Updated MANIFEST-2 Data With Pelabresib/Ruxolitinib Support Paradigm Shift in Myelofibrosis

The addition of pelabresib (CPI-0610) and ruxolitinib (Jakafi) led to a significant and durable reduction in splenomegaly, showed a trend toward reduced tumor symptom score (TSS) from baseline, and improved anemia and bone marrow fibrosis at week 24 vs ruxolitinib alone in JAK inhibitor–naive patients with myelofibrosis, according to updated data from the phase 3 MANIFEST-2 study (NCT04603495) presented at the 2024 ASCO Annual Meeting.¹

As previously presented at the 2023 ASH Annual Meeting, the trial met its primary end point when a higher percentage of those who received the doublet (n = 214) experienced a 35% or greater reduction in spleen volume (SVR35) at week 24 vs those given ruxolitinib alone (n = 216), at 65.9% and 35.2%, respectively (difference, 30.4; 95% CI, 21.6-39.3; P < .001).² The mean percentage change in spleen volume at week 24 in the pelabresib/ruxolitinib arm was -50.6% (95% CI, -53.2% to -48.0%) vs -30.6% (95% CI, -33.7% to -27.5%) in the ruxolitinib-alone arm.

When looking at all responders who achieved SVR35 response, the proportion who lost response at any point in the pelabresib/ruxolitinib arm was 13.4% and more than double in the ruxolitinib-alone arm, at 27.8%. When examining the criteria of loss of SVR35 response plus a spleen volume increase greater than 25% from nadir, this occurred in 9.3% and 14.8% of patients, respectively. Notably, SVR35 response was consistently higher with the doublet vs the monotherapy across all predefined subgroups and across hematologic subgroups.

A strong trend for numerical decrease in absolute change in TSS from baseline at week 24 was observed with the doublet vs the monotherapy, at -15.99 and -14.05, translating to a mean difference of -1.94 points (95% CI, -3.92 to 0.04; P = .0545). A higher proportion of patients who received the combination vs ruxolitinib alone achieved a 50% reduction in TSS (TSS50), at 52.3% vs 46.3% (difference, 6.0; 95% CI, -3.5 to 15.5; P = .216); this difference did not reach statistical significance. A two-fold increase in patients who achieved both SVR35 and TSS50 responses was observed with pelabresib plus ruxolitinib vs ruxolitinib alone, at 40.2% and 18.5%, respectively.

At the meeting, Raajit K. Rampal, MD, PhD, of the Department of Medicine, Leukemia Service, at Memorial Sloan Kettering Cancer Center in New York, New York, shared additional findings from a modified TSS (mTSS) analysis, which he said partially addresses the ceiling effect that is pronounced for the fatigue domain and may help demonstrate the full potential of the doublet to impact disease-associated symptoms.¹ Specifically, when utilizing mTSS, which does not include the fatigue subdomain, there is a numerical advantage with regard to reduction in TSS in favor of the combination regimen (mean difference, -2.10; 95% CI, -4.04 to -0.15; P = .035).

Additional updated data revealed a numerically higher proportion of patients who experienced hemoglobin response with the doublet vs the monotherapy. A hemoglobin response, defined as at least a 1.5-g/dL mean increase, was observed in 10.7% (95% CI, 6.60%-14.90%) of those in the pelabresib/ruxolitinib arm vs 6.0% (95% CI, 2.85%-9.19%) of those in the ruxolitinib-alone arm. In patients with anemia who had baseline hemoglobin of less than 10 g/dL, hemoglobin response was observed in 16.4% (95% CI, 7.55%-25.29%) and 14.1% (95% CI, 5.99%-22.18%) of patients in the doublet and monotherapy arms, respectively. Additionally, red blood cell transfusions (RBC) occurred in 30.3% of those who received the combination at any time during the first 24 weeks of therapy but in 40.3% of those who were given single-agent ruxolitinib.

With regard to hallmarks of the disease, bone marrow fibrosis was improved in 38.3% of those in the pelabresib/ruxolitinib arm vs 25.3% of those in the ruxolitinib-alone arm; it worsened in 17.0% and 27.7% of patients, respectively. Moreover, a significantly greater reduction in proinflammatory cytokine levels at week 24 from baseline were observed with the doublet vs the monotherapy.

“The combination of pelabresib and ruxolitinib showed significantly reduced splenomegaly, a trend toward improved symptom score, and improvements in multiple measures of anemia and in the bone marrow microenvironment compared with placebo plus ruxolitinib, impacting the four hallmarks of myelofibrosis,” Rampal said in a presentation of the data.

MANIFEST-2: Trial Design, Objectives, Baseline Disease Characteristics

The global, randomized, double-blind, active-control, phase 3 study enrolled patients with myelofibrosis who did not have prior exposure to JAK inhibitors, had a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1 or higher, splenomegaly defined as at least 450 cm3 by CT or MRI, and a TSS of at least 10 and at least 3 for two symptoms per the Myelofibrosis Symptom Assessment Form v4.0.

