MANIFEST-2 Meets Primary End Point With Pelabresib Plus Ruxolitinib in MF

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The combination of pelabresib (CPI-0610), an investigational BET inhibitor, with the ruxolitinib (Jakafi), a JAK inhibitor, demonstrated a statistically significant and clinically meaningful improvement in the proportion of JAK inhibitor-naive patients with myelofibrosis (MF) achieving at least a 35% reduction in spleen volume (SVR35) at week 24 compared with placebo plus ruxolitinib, according to topline results from the phase 3 MANIFEST-2 study (NCT04603495).¹

A total of 66% of patients treated with pelabresib plus ruxolitinib achieved SVR35 at week 24 vs 35% of patients given placebo plus ruxolitinib (95% CI, 21.6-39.3; P <.001), meeting the primary end point of the study.

Further, the key secondary end points of symptom improvement in patients achieving at least a 50% reduction in total symptom score (TSS50) and absolute change in total symptom score (TSS) from baseline at week 24 were also promising with a strong positive trend favoring pelabresib plus ruxolitinib combination with TSS reduced by 15.99 points at week 24 at baseline vs 14.05 points at week 24 in the placebo plus ruxolitinib arm (Δ -1.94; 95% CI, -3.92-0.04, P =.0545), using least square mean estimate.

“Pelabresib is a first-in-class oral inhibitor of BET proteins, primarily those containing the BD1 and BD2 domains. It's being developed currently in myelofibrosis. It has been tested in other diseases, but it has shown significant activity in myelofibrosis,” said Joseph M. Scandura, MD, PhD, Weill Cornell Medicine,in an interview with Targeted Oncology^TM.

“I believe MANIFEST-2 provides us with valuable evidence that the addition of pelabresib offers meaningful improvements over JAK inhibitor monotherapy as a first-line approach for patients with myelofibrosis,” said John Mascarenhas, MD, director of the adult leukemia program at The Tisch Cancer Institute at Mount Sinai, New York, in a press release.¹ “The pelabresib and ruxolitinib combination therapy significantly reduced spleen volume—the best prognostic indicator we have at our disposal for long-term myelofibrosis patient outcomes. Based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation.”

MANIFEST-2 is an ongoing, randomized, double-blind, phase 3 trial where 430 patients with JAK inhibitor-naive MF were randomly assigned in a 1:1 ratio to receive upfront pelabresib plus ruxolitinib vs ruxolitinib alone.²

Patients aged ≥ 18 years with a confirmed diagnosis of MF, adequate hematologic, renal, and hepatic function, and an ECOG performance status of ≤ 2 were eligible for inclusion in the trial. Enrollment was also open to patients who had at least 2 symptoms with an average score ≥ 3 or an average total score of ≥ 10 over the 7-day period prior to randomization using the MFSAF v4.0, a prognostic risk-factor score of intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS) scoring system, and a spleen volume of ≥ 450 cm³.

If patients had splenectomy or splenic irradiation in the previous 6 months, chronic or active conditions and/or concomitant medication use that would prevent them from receiving treatment, or had previously been treated with any JAK or BET inhibitor for treatment of a myeloproliferative neoplasm, they were excluded from the study.

Additional findings showed that treatment with the combination also showed significant improvements in both key secondary end points within an analysis of patients classified as intermediate risk who made up over 90% of patients in MANIFEST-2. DIPSS Int-1 and Int-2 was a predefined stratification factor in the protocol for the MANIFEST-2 trial. Here, TSS was reduced by 15.18 points at week 24 with pelabresib plus ruxolitinib vs 12.74 points at week 24 in the placebo plus ruxolitinib arm (Δ -2.44; 95% CI, -4.48- -0.40; P <.02).¹

Another key secondary end point, TSS50, was met among 52% of patients treated with pelabresib and ruxolitinib at week 24 vs 46% treated with placebo plus ruxolitinib (95% CI, -3.5-15.5; P =.216).¹ Among patients at intermediate-risk, 55% of patients achieved TSS50 in the pelabresib and ruxolitinib treatment arm at week 24 compared with 45% in the placebo plus ruxolitinib arm (95% CI, 0.35-19.76; P <.05).

Following a Type C meeting with the FDA in September 2023, absolute change in TSS was included as a key secondary end point in the study. Per clinical protocol, this continuous end point was created to directly measure change in the average TSS from baseline to week 24 to help accurately estimate the magnitude of symptom burden reduction among patients with MF.

Findings from MANIFEST-2 also demonstrated that more patients achieved hemoglobin response (≥ 1.5 g/dL from baseline)in the pelabresib and ruxolitinib arm vs the placebo and ruxolitinib arm. For safety, the safety profile of pelabresib and ruxolitinib was consistent with what was previously observed with the combination and no new safety signals were observed. Adverse events of anemia were seen less frequently among patients in the pelabresib and ruxolitinib arm than those in the placebo and ruxolitinib arm.

Findings from the phase 3 MANIFEST-2 study will be further presented during an oral presentation at the 65th American Society for Hematology Annual Meeting and Exposition. Based on this encouraging data, continued conversations with regulatory agencies will occur with hopes of submitting a new drug application for combination of pelabresib and ruxolitinib in MF to the FDA in the middle of 2024.

“Myelofibrosis patients experience a severely diminished quality-of-life due to symptoms such as severe fatigue, night sweats, bone pain and fever—symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” said Ruben A. Mesa, MD, FACP, president and executive director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, in a press release.¹ “Total symptom score assessment is a validated tool to document the challenges that patients encounter on a daily basis. The symptom reduction shown in MANIFEST-2 is an important result that should be strongly considered when evaluating the efficacy of the pelabresib and ruxolitinib combination therapy for myelofibrosis.”

REFERENCES:

1. MorphoSys’ phase 3 study of pelabresib in myelofibrosis demonstrates statistically significant improvement in spleen volume reduction and strong positive trend in symptom reduction. News release. MorphoSys AG. November 20, 2023. Accessed November 21, 2023. https://tinyurl.com/2n9swrer

2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated September 25, 2023. Accessed November 21, 2023. https://www.clinicaltrials.gov/study/NCT04603495