Parsaclisib Added to Ruxolitinib Improves Spleen Size and Symptom Burden in Myelofibrosis

The addition of parsaclisib to ruxolitinib (Jakafi) led to improvement in spleen volume reduction (SVR) and symptom burden in patients with myelofibrosis (MF) who had a suboptimal response on a standard dose of ruxolitinib alone, according to results from a phase 2 study (NCT02718300) presented during the virtual American Association of Cancer Research (AACR) Annual Meeting 2021.

Responses to ruxolitinib with a parsaclisib add-on in the study occurred early on in the course of treatment and were durable. Moreover, the combination appeared well-tolerated in patients with MPNs.

The JAK 1/2 inhibitor ruxolitinib has long demonstrated the ability to improve outcomes like spleen volume, symptom burden, and survival in patients with MF. There is a subset of patients, however, who either have suboptimal responses to ruxolitinib or whose responses decline over time. Preclinical research into these phenomena suggested that activation of the PI3K pathway could benefit this patient population, therefore warranting the use of the next-generation PI3K inhibitor, parsaclisib.

To test the JAK and PI3K inhibitor combination in patients with MF, patients aged 18 years or older with primary or secondary MF were enrolled in the study. Patients were required to have an ECOG performance status of 2 or lower and have had a suboptimal response to ruxolitinib monotherapy after being treated with the agent at 5 to 25 mg twice daily for at least 6 weeks. On prior treatment with ruxolitinib, it was required that patients achieved stable disease that lasted at least 8 weeks and have a spleen that is over 10 cm below the left subcostal margin at the time of screening. Alternatively, patients could be eligible for the study with a spleen 5 cm to 10 cm below the left subcostal margin along with active MF symptoms at baseline, which may include night sweats, pruritis, abdominal discomfort, pain under the ribs, bone or muscle pain, and inactivity. MF symptoms observed at baseline are graded on a 10-point scale. Finally, all patients enrolled must have had a platelet count of at least 50 x 109/L in the 4 weeks prior to screening.

Once enrolled and while receiving a stable dose of ruxolitinib, patients in 1 arm of the study received the addition of parsaclisib at 10 mg or 20 mg once daily for 8 weeks and the same dosage once weekly in the weeks following. In a second arm, parsaclisib was administered at 5 mg or 20 mg once daily for 8 weeks and 5 mg once daily thereafter. On treatment with ruxolitinib and a parsaclisib add-on, patients were evaluated for the primary end point of change in spleen volume from baseline to week 12, which was determined by imaging. In addition, change in spleen volume from baseline to week 24, change in spleen length from baseline to each visit, total symptom score (TSS) from baseline to weeks 12 and 24, and safety determined by the number of patient with adverse events (AEs).

A total of 53 patients were included in the study, 10 of whom were evaluated in the safety run-in portion and 43 of whom were randomized to receive ruxolitinib plus 10 mg to 20 mg parsaclisib or ruxolitinib plus 5 mg to 20 mg parsaclisib. Thirty-three patients were dosed daily and weekly, and 20 received all daily dosing. As of the data cutoff date, 82% of patients who received both daily and weekly discontinued treatment in the study compared with 40% in the daily only group. Treatment was ongoing in 6 patients who were being treated on a daily and weekly schedule and 12 of those being treated on a daily-only schedule.

The study population had a median age of 66 years (range, 41-89 years) at baseline and was predominantly male (47%). The median time since the initial diagnosis of MF was 31.2 months (range, 4.9-268.9 months), and the duration of prior ruxolitinib in patients was a median of 18 months (range, 4.8-94 months). Ninety-eight percent of patients had palpable spleen which measured a median of 13.5 cm (range, 5-30 cm). Median spleen volume at baseline was 1995 cm3 (range, 327-5324 cm3). According to the MPN Symptoms Assessment Form, the median TSS in patients at baseline was 25.5 (range, 0-69), and according to the Myelofibrosis Symptoms Assessment Form, the median baseline TSS was 12.9 (range, 0-47).

Hemoglobin levels assessed a baseline showed a median of 101 g/L (range, 63-159 g/L).

Patients presented with several different MF subtypes including primary MF (PMF), post-polycythemia vera MF (PPV-MF), and post-essential thrombocythemia (PET-MF).

In terms of efficacy, patients who received all daily parsaclisib had a higher SVR compared with those treated daily and weekly. A -15.4% reduction was achieved in patients treated daily compared with a -2.3% reduction in spleen volume in those in the daily/weekly group. Then, at 24 weeks, the daily group showed a -25.4% SVR compared with a -2.5% reduction in the daily/weekly group.

“Patients who received all daily parsaclisib dosing demonstrated a continued reduction in splenic length up to 24 weeks. By contrast, patients receiving the daily parsaclisib dosing appeared to plateau after switching to weekly dosing at week 8,” said Abdulraheem Yacoub, MD, associate professor of Medicine, University of Kansas Medical Center, during the AACR poster presentation.

By week 24, 18 patients in the daily/weekly parsaclisib dosing group had palpable spleen compared with 3 in the daily dosing group.

Yacoub also explained that a higher percentage of patients who received all daily dosing demonstrated improvement in symptoms at 12 and 24 weeks. At week 12, there was a 50% or greater symptom reduction in 31% of the all-daily dosing population versus 15% of the daily/weekly dosing population, and at 24 weeks, the same symptom reduction was observed in 17% versus 4%, respectively.

The safety results also favored the daily dosing schedule over the daily/weekly schedule. Overall, the majority of the hematologic treatment-emergent AEs (TEAEs) were grade 1 or 2 in severity. The most common any-grade hematologic TEAEs observed in the all-daily dosing group were cough (25%) and nausea (20%). In the daily/weekly dosing group, the most common any-grade hematologic TEAEs were diarrhea, nausea, and fatigue, which occurred in 33%, 30%, and 30% of patients, respectively.

At least 2% of patients in the study experienced serious TEAEs which included urinary tract infection in 3 patients, and pneumonia, pyrexia, and fall in 2 patients each. AEs were fatal for 1 patient who received all daily dosing and 6 treated daily/weekly. New onset of grade 3 thrombocytopenia was observed in 30% of patients in the all-daily dosing population versus 18% with daily/weekly dosing. No patients who received all daily dosing had new-onset grade 4 thrombocytopenia compared with 21% of the daily/weekly group.

Notably, hemoglobin levels in all study subjects remained stable during the study and there were no cases of anemia. Also, in the daily dosing-only group, there was no colitis, grade 2 or higher diarrhea, or rash. One AE of special interest in the all-daily dosing group was varicella-zoster virus infection, which occurred in only 1 patient. AEs of special interest among patients treated daily/weekly were grade 2 or greater diarrhea in 4 patients, elevated liver function tests in 2 patients, grade 2 or greater rash in 1 patient, and varicella-zoster virus infection in 1 patient.

Grade 3/4 AEs were rare overall, and the AEs commonly observed with PI3K inhibitors were infrequent after adding parsaclisib to ruxolitinib.

Results from the study lead to the development of a phase 3 study exploring parsaclisib as an add-on to ruxolitinib or in combination with ruxolitinib as frontline treatment of patients with MF (NCT04551053).

_Reference

_{Yacoub A, Wang ES, Rampal RR, et al. Addition of parsaclisib (INCB050465), a PI3Kδ inhibitor, in patients with suboptimal response to ruxolitinib: A phase 2 study in patients with myelofibrosis. Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT162.}