Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis

Abstract

Background: Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor.

Methods: We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis.

Results: A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis.

Conclusions: INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)

Figure 1. Clinical Responses to INCB018424 Therapy

Patients who received INCB018424 had clinical improvement (according to the criteria of the International Working Group for Myelofibrosis Research and Treatment) on the basis of a reduction of 50% or more in palpable splenomegaly, which was durable for 12 cycles (12 months) (Panel A). The proportion of patients with a 0 to 24%, 25 to 49%, 50 to 99%, or 100% decrease in palpable spleen length relative to baseline was similar between the groups of patients in the intention-to-treat population who received 15 mg twice daily and 25 mg twice daily; 10 mg twice daily provided a lesser, but durable, response (Panel B). Reduction in the spleen size was rapid and durable for approximately 2 years, as shown by the mean spleen size over time. The initial response to INCB018424 therapy (reduction in mean spleen length) is shown for the patients who received 15 mg twice daily and 25 mg twice daily (Panel C) and for the subgroup of patients who received their originally assigned dose for at least 6 months (Panel D). I bars denote standard errors.

Figure 2. Effects of INCB018424 on Symptoms of Myelofibrosis and Weight

Panel A shows the proportion of patients who received INCB018424 at a dose of 10 to 25 mg twice daily who had at least a 50% decrease in the individual symptom score on the Modified Myelofibrosis Symptom Assessment Form (MFSAF) relative to baseline that was durable for 6 months. After 1 month, 75%, 82%, 52%, and 63% of the patients had at least a 50% improvement in scores for night sweats, itching, abdominal pain or discomfort, and bone or muscle pain, respectively. After 6 months, 88%, 82%, 55%, and 40% of the patients had at least a 50% improvement in scores for night sweats, itching, abdominal pain or discomfort, and bone or muscle pain, respectively. A combined symptom score comprising scores for night sweats, itching, abdominal pain or discomfort, and bone or muscle pain was calculated, and the proportion of patients with a 50% or greater improvement relative to baseline was determined. As shown in Panel B, similar proportions of patients had improvement in symptoms at doses of 10 mg twice daily (75% at 1 month and 63% at 6 months), 15 mg twice daily (56% at 1 month and 56% at 6 months), or 25 mg twice daily (55% at 1 month and 64% at 6 months). As shown in Panel C, an increase in weight was observed after INCB018424 treatment in patients who received twice-daily doses of 10 mg to 25 mg; this increase was more pronounced in patients in the lowest quartile of the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) (16.2 to 22.5) than in those in the highest quartile (27.9 to 49.7). I bars denote standard errors.

Figure 3. Effect of INCB018424 Treatment on Biomarkers

Plasma levels of various biomarkers were evaluated in samples obtained from healthy controls and patients at baseline and after one or six cycles of therapy, with the use of the HumanMAP, version 1.6 panel (Rules-Based Medicine). Plasma levels of selected markers are shown as heat maps (Panels A and B). Each row constitutes one plasma marker, with the data for individual patients organized in columns. Green and red denote markers that are present at lower and higher levels, respectively, in baseline samples from patients relative to control samples. Biomarker data obtained from patients who received INCB018424 (at a dose of 25 mg twice daily) after one cycle of treatment were compared with baseline values for the same patients (Panel B). Green denotes markers that decreased with INCB018424 treatment, and red denotes markers that increased with therapy. Changes in selected cytokines and C-reactive protein, an acute-phase reactant and a marker for inflammation, are shown in patients with a 50% or greater decrease, those with less than a 50% decrease, and those with no change or an increase in the composite symptom score after 6 cycles of treatment as compared with baseline (Panel C). EN-RAGE denotes extracellular newly identified receptor for advanced glycosylation end products–binding protein, FGF fibroblast growth factor, ICAM-1 intracellular adhesion molecule 1, MIP-1β macrophage inflammatory protein 1β, MMP-2 matrix metalloproteinase 2, PET post–essential thrombocythemia myelofibrosis, PMF primary myelofibrosis, PPV post–polycythemia vera myelofibrosis, TNF-α tumor necrosis factor α, VCAM-1 vascular adhesion molecule 1, and VEGF vascular endothelial growth factor.