CHICAGO—Results of COMFORT-I, a randomized, double-blind, Phase 3 trial of ruxolitinib (INCB18424) demonstrated marked and sustained clinical benefits in spleen size, debilitating symptoms, quality of life (QOL), and an acceptable safety profile relative to placebo in patients with myelofibrosis, according to study results presented at the American Society of Clinical Oncology’s 2011 Annual Meeting.
Ruxolitinib is a selective JAK 1 and 2 inhibitor with clinical activity in myelofibrosis. Dysregulated JAK-STAT signaling is a key feature in myelofibrosis, which is characterized by splenomegaly, debilitating symptoms, cytopenias and shortened survival. There are currently no effective drug therapies for myelofibrosis.
Patients with intermediate-2 or high-risk myelofibrosis, palpable spleen ≥5cm, and regardless of JAK2 V617F permutation were randomized (n=309) to start placebo or ruxolitinib at a dose of 15mg or 20mg orally twice daily depending on baseline platelet count (100–200 X 109/L or >200 X 109/L, respectively). The dose was optimized for efficacy and safety during treatment. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume at Week 24 of therapy, assessed by blinded review of spleen MRI or CT. Secondary endpoints included durability of spleen response of ≥35% reduction from baseline spleen volume, changes in symptom burden (≥50% of Total Symptom Score [SS] measured daily with MFSAF v2.0), and overall survival. Exploratory endpoints included change in QOL (EORTC-QLQ C30) and fatigue (PROMIS-FS), molecular and serum biomarkers, and transfusion dependence.
Srdan Verstovsek, MD, PhD, and colleagues from University of Texas M.D. Anderson Cancer Center, Houston, evaluated a total of 309 randomized patients (155 ruxolitinib; 154 placebo) with a median follow-up of 32.2 weeks. The primary endpoint response rate was 41.9% vs. 0.7% (ruxolitinib vs. placebo; P<0.0001). The median duration of response has not been reached. At Week 24, the proportion of patients with ≥50% improvement in SS 45.9% vs. 5.3% (ruxolitinib vs. placebo; P<0.0001) and change in total SS was an improvement of 46.1% vs. a worsening of 41.8% (ruxolitinib vs. placebo; P<0.0001). There were 10 deaths in the ruxolitinib group vs. 14 deaths in the placebo group (HR 0.67; P=0.3268). Changes in both QOL and fatigue mirrored changes in SS over time and all showed improvement relative to placebo regardless of changes in hemoglobin.
The most common adverse events of any grade seen in >20% of patients on either treatment arm of the study (ruxolitinib vs. placebo, respectively) were: abdominal pain (10.3% vs. 41.1%;), thrombocytopenia (34.2% vs. 9.3%), fatigue (25.2% vs. 33.8%), anemia (31% vs. 13.9%), diarrhea (23.2% vs. 21.2%) and peripheral edema (18.7% vs. 22.5%). Non-hematological AEs that occurred more frequently in the ruxolitinib arm included: ecchymosis (19% vs. 9%), dizziness (19% vs.7%), and headache (19% vs. 7%). Anemia and thrombocytopenia were manageable and rarely (0.6% vs. 0.7%) led to withdrawal from the study.
Dr. Verstovsek concluded that, “ruxolitinib demonstrated marked and sustained clinical benefits in spleen size and symptomatic burden. These improvements were similar regardless of the presence of the JAK2 V617F mutation.”