The New England Journal of Medicine (NEJM) today published results from two Phase III studies (COMFORT-I and COMFORT-II) of Jakafi™ (ruxolitinib), a JAK1 and JAK2 inhibitor recently approved by the Food and Drug Administration (FDA) for the treatment of intermediate or high-risk myelofibrosis (MF). These data, which were included in the New Drug Application for Jakafi submitted by Incyte Corporation (Nasdaq:INCY), showed that the treatment significantly reduced spleen volume and improved symptoms of MF. Additionally, in an updated analysis of COMFORT-I, treatment with Jakafi was associated with improved overall survival compared to placebo.
MF is a life-threatening blood cancer characterized by an enlarged spleen and progressive, debilitating symptoms such as fatigue, severe itching (pruritus), night sweats, bone pain, early satiety (a feeling of fullness), and weight loss that can lead to impaired quality of life.
"Given the life-threatening nature and disease burden of myelofibrosis, it's gratifying to see a treatment that may provide an overall survival benefit as well as reduce the splenomegaly and symptoms that impact so many of these patients. Importantly, patients receiving ruxolitinib experienced these benefits regardless of their JAK2V617F mutation status," stated Srdan Verstovsek, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and the principal investigator of the COMFORT-I pivotal trial.
Dr. Verstovsek added, "Another key finding from the Phase III trials is that patients receiving placebo or best available therapy continued to see their spleens increase in size and their symptoms worsen, further supporting the therapeutic benefit of ruxolitinib."
In COMFORT-I, a Phase III double-blind, placebo-controlled trial of 309 patients, 41.9% of patients receiving ruxolitinib achieved the primary endpoint of at least a 35% reduction in spleen volume reduction roughly equivalent to a reduction in palpable spleen size by 50% at week 24 compared with 0.7% of patients in the placebo group (p<0.001). The reductions in spleen volume observed with ruxolitinib therapy were durable, with 67% of responding patients maintaining this response for at least 48 weeks. Almost all patients treated with ruxolitinib had some reduction in spleen volume, whereas the majority of patients receiving placebo had spleen growth.
Significantly more patients in the group receiving ruxolitinib than in the placebo group experienced at least a 50% improvement in Total Symptom Score (which comprises scores for night sweats, itching, abdominal discomfort, pain under the ribs on the left side, early feeling of fullness, and muscle/bone pain) at week 24 (45.9% vs 5.3%; p<0.001). The majority of responses occurred within the first 4 weeks of treatment. Most patients treated with ruxolitinib had some improvement in Total Symptom Score, while the majority of patients receiving placebo experienced worsening of their symptoms.
A survival analysis conducted at the time of a planned safety data cutoff with 4 additional months of follow-up suggests a survival advantage for ruxolitinib over placebo with 13 (8.4%) deaths in the ruxolitinib and 24 (15.6%) in the placebo group (median follow-up, 51 weeks; HR, 0.50; 95% CI, 0.25-0.98)
The clinical benefits of ruxolitinib therapy were also observed in other patient-reported outcomes, including the Patient Global Impression of Change. At week 24, 67% of patients treated with ruxolitinib rated their overall condition as much improved or very much improved, whereas most placebo-treated patients rated it as unchanged or worse.
Anemia and thrombocytopenia were the most common adverse events, but rarely led to discontinuation (1 patient in each treatment group for each event). Non-hematologic adverse events that occurred more frequently in the ruxolitinib group were bruising, dizziness, and headache. Adverse events that occurred after interruption or discontinuation of ruxolitinib treatment showed no pattern of a withdrawal effect; rather, and as expected, myelofibrosis symptoms gradually returned to baseline levels over approximately one week after stopping therapy.
In the COMFORT-II trial, an open label trial comparing ruxolitinib to best available therapy, conducted by Novartis, Incyte's collaboration partner outside of the U.S., ruxolitinib produced a volumetric spleen size reduction of 35% or greater in 28.5% of myelofibrosis patients compared to 0% of patients in the best available therapy (BAT) arm at 48 weeks (p<0.001). At week 24, 32% of patients treated with ruxolitinib demonstrated a 35% or greater volumetric spleen size reduction compared to 0% of patients treated with BAT (p<0.001) for the key secondary endpoint. Additionally, ruxolitinib was associated with improvements in myelofibrosis symptoms at each evaluation as compared to BAT.
Consistent ruxolitinib therapy during COMFORT-II also provided a marked and durable improvement in overall quality of life measures, functioning and symptoms, including appetite loss, dyspnea, fatigue, insomnia and pain, by week 48, compared to a worsening of symptoms in BAT-treated patients. In the group treated with ruxolitinib, the most common adverse events were anemia and thrombocytopenia. The most frequently reported serious adverse event (SAE) was anemia for both arms (ruxolitinib, 5%; BAT, 4%). Pneumonia was the only SAE reported in ≥5% of patients in either arm (ruxolitinib, 1%; BAT, 5%).
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