruxolitinib, Mascarenhas states. Additionally, data from a phase 1 trial (NCT04562389), which were presented at the 2023 ASH Annual Meeting, demonstrated early signals of clinical activity with selinexor and ruxolitinib in JAK inhibitor–naive patients, including promising spleen volume reduction rates and total symptom score reduction. Furthermore, early data have also shown that patients receiving low-dose ruxolitinib still experience significant spleen and symptom responses, Mascarenhas adds. This suggests that full doses of ruxolitinib may not be necessary to enhance the effectiveness of the combination approach, he explains.

Similar findings have been observed with other ruxolitinib-based combination therapies, Mascarenhas continues. For example, treatment with the second-generation MDM2 inhibitor navtemadlin (KRT-232) plus low doses of ruxolitinib produced deep responses while mitigating toxicity, he details. This indicates the potential to achieve meaningful therapeutic effects with lower doses of JAK inhibitors in combination with certain agents, Mascarenhas says.

These positive outcomes supported the initiation of the phase 3 XPORT-MF-034 (NCT04562389) trial. In this global, randomized, placebo-controlled study, patients with JAK inhibitor–naive myelofibrosis will be randomly assigned in a 2:1 ratio to receive either oral selinexor at 60 mg or placebo once a week alongside twice-daily ruxolitinib. The study will further elucidate the combination’s therapeutic benefit in this patient population. XPORT-MF-034 phase 3 trial is currently open for enrollment.

Although knowledge and understanding of the underlying biology, mechanisms, and optimal patient populations for such combinations is still evolving, these early signals highlight the potential to enhance efficacy while managing toxicity through strategic drug combinations, Mascarenhas emphasizes. Further research is needed to unravel the complexities of these interactions and identify specific patient subsets that may benefit most from ruxolitinib-based approaches, he concludes.