A phase 3 study of pelebresib plus ruxolitinib for JAK inhibitor-naive patients with myelofibrosis

Background Current treatment strategies in myelofiboris are based on Janus kinase (JAK) inhibitors. Unfortunately, these treatments provide limited depth and durability of response. A potential new treatment paradigm is the combination of novel agents targeting different patways with the current used JAK inhibitors. Herein we present the results of a randomized clinical trial comparing pelabresib, a bromodomain and extraterminal domain (BET) inhibitor, plus ruxolitinib, to placebo plus ruxolitinib in myelofibrosis. Methods In this Phase 3 study, JAK inhibitor-naïve patients with myelofibrosis were randomized 1:1 to pelabresib (125–175 mg) once daily for 14 days then a 7-day break (21-day cycle), or placebo, in combination with ruxolitinib (10–25 mg) twice daily. Primary endpoint was reduction in spleen volume of at least 35% from baseline at week 24. Key secondary endpoints were absolute change in total symptom score (TSS), and TSS50 response (at least 50% reduction from baseline at week 24). Results The primary endpoint was achieved in 65.9% of patients randomized to pelabresib–ruxolitinib (n=214) versus 35.2% randomized to placebo–ruxolitinib (n=216) (difference: 30.4%; 95% confidence interval [CI]: 21.6, 39.3; p<0.001). Absolute change in symptom score was -15.99 versus -14.05 (difference: -1.94; 95% CI: -3.92, 0.04; p=0.0545), and TSS50 was achieved in 52.3% versus 46.3% (difference: 6.0%; 95 CI: -3.5, 15.5; p=0.216), in the pelabresib–ruxolitinib group versus placebo–ruxolitinib group, respectively. Anemia and thrombocytopenia were the most common treatment-emergent adverse events (TEAEs). TEAEs of anemia were less frequent with pelabresib–ruxolitinib (43.9%; Grade ≥3: 23.1%) compared to placebo–ruxolitinib (55.6%; Grade ≥3: 36.4%). 2 Conclusions Pelabresib in combination with ruxolitinib provided substantial clinical benefit and was generally well tolerated, supporting a paradigm shift in front-line treatment for patients with myelofibrosis.