Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis

Abstract

Ruxolitinib is a Janus kinase (JAK) (JAK1/JAK2) inhibitor that has demonstrated superiority over placebo and best available therapy (BAT) in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies. COMFORT-II was a randomized (2:1), open-label phase 3 study in patients with myelofibrosis; patients randomized to BAT could crossover to ruxolitinib upon protocol-defined disease progression or after the primary end point, confounding long-term comparisons. At week 48, 28% (41/146) of patients randomized to ruxolitinib achieved ⩾35% decrease in spleen volume (primary end point) compared with no patients on BAT (P<0.001). Among the 78 patients (53.4%) in the ruxolitinib arm who achieved ⩾35% reductions in spleen volume at any time, the probability of maintaining response was 0.48 (95% confidence interval (CI), 0.35-0.60) at 5 years (median, 3.2 years). Median overall survival was not reached in the ruxolitinib arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with ruxolitinib compared with BAT by intent-to-treat analysis (hazard ratio (HR)=0.67; 95% CI, 0.44-1.02; P=0.06); the crossover-corrected HR was 0.44 (95% CI, 0.18-1.04; P=0.06). There was no unexpected increased incidence of adverse events with longer exposure. This final analysis showed that spleen volume reductions with ruxolitinib were maintained with continued therapy and may be associated with survival benefits.

Conflict of interest statement

CNH has received research support from Novartis, Cell Therapeutics, Gilead and Baxaltra through the institution; has received personal fees from Novartis, Shire, Gilead and Baxaltra; and has received grant and non-financial support from Novartis outside the submitted work. AMV has received grant and personal fees from Novartis during the conduct of the study. J-JK has received travel grant, and research funding paid to the institution from Novartis; has acted as a consultant to Novartis and Incyte. HKA-A has received research funding from Novartis and Celgene; acted as a consultant to Novartis; and has received honoraria from Novartis and Celgene. HG has received honoraria from Novartis, Celgene and AOP Orphan Pharmaceuticals; and has two licensed patents: EP 13.18.6939.8 and 13.18.4632.1. FC has received personal fees from Novartis, CTI-Baxter and Sanofi. MMJ and KS are employees of Incyte. MM and VS are employees of and own stock in Novartis. PG is an employee of Novartis.

Figures

Figure 1

Best change from baseline in spleen volume for individual patients.a aOnly patients with baseline and ⩾1 postbaseline spleen volume assessments were included (ruxolitinib, n=136; BAT crossover, n=39). bPatients with a ⩾35% reduction in spleen volume were considered as responders.

Figure 2

Duration of maintenance of spleen response.a aDefined as the interval from first spleen volume measurement of ⩾35% reduction from baseline at any time on study and the first scan that is no longer a 35% reduction and that is a >25% increase over on-study nadir.

Figure 3

Best absolute reduction in JAK2 V617F allele burden for individual patients.a aOnly ruxolitinib-randomized patients with positive Janus kinase 2 (JAK2) V617F mutation status at baseline and ⩾1 postbaseline assessment were included (n=108).

Figure 4

Kaplan–Meier analysis of OS by ITT analysis and RPSFT corrected for crossover from the BAT arm.