Pelabresib/ruxolitinib tablets: latest MANIFEST-2 data supporting paradigm shift in myelofibrosis

Based on data from the phase 3 MANIFEST-2 study (NCT04603495), the addition of peabresib (CPI-06) in myelofibrosis patients treated with JAK inhibitors 10) and Ruxolitinib significantly and durably reduced splenomegaly, showed a trend toward lower Tumor Symptom Score (TSS) from baseline, and improved anemia and myelofibrosis at week 24.

As described in the previous study, the trial met its primary endpoint, with a greater proportion of patients receiving dual therapy (n=214) having a 35% or greater reduction in spleen volume (SVR35) at week 24 than those taking ruxolitinib alone (n=216), 65.9% versus 35.2%, respectively (difference, 30.4; 95% CI, 21.6-39.3; P<0.001). %CI is -33.7%--27.5%). At Week 24, the mean percentage change in spleen volume was -50.6% (95% CI, -53.2% to -48.0%) in the peabresib/ruxolitinib group and -30.6% (95% CI, -33.7% to -27.5%) in the ruxolitinib alone group.

When looking at all responders who achieved an SVR35 response, the proportion who lost response at any time was 13.4% in the Pelabresib/ruxolitinib group compared with 27.8% in the ruxolitinib alone group, which was more than twice as high. When examining the criteria for loss of SVR35 response plus an increase in spleen volume from nadir exceeding 25%, this occurred in 9.3% and 14.8% of patients, respectively. Notably, SVR35 responses were consistently higher with dual versus monotherapy across all predefined and hematological subgroups.

At week 24, there was a significant downward trend in the numerical absolute change in TSS for dual therapy compared with monotherapy, which was -15.99 and -14.05, respectively, with a mean difference of -1.94 points (95% CI, -3.92 to 0.04; P=0.0545). A higher proportion of patients receiving the combination versus ruxolitinib alone had a 50% reduction in TSS (TSS50), 52.3% versus 46.3%, respectively (difference, 6.0; 95% CI, -3.5-15.5; P=0.216); this difference did not reach statistical significance. Pelabresib plus ruxolitinib tripled the number of patients achieving both SVR35 and TSS50 responses compared with ruxolitinib alone, at 40.2% and 18.5%, respectively.

Other more recent data show that the proportion of patients with a hemoglobin response is numerically higher with dual therapy compared with single therapy. In the Pelabresib/ruxolitinib group, hemoglobin response (defined as at least 1.5g/dL mean increase) was 10.7% (95%CI, 6.60%-14.90%), compared with 6.0% (95%CI, 2.85%-9.19%) in the ruxolitinib alone group. Among anemic patients with baseline hemoglobin less than 10 g/dL, hemoglobin response rates were 16.4% (95% CI, 7.55%-25.29%) and 14.1% (95% CI, 5.99%-22.18%) in the dual- and single-therapy groups, respectively. Additionally, during the first 24 weeks of treatment, red blood cell transfusions (RBCs) occurred in 30.3% of patients receiving the combination compared with 40.3% of patients receiving single-agent ruxolitinib.

Concerning the hallmarks of the disease, the rate of improvement in myelofibrosis was 38.3% in the pelabresib/ruxolitinib group and 25.3% in the ruxolitinib group; 17.0% and 27.7% of patients worsened, respectively. Furthermore, a significant reduction in pro-inflammatory cytokine levels from baseline was observed at week 24 with dual treatment compared with monotherapy. Compared with placebo plus ruxolitinib, the combination treatment of pelabresib and ruxolitinib showed a significant reduction in splenomegaly, a trend of improvement in symptom scores, and improvements in multiple indicators of anemia and bone marrow microenvironment, affecting four markers of myelofibrosis.

The incidence of any-grade treatment-emergent adverse effects (TEAEs) was 96.7% compared with 96.7% in the monotherapy arm; these effects were grade 3 or higher in 49.1% and 57.0% of patients, respectively. The incidence rates of serious adverse events were 29.7% and 29.4% respectively. TEAEs resulted in a dose reduction of pelabresib or placebo in 32.5% and 29.0% of patients, respectively, or a dose reduction of ruxolitinib in 47.6% and 41.6% of patients, respectively. TEAEs resulted in dose interruptions of pelabresib or placebo in 32.1% and 22.9% of patients, respectively, or ruxolitinib in 23.1% and 16.4% of patients, respectively. TEAE caused 12.3% and 7.5% of patients to discontinue pelabresib or placebo, respectively, and 9.9% and 6.1% of patients to discontinue ruxolitinib, respectively.

With respect to anemia, granulocytosis, the proportion of anemia was higher with ruxolitinib alone, including 36.5% of grade 3 or higher events. The proportion of thrombocytopenia was higher with combination therapy. In terms of non-hematological adverse effects, with two notable exceptions, adverse effects were essentially similar between the two groups. One is dysgeusia, with a higher proportion of patients receiving combination therapy, but it is worth noting that this is a dose-dependent effect, and reducing the dose did alleviate this adverse reaction; only 1 patient withdrew due to this adverse reaction. Another note of note was that 11% of patients on the combination therapy developed muscle cramps.

Accelerated and blast phase progression occurred in 3.3% of patients who received the combination and in 2.3% of patients who received ruxolitinib alone. A higher proportion of patients treated with ruxolitinib progressed to accelerated phase disease, and a higher proportion of patients receiving combination therapy progressed to blast phase disease. In terms of actual numbers,Five patients [in the combination group] progressed to blast phase disease at the first data cutoff, compared with 1 patient in the ruxolitinib group. However, upon further judgment, one of the blast phase cases was actually diffuse large B-cell lymphoma, so the actual number here is 4 patients compared to 1 patient in the corresponding group.