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Pelabresib (CPI-0610) plus ruxolitinib (Jakafi) demonstrated improvements in spleen volume, total symptom score, anemia, and the bone marrow microenvironment at week 48 vs placebo plus ruxolitinib in patients with JAK inhibitor–naive myelofibrosis, according to results from the phase 3 MANIFEST-2 study (NCT04603495).1
Data presented at the 2024 ASH Annual Meeting showed that at a median follow-up of 72 weeks, the primary end point of spleen volume reduction of 35% (SVR35) was maintained, with a 48-week response rate of 57.0% with pelabresib and ruxolitinib vs 37.5% with ruxolitinib plus placebo. Total symptom score (TSS) improvement of at least 50% at week 48 was 45.3% vs 39.4%, respectively. Fewer patients required red blood cell transfusions, and bone marrow fibrosis improvement of at least 1 grade was reported in 41.0% vs 15.0%, respectively.
“Results at 48 weeks showed deep and sustained SVR35 response with biomarker evidence suggesting additional benefit of the combination of pelabresib plus ruxolitinib vs ruxolitinib alone,” said John O. Mascarenhas, MD, director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai, in his poster presentation.
Pelabresib is an investigational small molecule BET inhibitor that can decrease the BET-mediated gene expression associated with MF.
The phase 3 MANIFEST-2 trial is a global, randomized, double-blind study that assigned 430 patients to receive ruxolitinib twice daily plus pelabresib or placebo once daily for 14 consecutive days of 21-day cycles. At the 2023 ASH meeting, the MANIFEST-2 trial investigators reported that it had met its primary end point of 24-week SVR. Key secondary end points were absolute change in TSS and 50% or greater reduction in TSS from baseline (TSS50) at week 24, with other end points including SVR35 at week 48, hemoglobin response, bone marrow fibrosis, and safety.
Patients had to have intermediate-1 or higher risk myelofibrosis by Dynamic International Prognostic Scoring System (DIPSS), platelet count of at least 100,000/μL, spleen volume of at least 450 cm3, TSS of 10 or greater (≥3 for 2 symptoms), and ECOG performance status of 2 or lower. The study arms were balanced in terms of age and DIPSS risk status.
At the data cutoff of March 29, 2024, 126 of 214 patients (58.9%) receiving the combination and 134 of 216 patients (62.0%) receiving ruxolitinib plus placebo were still being treated in a double-blind fashion.
In addition to a higher number of patients showing SVR35 response at week 48, only 13.1% of patients had a loss of SVR35 response and increase of 25% from nadir with pelabresib vs 20.0% with placebo, or 21.0% vs 36.8%, respectively by alternate definition of loss of SVR35 response. The mean change was -54.5% with the combination vs -33.5% with ruxolitinib plus placebo, and 82.2% had a response at any time with the combination vs 57.9% with ruxolitinib plus placebo.
The absolute change from baseline TSS was -15.99 for pelabresib plus ruxolitinib vs -14.05 for ruxolitinib plus placebo at week 24, and -16.24 vs -14.11, respectively at week 48. TSS individual domain scores were similar between the 2 arms and similar to national norms for people without MF, according to the investigators. An analysis of Myelofibrosis Symptom Assessment Form excluding fatigue showed a least square mean change from baseline of -16.19 with pelabresib plus ruxolitinib vs -13.86 with placebo plus ruxolitinib. Mascarenhas said that “additional symptom benefit of pelabresib could be difficult to detect due to a ceiling effect in TSS, especially in the fatigue domain.”
When looking at patients who had both SVR35 and TSS improvement of 50%, there were 77 (36%) who received the combination vs only 41 (19%) in the placebo arm.
A hemoglobin response as defined as a 1.5 g/dL or greater mean increase from baseline in the absence of transfusions in the past 12 weeks was observed in a numerically greater proportion of patients who received pelabresib (13.1% vs 7.9%), and hemoglobin levels rose and approached baseline in patients with anemia. In the combination arm, 27.6% required transfusion in the first 24 weeks and 21.8% required it in the next 24 weeks, compared with 38.6% and 33.2%, respectively, in the placebo plus ruxolitinib arm.
At week 48, bone marrow fibrosis had improved in 41.0%, remained unchanged in 45.0%, and worsened in 14.0% of those receiving pelabresib vs improving in 15.0%, remaining unchanged in 54.2%, and worsening in 30.8% of those receiving placebo. The improvement of bone marrow fibrosis of at least 1 grade at week 24 was 38.3% vs 25.3% in the respective arms, showing that the difference widened at week 48.
Based on a descriptive analysis of an exploratory end point, disease-relevant proinflammatory cytokines showed a numerically greater reduction at week 48 in the pelabresib plus ruxolitinib arm. The level of proinflammatory cytokines was lower in those who had an SVR35 response, regardless of which treatment they received.
Another exploratory end point was change in mutant clone burden in peripheral blood samples by next-generation sequencing. At week 48, there was greater reduction in the pelabresib plus ruxolitinib group, with a variant allele frequency reduction of 50% in 15% vs 9.0% of those receiving placebo plus ruxolitinib. The mean change from baseline was -24.1% vs -16.3% in the respective arms, and a correlation was found between SVR35 response and reduced mutation clone burden.
In terms of safety, grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 57.1% of the pelabresib plus ruxolitinib arm vs 62.1% of the placebo plus ruxolitinib arm. Grade 3 or higher anemia was reported in 25.9% and 38.3%, respectively, and grade 3 or higher thrombocytopenia was reported in 15.1 and 6.1%, respectively. The most common nonhematologic TEAEs including diarrhea, constipation, dysgeusia, cough, and nausea. Death occurred in 20 of 214 patients (9.3%) in the pelabresib plus ruxolitinib arm and 18 of 216 (8.3%) in the placebo plus ruxolitinib arm.
Accelerated and blast-phase progression to leukemia transformation was reported in 6.1% of the pelabresib plus ruxolitinib arm and 4.2% of the placebo plus ruxolitinib arm at a data cutoff of August 30, 2024. Newly acquired mutations were detected in 26% and 22%, respectively, and high molecular risk (HMR) mutations were seen in 4% and 2%, respectively. Mutations were no longer detectable in 11% and 12%, and HMR mutations were no longer detectable in 3% and 1%, respectively. Investigators proposed that the similar number of patients indicated that pelabresib does not have an additional mutagenic effect when combined with ruxolitinib.
The investigators intend to present longer follow-up data from MANIFEST-2 at future medical congresses. “Rates of grade 3 or greater TEAEs were similar in both arms and leukemia transformation continues to be followed up closely,” said Mascarenhas.
Reference
Mascarenhas JO, Grosicki S, Chraniuk D, et al. Updated Results from the Phase 3 Manifest-2 Study of Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor-Naïve Patients with Myelofibrosis. Blood. 2024;144(suppl 1):3178. doi:10.1182/blood-2024-193193