Jakafi Efficacy:
Clinical Trial Results
...ruxolitinib as a treatment option for patients with myelofibrosis (MF)1
Jakafi is indicated for treatment of intermediate or high-risk MF, including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF in adults.
In COMFORT-I,* significantly more patients receiving Jakafi achieved the primary endpoint compared with those who received placebo.2,3
*COMFORT-I (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment-I) was a randomized, double-blind, placebo-controlled phase 3 study with 309 patients with intermediate-2–risk or high-risk myelofibrosis. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to week 24 as measured by CT or MRI. A secondary endpoint was the proportion of subjects with a ≥50% reduction in Total Symptom Score from baseline to week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form.2
In COMFORT-I at week 24, 46% of patients receiving Jakafi achieved a ≥50% improvement in Total Symptom Score† vs 5% of patients receiving placebo (P<0.0001)2,3
†Total Symptom Score was captured by a daily patient diary, the Myelofibrosis Symptom Assessment Form. Total Symptom Score encompasses score symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats, and bone/muscle pain. Symptom scores ranged from 0 to 10, with 0 representing symptoms “absent" and 10 representing symptoms “worst imaginable." These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean Total Symptom Score was 18.0 in the group receiving Jakafi and 16.5 in the group receiving placebo.2,3
COMFORT-I 5-year overall survival probability data4: Jakafi and placebo
At 3 years, survival probability was 70% for patients originally randomized to Jakafi and 61% for those originally randomized to placebo.2
Overall survival was a prespecified secondary endpoint in COMFORT-I.2
Adapted with permission from the Journal of Hematology & Oncology.
aThe 5-year overall survival analysis is not included in the Full Prescribing Information for Jakafi. Although the 3-year overall survival analysis is presented in the Full Prescribing Information, P values and hazard ratios are omitted from the overall survival Kaplan-Meier curves.5
b COMFORT-I was not designed to compare survival probabilities between Jakafi and placebo at 3 or 5 years.5
cPatients randomized to placebo were eligible to cross over to receive Jakafi because of progression-driven events or at the physician’s discretion; however, these patients continued to be grouped within their original randomized assignment for analysis purposes.5
In COMFORT-II,‡ significantly more patients receiving Jakafi achieved the primary endpoint compared with those who received best available therapy (BAT). 2,6§
BAT, best available therapy.
‡COMFORT-II (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment-II) was a randomized, open-label phase 3 study with 219 patients with intermediate-2–risk or high-risk myelofibrosis. The primary endpoint was the proportion of patients achieving a ≥35% reduction in spleen volume from baseline at week 48 as measured by computed tomography (CT) or magnetic resonance imaging (MRI).5
§Best available therapy in COMFORT-II included hydroxyurea (46.6%) and glucocorticoids (16.4%), as well as no medication, anagrelide, epoetin alfa, thalidomide, lenalidomide, mercaptopurine, thioguanine, danazol, peginterferon alfa-2a, interferon-α, melphalan, acetylsalicylic acid, cytarabine, and colchicine.5
COMFORT-II 5-year overall survival probability data7: Jakafi and best available therapy
At 3 years, survival probability was 79% for patients originally randomized to Jakafi and 59% for those originally randomized to BAT.2
Overall survival was a prespecified secondary endpoint in COMFORT-II.2
Adapted with permission from Leukemia.
BAT, best available therapy.
a The 5-year overall survival analysis is not included in the Full Prescribing Information for Jakafi. Although the 3-year overall survival analysis is presented in the Full Prescribing Information, P values and hazard ratios are omitted from the overall survival Kaplan-Meier curves.5
bCOMFORT-II was not designed to compare survival probabilities between Jakafi and best available therapy at 3 or 5 years.5
cPatients randomized to best available therapy were eligible to cross over to receive Jakafi because of progression-driven events or at the physician’s discretion; however, these patients continued to be grouped within their original randomized assignment for analysis purposes.5
Video
Hematologist-oncologist Dr Gary Grad reviews data from the COMFORT|| trials in MF, which included patients with intermediate-2 or high-risk myelofibrosis. Dr Grad begins with a discussion of risk level and corresponding survival in MF. He then discusses results including reduction in spleen volume, symptom reduction (COMFORT-I only), and overall survival probability (which was a secondary endpoint in both trials).
||COMFORT, COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment
References
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myeloproliferative Neoplasms V.2.2019. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed October 29, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
- Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.
- Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
- Verstovsek S, Mesa RA, Gotlib J, et al; for the COMFORT-I investigators. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55.
- Data on file. Incyte Corporation. Wilmington, DE.
- Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.
- Harrison CN, Vannucchi AM, Kiladjian J-J, et al; on behalf of the COMFORT-II Investigators. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701-1707.
COMFORT, COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment; MFSAF, Myelofibrosis Symptom Assessment Form.
aPatients with myelofibrosis who are refractory to or not candidates for available therapy.2
bPatients with platelet counts between 100 × 109/L and 200 × 109/L received 15 mg twice daily; patients with platelet counts >200 × 109/L received 20 mg twice daily.1
cAs measured by MRI or CT scan.2
dSymptoms were measured by the MFSAF v2.0 tool, a daily diary capturing the debilitating symptoms of myelofibrosis (abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats, and bone/muscle pain).2
References
-
Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.
-
Verstovsek S, Mesa RA, Gotlib J, et al. Engl J Med. 2012;366:799-807. [also supplementary appendix: http://www.nejm.org/action/showSupplements?doi=10.1056%2FNEJMoa1110557&viewType=Popup&viewClass=Suppl]
Jakafi significantly reduced spleen volume and improved symptoms of myelofibrosis
Superior reductions in spleen volume and improvements in Total Symptom Score (TSS) vs placebo in COMFORT-I1,2
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41.9% of patients receiving Jakafi achieved a ≥35% reduction in spleen volume (primary endpoint) at week 24 vs 0.7% of patients receiving placebo (P <0.0001)1,2
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45.9% of patients receiving Jakafi achieved a ≥50% improvement in TSS (secondary endpoint) at week 24 vs 5.3% of patients receiving placebo (P <0.0001)1,2
- TSS captured in daily patient diary, including abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 1 to 10. These scores were added to create the daily total score, with a maximum of 601,3
- At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group1
A subgroup analysis of final titrated dose from the COMFORT-I trial
Adapted from Verstovsek S, et al. Onco Targets Ther. 2013;7:13-21.4
BID, twice daily.
aFinal titrated dose was defined as the average daily dose from weeks 21–24.
bTotal Symptom Score was the sum of scores for abdominal discomfort, pain under the ribs on the left side, early satiety, night sweats, pruritus, and muscle/bone pain.
cA negative value indicates improvement.
- The starting dose of Jakafi is based on patient’s baseline platelet count1:
- Greater than 200 X 109/L: 20 mg given orally twice daily
- 100 X 109/L to 200 X 109/L: 15 mg given orally twice daily
- 50 X 109/L to less than 100 X 109/L: 5 mg given orally twice daily
References
-
Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.
-
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.N Engl J Med. 2012;366:799-807.
-
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(suppl):1-38.
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Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13-21.
Primary Endpoint Results
Each bar represents an individual patient's response.
Adapted with permission from the Massachusetts Medical Society.
JAK, Janus-associated kinase.
99% of patients receiving Jakafi experienced some reduction in spleen volume, while most patients receiving placebo experienced an increase in spleen volume.2,3
References
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Data on file. Incyte Corporation. Wilmington, DE.
-
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
-
Deisseroth A, Kaminskas E, Grillo J, et al. US Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res. 2012;18(12):3212-3217.
aPatients with platelet counts between 100 × 109/L and 200 × 109/L received 15 mg twice daily; patients with platelet counts >200 × 109/L received 20 mg twice daily.1
bBest available therapy in COMFORT-II included hydroxyurea (46.6%) and glucocorticoids (16.4%), as well as no medication, anagrelide, epoetin alfa, thalidomide, lenalidomide, mercaptopurine, thioguanine, danazol, peginterferon alfa-2a, interferon-α, melphalan, acetylsalicylic acid, cytarabine, and colchicine.2,3
cAs measured by MRI or CT scan.1
References
-
Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.
-
Data on file. Incyte Corporation. Wilmington, DE.
-
Harrison C, Kiladjian JJ, Al-Ali HK, et al. N Engl J Med. 2012;366:787-798.