Matching-adjusted indirect comparison of pelabresib/ruxolitinib combination vs JAKi monotherapy in myelofibrosis.

Janus kinase (JAK) inhibitors (JAKis) ruxolitinib, fedratinib and pacritinib are the current standard of care in symptomatic myelofibrosis (MF). However, progressive disease and toxicities frequently lead to JAKi discontinuation. Preclinical data indicate that combining JAK and bromodomain and extraterminal domain (BET) inhibition leads to overlapping effects in MF. Pelabresib (CPI-0610), an oral, small-molecule BET1,2 inhibitor (BETi), in combination with ruxolitinib, showed improvements in spleen volume reduction (SVR35) and total symptom score reduction (TSS50) from baseline in the phase 2 MANIFEST study (NCT02158858) in patients with MF. Given the absence of a head-to-head clinical comparison between JAKi monotherapy and JAKi with BETi combination therapy, we performed an unanchored matching-adjusted indirect comparison analysis to adjust for differences between studies and allow for comparison of SVR35, TSS50, and total symptom score (TSS) measured at several timepoints in Arm 3 of MANIFEST (pelabresib with ruxolitinib in JAKi treatment-naïve patients with MF) with data from JAKi monotherapy studies in JAKi treatment-naïve patients: COMFORT-I and COMFORT-II (ruxolitinib), SIMPLIFY-1 (ruxolitinib, momelotinib), and JAKARTA (fedratinib). Response rate ratios >1 were observed for pelabresib with ruxolitinib versus all comparators for SVR35 and TSS50 at Week 24. Improvements in TSS were observed as early as Week 12 and were durable. These results indicate that pelabresib with ruxolitinib may have a potentially higher efficacy than JAKi monotherapy in JAKi treatment-naïve MF.