Pelabresib plus ruxolitinib showed “potentially higher efficacy” than Janus kinase (JAK) inhibitor monotherapy in patients with myelofibrosis who were JAK-inhibitor naïve, according to a recent study.
Vikas Gupta, MD, of the Princess Margaret Cancer Centre and colleagues conducted the study because preclinical data “indicate that combining JAK and bromodomain and extraterminal domain (BET) inhibition leads to overlapping effects” in myelofibrosis.
For example, the oral BET inhibitor pelabresib plus ruxolitinib showed improvement in spleen volume reduction and total symptom score reduction from baseline in patients with myelofibrosis in the phase II MANIFEST study, the study’s authors noted.
Researchers Use Indirect Comparison Analysis to Evaluate JAK Inhibitor Combination, Monotherapy
Dr. Gupta and colleagues performed an unanchored matching-adjusted indirect comparison analysis among multiple clinical trials. They used this approach to adjust for differences between studies and allow for a comparison of outcomes from arm three of the MANIFEST trial with outcomes from the COMFORT-I, COMFORT-II, SIMPLIFY-1, and JAKARTA trials.
Arm three of the MANIFEST trial evaluated pelabresib with ruxolitinib in patients with myelofibrosis who were JAK-inhibitor naïve. COMFORT-I and COMFORT-II evaluated ruxolitinib in patients with myelofibrosis who were JAK-inhibitor naïve. SIMPLIFY-1 evaluated ruxolitinib and momelotinib in patients with myelofibrosis who were JAK-inhibitor naïve, and JAKARTA evaluated fedratinib in patients with myelofibrosis who were JAK-inhibitor naïve.
Dr. Gupta and colleagues compared outcomes including spleen volume reduction of at least 35% (SVR35), total symptom score (TSS), and TSS with a reduction of at least 50% (TSS50) among the trials.
In arm three of the phase II MANIFEST study, patients with intermediate- or high-risk myelofibrosis who had not previously received a JAK inhibitor had an SVR35 rate of 68% and a TSS50 rate of 56%. The researchers found response rate ratios of at least one for pelabresib with ruxolitinib versus all comparators (ruxolitinib, momelotinib, or fedratinib monotherapy) for SVR35 and TSS50 at week 24. They noted that TSS improvements were reported as early as week 12 and were durable.
“These results indicate that pelabresib with ruxolitinib may have a potentially higher efficacy than JAK [inhibitor] monotherapy in JAK [inhibitor] treatment-naïve [myelofibrosis],” the study’s authors concluded.
Gupta V, Mascarenhas JO, Kremyanskaya M, et al. Matching-adjusted indirect comparison of pelabresib/ruxolitinib combination vs JAKi monotherapy in myelofibrosis. Blood Adv. 2023. doi:10.1182/bloodadvances.2023010628