The FDA has now approved fedratinib (Inrebic®, Impact Biomedicines, Inc./Celgene Corporation) for the treatment of intermediate-2 or high-risk primary or secondary myelofibrosis.
A myeloproliferative neoplasm, myelofibrosis can either present as a primary condition or as a secondary condition following the transformation of polycythemia vera or essential thrombocythemia. Myelofibrosis causes anemia, splenomegaly, and debilitating symptoms, and it shortens survival.
"Prior to today, there was one FDA-approved drug to treat patients with myelofibrosis, a rare bone marrow disorder," commented Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, referring to ruxolitinib (Jakafi®, Incyte), which was approved by the FDA in 2011. "Our approval today provides another option for patients."
The approval was based on data from the phase 3 JAKARTA trial (NCT01437787), led by first author Animesh Pardanani, MBBS, PhD, and senior author Ayalew Tefferi, MD, both Professors of Medicine and Consultants in the Division of Hematology at Mayo Clinic in Rochester, Minnesota. For this study, 289 adults with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis were randomized in a 1:1:1 ratio to receive once-daily oral fedratinib at a dose of 400 mg or 500 mg or placebo for at least six consecutive four-week cycles. The trial's primary end point was spleen response, constituting at least 35% reduction in spleen volume from baseline at week 24 with confirmation four weeks later, with a secondary end point of at least 50% reduction in total symptom score, assessed per the modified Myelofibrosis Symptom Assessment Form.
Dr. Pardanani and colleagues reported that fedratinib produced at least a 35% reduction in spleen volume in 36% of patients in the fedratinib 400-mg group and 40% of patients in the fedratinib 500-mg group, compared with 1% of patients in the placebo group. At week 24, symptom response rates were 36% for 400 mg fedratinib, 34% for 500 mg fedratinib, and 7% for placebo.
The phase 2 JAKARTA-2 study (NCT01523171), led by Claire Harrison, MD, FRCP, FRCPath, Consultant Hematologist and Deputy Director of Guys' and St. Thomas' Hospital in London, evaluated fedratinib in 97 patients with intermediate- or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis who were ruxolitinib resistant or intolerant after at least 14 days of treatment. Of the 83 evaluable patients, 55% achieved a spleen response.
Frequent adverse events in patients taking fedratinib included anemia, gastrointestinal symptoms, fatigue, muscle spasms, and increased liver transaminase, serum creatinine, and pancreatic enzyme levels. Due to the occurrence of encephalopathy in 4 women in the 500-mg fedratinib arm of the JAKARTA trial, for which a diagnosis of Wernicke encephalopathy—a neurologic emergency related to thiamine deficiency—was supported by magnetic resonance imaging (MRI) in 3 cases and clinically suspected in 1 case, the clinical development of fedratinib was discontinued in 2013. The FDA lifted the hold on fedratinib development in October 2017 following the review of additional clinical data.
At the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting, Dr. Harrison and colleagues presented a reanalysis of the JAKARTA-2 data, using more stringent criteria to define myelofibrosis that was relapsed or refractory to ruxolitinib. In the 79 enrolled patients who met the more stringent criteria for ruxolitinib failure, fedratinib produced a spleen volume response rate of 30% and a symptom response rate of 27%.
The prescribing information for fedratinib contains a boxed warning concerning the risk of serious and fatal encephalopathy, including Wernicke encephalopathy. If a health care professional suspects encephalopathy, fedratinib should be discontinued immediately. The prescribing information also contains warnings regarding severe anemia and thrombocytopenia. Patients should be monitored for gastrointestinal and hepatic toxicities, with treatment discontinuation if a patient develops severe diarrhea, nausea, or vomiting. High amylase or lipase levels in the blood should also be managed by dose reduction or treatment discontinuation.
For More Information
Harrison CN, Schaap N, Vannucchi AM, et al (2019). Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): a reanalysis of the JAKARTA-2 study. J Clin Oncol (ASCO Annual Meeting Abstracts), 37(suppl_15). Abstract 7057. DOI:10.1200/JCO.2019.37.15_suppl.7057
Harrison CN, Schaap N, Vannucchi AM, et al (2017). Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol, 4(7):E317-E324. DOI:10.1016/S2352-3026(17)30088-1
Pardanani AD, Cortes JE, Cervantes F, et al (2017). JAKARTA: A phase III, multicenter, randomized, double-blind, placebo-controlled, three-arm study of SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF with splenomegaly. J Clin Oncol, 30(suppl_15). Abstract TPS6639. DOI:10.1200/jco.2012.30.15_suppl.tps6639
Pardanani A, Harrison C, Cortes JE, et al (2015). Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol, 1(5):643-651. DOI:10.1001/jamaoncol.2015.1590
Image credit: Ed Uthman. Licensed under CC BY 2.0