Dr Kuykendall on the Efficacy of Pelabresib Plus Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis

Andrew Kuykendall, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the efficacy of the combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis based on data from the phase 3 MANIFEST-2 trial (NCT04603495).

In the randomized, double-blind, placebo-controlled trial, patients with treatment-naive disease were randomly assigned 1:1 to receive pelabresib in combination with ruxolitinib or placebo plus ruxolitinib.

Results presented at the 2023 ASH Annual Meeting showed that the combination of pelabresib and ruxolitinib produced a statistically significant and clinically meaningful improvement in spleen volume reduction of at least 35% (SVR35) vs placebo plus ruxolitinib in patients with JAK inhibitor-naive myelofibrosis, Kuykendall reports. At a median follow-up of 45.4 weeks, 65.9% of patients treated with the combination experienced SVR35 at week 24 vs 35.2% of patients treated with placebo plus ruxolitinib. This difference was statistically significant (95% CI, 21.6-39.3; P < .001). Moreover, the mean percentage change in spleen volume at week 24 was –50.6% (n = 171; 95% CI, –53.2% to –48%) with the combination and –30.6% (n = 183; 95% CI, –33.7 to –27.5) with the placebo regimen.

Additionally, pelabresib and ruxolitinib trended toward reducing mean absolute total symptom score (TSS) and improving TSS reduction by 50% (TSS50) at 24 weeks, Kuykendall states, noting that this improvement was not statistically significant. The combination reduced the absolute total symptom score (TSS) from baseline by 15.99 points at week 24. In comparison, the median reduction in TSS was 14.05 points in those treated with placebo plus ruxolitinib (delta, –1.94; 95% CI, –3.92 to 0.04; P = .0545). At week 24, the combination produced a numerically greater TSS50 response of 52.3% vs 46.3% with placebo (95% CI, –3.5 to 15.5; P = .0216).

Overall, findings show that pelabresib plus ruxolitinib is a safe and clinically active combination that could improve the lives of patients in patients with treatment-naive myelofibrosis, Kuykendall says. Although these are encouraging initial data, further research is needed to confirm the combination's ability to improve symptoms and provide durable responses in this population, he concludes.