QW Selinexor 60 mg Plus Ruxolitinib Elicits Lasting Responses in Myelofibrosis

Haris Ali, MD

Once-weekly (QW) selinexor administered at 60 mg in combination with ruxolitinib (Jakafi) achieved rapid and deep spleen responses that were sustained, as well as robust symptom improvements in patients with treatment-naïve myelofibrosis, according to phase 1/2 study (NCT04562389) results presented at the American Society for Cancer Research (AACR) Annual Meeting 2023.¹

"There remains significant unmet need in the treatment of myelofibrosis, with less than half of patients achieving an SVR35 with the current standard of care therapy," said Haris Ali, MD, City of Hope Comprehensive Cancer Center, presenter of the data, in a press release. "The spleen responses and symptom improvements seen across all patients with the 60 mg selinexor dose is very compelling. These data suggest this tolerable and unique combination of XPO1 and JAK inhibition has the potential to significantly improve these key efficacy measures first-line myelofibrosis."

As of the data cutoff date of February 24, 2023, 24 patients with treatment-naïve myelofibrosis were randomized 1:1 to receive selinexor (40 mg or 60mg) QW plus ruxolitinib (15 mg or 20 mg), or ruxolitinib alone.

At week 12, the rate of 35% spleen volume reduction rate (SVR35) was 83.3% with selinexor 60 mg in the efficacy evaluable population. In the intent-to-treat (ITT) population, the SVR35 rate was 71.4% with selinexor 60 mg. The rate of ≥ 50% reduction in total symptom score (TSS50) at the 60-mg dose level was 80.0% in the efficacy evaluable population and 66.7% in the ITT population.

The 24-week SVR35 rate was 91.7% in the efficacy evaluable population, and the rate of TSS50 was 78.6%. In the ITT population, the 78.6% of patients had SVR35 and the rate of TSS50 was 58.3%.

Response rates were consistent in the subgroup population assessed, which included male patients, and those who received low-dose ruxolitinib. In addition, selinexor 60 mg plus ruxolitinib led to improvements in major spleen- and cytokine-related symptoms all Myelofibrosis Symptom Assessment Form areas.

At the 40 mg dose level, selinexor in combination with ruxolitinib achieved a 30.0% SVR35 and 66.7% TSS50 in the efficacy evaluable population, and a 40.0% SVR35 and 40.0% TSS50 in the ITT population.

"We are enthusiastic about the impressive spleen volume reductions and robust symptom improvement observed with the 60 mg dose of selinexor and ruxolitinib combination at week 24, which represent very meaningful improvements relative to the current standard of care of ruxolitinib alone. These data suggest that the combination of selinexor and ruxolitinib has the potential to be a transformative therapy for first line myelofibrosis patients," said Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, in the press release. "We are also very encouraged by the preliminary data showing rapid normalization in platelets and stability of hemoglobin levels, as potential evidence of disease modification for these patients. We look forward to building upon these findings as we plan the initiation of a pivotal phase 3 study in front-line myelofibrosis later this quarter."

The safety analysis showed that selinexor was well-tolerated at both dose levels and toxicities were manageable. Due to the safety profile of selinexor in this study, most patients remained on the study for up to 68 weeks.

The most common any-grade treatment-emergent adverse events (TEAEs) in the 40 mg and 60 mg dose cohorts, respectively, were nausea (70.0% and 78.6%), anemia (40.0% and 64.3%) and fatigue (60.0% and 57.1%). These TEAEs were predominantly grade 1 or 2 in severity. Grade 3 or higher TEAEs that occurred frequently during the study included anemia (30.0% and 42.9%), thrombocytopenia (10.0% and 28.6%) and neutropenia (20.0% and 7.1%).

Two patients in the study discontinued treatment due to cases of thrombocytopenia and peripheral neuropathy. Notably, 75% of nausea were grade 1 and did not required patients to discontinue treatment. Treatment with prophylactic antiemetics reduced nausea rates and grades.

John Mascarenhas, MD

According to the study investigators, these data support proceeding with 60 mg as the recommended dose of selinexor when used in combination with ruxolitinib. A phase 3 study of selinexor plus ruxolitinib vs placebo is planned to being this year.

“JAK does afford our patients benefit, but unfortunately, doesn’t cure our patients and outcomes are dismal when the dose is reduced or the drug has to be stopped,” said John Mascarenhas, MD, during a conference call hosted by Karyopharm Therapeutics following the AACR presentation.² “Over the next 3 years, a likely paradigm shift to upfront combination therapy approach is being explored with selinexor. and given novel agents in late-stage development, I think that a new era of treating myelofibrosis is ahead. I think the opportunity to exploit non-JAK2 inhibitor sequencing such with imetelstat, or an MDM2 inhibitor like naphthalene, offer other opportunities to treat patients down the line,” Mascarenhas added.

_REFERENCES:

_{1. Karyopharm Announces presentation of updated phase 1 selinexor data in patients with treatment-naïve myelofibrosis at AACR 2023. News release. Karyopharm Therapeutics, Inc. April 18, 2023. Accessed April 19, 2023. https://bit.ly/3KRRpM9}

_{2. AACR 2023 - Karyopharm Therapeutics Virtual Investor Presentation. Karyopharm Therapeutics Presented April 18, 2023. Virtual. https://bit.ly/3LaQcjx}