Participants were randomly assigned 1:1 to receive ruxolitinib per label with a 5-mg twice daily lower starting dose on days 1 to 21 plus placebo or pelabresib at 125 mg on days 1 to 14 as part of 21-day cycles. Stratification factors included DIPSS risk category (intermediate-1 vs intermediate-2 vs high), platelet count (>200 x 109/L vs 100 to 200 x 109/L), and spleen volume (≥1800 cm3 vs <1800 cm3).

The primary end point was SVR35 response at week 24, and key secondary end points included absolute change in TSS from baseline at week 24 and TSS50 response at week 24. Safety was also evaluated.

The median patient age in both the doublet and monotherapy arms was 66 years (range, 19-88). Most patients were male (60.3% vs 56.5%) and White (74.8% vs 75.5%). Approximately half had primary myelofibrosis (50.0% vs 50.9%) and an ECOG performance status of 0 (50.0% vs 50.5%) Regarding DIPSS score in the doublet arm, 59.8% had intermediate-1 disease, 35.0% had intermediate-2 disease, and 5.1% had high-risk disease; these rates were 58.8%, 34.3%, and 6.9%, respectively, in the monotherapy arm. Slightly more than half of patients had a JAK2 V617F mutation (58.4% vs 56.5%).

The median baseline hemoglobin level was 10.9 g/dL (range, 5.8-18.0) in the doublet arm and 11.0 g/dL (range, 6.7-17.9) in the monotherapy arm. The respective median platelet counts at baseline were 285 x 109/L (range, 99-1303) and 287 x 109/L (range, 66-1084). Mean peripheral blasts was 0.8 in both arms. Median spleen volume was 1308.89 (range, 200.24-7117.03) and 1382.97 (range, 277.87-5540.45). The percentage of patients who required RBC transfusions at baseline was 10.3% of those in the doublet arm and 9.7% of those in the monotherapy arm; 3.7% vs 0.9% of patients were transfusion dependent at the time of enrollment. The median TSS at baseline was 26.6 (range, 7.3-66.4) vs 24.7 (range, 9.0-68.4).

Safety Data

The combination of pelabresib and ruxolitinib at 24 weeks was reported to be generally comparable to what has been observed with ruxolitinib alone, according to Rampal.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 96.7% of those in the doublet arm vs 96.7% of those in the monotherapy arm; these effects were grade 3 or higher for 49.1% and 57.0% of patients, respectively. Serious AEs occurred in 29.7% and 29.4% of patients, respectively.

TEAEs led to dose reduction of pelabresib or placebo in 32.5% and 29.0% of patients, respectively, or dose reduction of ruxolitinib in 47.6% and 41.6% of patients, respectively. TEAEs led to dose interruptions of pelabresib or placebo for 32.1% and 22.9% of patients, respectively, or dose interruption of ruxolitinib for 23.1% and 16.4% of patients, respectively. TEAEs led to pelabresib or placebo discontinuation in 12.3% and 7.5% of patients, respectively, and ruxolitinib discontinuation for 9.9% and 6.1% of patients, respectively.

“Getting more granular, in terms of anemia, there was a higher proportion of anemia seen with ruxolitinib alone, including 36.5% of grade 3 or higher events. There was a higher proportion of thrombocytopenia seen with the combination therapy,” Rampal reported. “In terms of non-hematologic AEs, these were essentially similar in both arms with two notable exceptions. One is dysgeusia, which was seen with a higher proportion of the combination-treated patients but notably this was a dose-dependent effect and reducing the dose did attenuate this AE; only 1 patient withdrew due to that AE. The other notable thing is muscle spams occurring in 11% of patients on the combination.”

Accelerated and blast-phase progression occurred in 3.3% of those who received the combination vs 2.3% of those given ruxolitinib alone. “A higher proportion of patients treated with ruxolitinib progressed to accelerated-phase disease and higher proportion of patients treated with the combination progressed to blast-phase disease,” Rampal noted. “One important point to make here is that in terms of actual numbers, 5 patients [on the combination arm] progressed at first data cutoff to blast-phase disease vs 1 patient in the ruxolitinib arm. However, upon further adjudication, one of these blast-phase cases actually turned out to be diffuse large B-cell lymphoma, and thus, the actual number here is 4 patients vs 1 patient in the respective arms.”

Leukemic transformation continues to be followed up, Rampal concluded.

References

1. Rampal R, Grosicki S, Chraniuk D, et al. Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naive patients with myelofibrosis. J Clin Oncol. 2024;42(suppl 16):6502. doi:10.1200/JCO.2024.42.16_suppl.6502
2. Rampal R, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus Kinase Inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141