Selinexor/Ruxolitinib Combo Is Tolerable, Shows Durable Spleen, Symptom Responses in JAK Inhibitor–Naive Myelofibrosis

The oral XPO1 inhibitor selinexor in combination with ruxolitinib (Jakafi) was associated with a tolerable and manageable adverse effect (AE) profile and elicited signals of clinical efficacy in patients with JAK inhibitor–naive myelofibrosis, according to data from the phase 1/3 XPORT-MF-034 trial (NCT04562389) presented at the 2023 ASH Annual Meeting.

In an evaluation of 14 patients, the median time to both spleen and symptom response was 12.1 weeks on the study. At a median duration follow-up of 32 weeks (range, 12-78), it is a 100% probability that these patients will have achieved a spleen volume response (SVR). At a median follow-up of 51 weeks (range, 12-64), 100% of these patients are expected to maintain total symptom score (TSS) response.

Investigators also evaluated SVR at 35% or greater (SVR35) and TSS at a 50% or more improvement (TSS50) with selinexor plus ruxolitinib. The SVR35 at week 24 was 92% in the efficacy-evaluable population and 79% in the intent-to-treat patient population; the TSS50 was 78% and 58%, respectively.

“Encouraging signals of durable SVR and symptom improvement were observed with selinexor at 60 mg weekly plus ruxolitinib,” Srinivas K. Tantravahi, MBBS, MRCP, of the University of Utah Huntsman Cancer Institute, said in an interview with OncLive.

Myelofibrosis is an advanced myeloproliferative neoplasm that, despite currently present treatment options, still has various unmet needs due to the overactive JAK/STAT pathway and activating mutations. Treatment options, such as JAK inhibitors including ruxolitinib (Jakafi), may present with limitations such as low response rates and non-durable responses, leading to worsening cases of cytopenia. Based on these unmet needs, further investigations into aggressive upfront treatment may enhance disease modification.

Selinexor is highly selective as it targets XPO1, which has the ability to target both the JAK/STAT and non-JAK/STAT pathways in myelofibrosis.

Based on preliminary evidence, as well as mouse model investigations, investigators have shown that selinexor decreases phosphorylation and other key downstream proteins, as well as increases p53-driven cell death, causing cell cycle arrest. These outcomes led to the investigation of this combination in JAK-naive patients with myelofibrosis.

Patients were eligible for enrollment if they presented with a spleen volume of 450 cm³ or greater by magnetic resonance imaging or computed tomography; a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1 and symptomatic, as well as intermediate-2, or high risk; an ECOG performance statues of no more than 2; and a platelet count of 100 x 10⁹/L or greater.

The investigation began with the phase 1a dose-escalation phase, wherein patients were treated with selinexor at 40 mg (n = 3) or 60 mg (n = 3) once weekly and ruxolitinib given at 15 or 20 mg twice daily. This then led to the phase 1b dose-expansion portion of the study of selinexor at 40 or 60 mg once weekly given with ruxolitinib (n = 18).

This has led to the ongoing, randomized phase 1/3 trial of 306 patients who will be randomly assigned 2:1 fashion to receive oral selinexor 60 mg once weekly with ruxolitinib vs placebo with ruxolitinib.

The data cutoff date was August 1, 2023, and investigators evaluated patients for safety, durability of the agent, and disease modification, as assessed by biomarkers.

The primary end points included establishing a maximum-tolerated dose or recommended phase 3 dose, as well as safety. Secondary end points included SVR35, TSS50, anemia response, and AEs.

Regarding baseline characteristics, the median age was 64.5 years (range, 58-77), 35.7% of patients were female, and the median weight of patients was 77.5 kg (range, 54.7-141.9). Furthermore, 92.9% of patients were transfusion independent and 7.1% were transfusion dependent; 50% of patients had primary myelofibrosis; 28.6% had post-essential thrombocythemia myelofibrosis; and 21.4% had post polycythemia vera myelofibrosis.

Regarding mutational statuses, 78.6%, 14.3%, 7.1%, and 35.7% of patients had JAK2, CALR, MPL, and high molecular risk mutations, respectively. A total 21.4% of patients had a DIPSS score of intermediate-1, while 57.1% and 21.4% had a DIPSS score of intermediate-2 or high risk.

Looking to hemoglobin at baseline, 57.1% of patients had a baseline hemoglobin of less than 10 g/dL and 85.7% of patients had a platelet count (10⁹/L) of 150 or greater. The median baseline spleen volume of patients was 1961.6 cm³ (range, 650.1-3657.0) and the mean baseline TSS was 21.6.

Investigators noted that in patients who received 5 mg or less twice daily of ruxolitinib in combination with 60 mg selinexor for at least 5 out of the first 6 cycles, spleen volume and symptom score reduction still occurred.

Investigators examined cytokine changes, as well, which showed that early decreases in proinflammatory cytokines observed by week 4 after selinexor plus ruxolitinib in evaluable patients were associated with SVR at week 24. Variant allele frequency was also measured at week 24 with both doses of selinexor plus ruxolitinib, which showed that reduced allele burden was observed in 13 evaluable patients, regardless of driver gene mutations.

A 20% or greater decrease in variant allele frequency was observed in 5 patients, 3 of which had a 50% or greater variant allele frequency at baseline and were high molecular risk. Notably, 13 of 24 patients had variant allele frequency values at baseline, and 11 of these 13 patients achieved SVR35 at any time.

Looking to safety, any-grade treatment-emergent adverse effects (TEAEs) to occur in patients treated with 60 mg of selinexor included nausea (78.6%), anemia (64.3%), thrombocytopenia (64.3%), fatigue (57.1%), constipation (50.0%), vomiting (50.0%), dyspnea (35.7%), headache (35.7%), hyponatremia (35.7%), leukopenia (35.7%), and neutropenia (35.7%). Nausea was transient with a median duration of 2 cycles. Sixty-four percent of patients received 1 prophylactic anti-emetic. In the subgroup that received 1 prophylactic anti-emetic, 67% of patients experienced nausea (grade 1 only) vs 100% of those without prophylactic anti-emetics who had nausea (grades 1-3).

Grade 3 or greater TEAEs reported were anemia (42.9%), thrombocytopenia (28.6%), back pain (14.3%), neutropenia (7.1%), atrial fibrillation (7.1%), and leukopenia (7.1%). Furthermore, treatment-related AEs that led to treatment discontinuations included 1 patient with grade 3 thrombocytopenia and 1 patient with grade 3 peripheral neuropathy.

“This is really encouraging and indicate that the combination treatment can be well tolerated, and patients can stay on treatment,” Tantravahi concluded.

Reference

Tantravahi SK, Kishtagari A, Maher K, et al. Selinexor plus ruxolitinib in JAK inhibitor (JAKi) treatment-naïve patients with myelofibrosis: long term follow up from XPORT-MF-034 suggestive of disease modification. Blood. 2023;142(suppl 1):622. doi:10.1182/blood-2023-180844