Of other JAK inhibitors, pacritinib, a multikinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R, is furthest in clinical development and has been studied in the PERSIST trials.
PERSIST-1 was a phase 3 study that compared pacritinib 400 mg daily to BAT in 327 JAK inhibitor-naive patients with intermediate- to high-risk MF, palpable splenomegaly (≥ 5 cm) and MPN SAF TSS ≥ 13.
At week 24, the SVR rates were 19% for the pacritinib group and 5% for the BAT group (P = .0003) in the intent-to-treat (ITT) population. In the same population, symptom response rates, measured by MPN SAF TSS, were 25% for the pacritinib group and 7% for the BAT group (P < .0001). Responses were seen regardless of baseline platelet levels. In patients with less than 100 × 109 platelets/L, SVR rates were 17% for pacritinib compared with 0% for BAT; corresponding rates in patients with less than 50 × 109 platelets/L were 23% for pacritinib compared with 0% for BAT (P = .009). In transfusion-dependent patients, 26% became transfusion independent after treatment with pacritinib versus 0% for the BAT group (P = .043).13
PERSIST-2 was a phase 3 randomized, multicenter study that compared 2 dose schedules of pacritinib with BAT. The study enrolled 311 patients with MF and platelet count less than or equal to 100 × 109/L. Patients were randomly assigned in a 1:1:1 ratio to receive 400 mg pacritinib once daily, 200 mg pacritinib twice daily, or BAT. Patients on BAT were allowed to crossover to pacritinib after week 24 or for progression of splenomegaly.14
Of the 311 patients enrolled, 48% had received prior ruxolitinib therapy. The most common BAT was ruxolitinib (45%) and 19% of patients received watchful waiting. The ITT efficacy population included 75 patients randomly assigned to pacritinib once daily, 74 to pacritinib twice daily, and 72 to BAT.14
For the primary end point (measured at week 24), 18% of the pooled pacritinib patients achieved at least 35% SVR compared with 3% of patients on BAT (P = .001). Patients on pacritinib also had a nonsignificant reduction of less than or equal to 50% in TSS: 25% for pacritinib versus 14% for BAT (P = .08).14
Twice-daily pacritinib provided more significant improvement in at least 35% SVR (22% compared with 3% for BAT; P = .001) as well as a reduction of at least 50% in TSS (32% compared with 14% for BAT; P = .01). Pacritinib twice daily was also associated with clinical improvement in anemia and reduction in transfusion burden.14
The most common grade 3/4 adverse events (pacritinib once daily vs pacritinib twice daily vs BAT) were thrombocytopenia (31% vs 32% vs 18%) and anemia (27% vs 22% vs 14%). 14
In an editorial accompanying the publication of PERSIST-2, it was noted the PERSIST program developed a serious setback due to the US Food and Drug Administration’s (FDA’s) full clinical hold in February 2016 on all clinical trials of pacritinib due to a concern of increased risk for intracranial hemorrhage and cardiovascular events (and concerns over deaths in PERSIST-1).15 Maximilian Stahl, MD, and Amer M. Zeidan, MBBS, MHS, both from Yale Cancer Center in New Haven, Connecticut, coauthored the editorial.
A longer-term follow-up of PERSIST-1 mitigated these concerns. The analysis showed that at least 35% SVR responses were maintained from weeks 24 to 72; 25% versus 24% for BAT. In addition, 84% of patients who received BAT initially and then crossed over to receive pacritinib achieved similar responses to those initially treated with pacritinib.16
Moreover, there was no statistically significant difference in OS between the pacritinib and BAT groups, primarily due to an imbalance between the two arms: There were higher-risk patients in the pacritinib versus the BAT arm. The 84% of patients on the BAT arm who crossed over to receive pacritinib confounded the OS analysis, which was longer for pacritinib-treated patients who achieved at least 20% SVR compared to patients who did not.16
Based on this analysis the FDA lifted its hold on the clinical development of pacritinib in January 2017. However, the FDA hold on the development of pacritinib posed limitations on PERSIST-2, indicated investigators of the trial, which was led by Dr Mascarenhas. “Study truncation due to the clinical hold compromised the ability to evaluate the effect of treatment on week 24 end points (including coprimary end points) by reducing the effective sample size, and also compromised time-to-event end points (including overall survival) by reducing follow-up time for assessment that would enable analyses that follow the intention-to-treat principle ,” Dr Mascarenhas and his colleagues wrote.
“Truncation of the study also limited the follow-up of patients for additional safety data. Despite these limitations, pacritinib 200 mg twice daily was more effective than BAT with a benefit-risk profile that compared favorably with pacritinib once daily and BAT,” they added.
The complete analysis of PERSIST-2 also reported bleeding events occurring at a similar frequency in patients across all three arms — 36% for pacritinib once daily, 42% with pacritinib twice daily, and 41% for BAT. Correspondingly, grade 3/4 bleeding events were reported for 4%, 14%, and 7% of patients, respectively, and were seen at similar rates in patients with baseline platelet count of less than 50 × 109/L or at least 50 × 109/L.14
Dr Mascarenhas indicated that a phase 2 study (PAC203; ClinicalTrials.gov Identifier: NCT03165734) will examine pacritinib at 3 lower-dose levels (100 mg once daily, 100 mg twice daily, and 200 mg twice daily) in patients with MF who previously received ruxolitinib.
Other JAK Inhibitors in Clinical Development
“Momelotinib, another JAK inhibitor, also made a stop in the road of broken dreams,” wrote Dr Stahl and Dr Zeidan in their editorial. It is the third JAK 1/2 inhibitor that has less compelling data from its phase 3 SIMPLIFY program.
In SIMPLIFY-1, momelotinib was found to be noninferior to current standard therapy (ruxolitinib) in reducing spleen volume, but not for symptom response in patients with MF who have never been treated with a JAK inhibitor. However, momelotinib was associated with reduced transfusion requirements.17
In SIMPLIFY-2, in patients with primary or secondary myelofibrosis (MF) who have already received treatment with ruxolitinib, momelotinib was not superior to BAT in reducing spleen volume, but was significant in improving disease-related symptoms, according to data from SIMPLIFY-2.18
Dr Mascarenhas indicated that based on these two drug failures, the future of momelotinib is unclear. “However, momelotinib does provide durable anemia responses,” he noted.
The development of yet another selective JAK2 inhibitor, fedratinib, was stalled when the FDA put a hold on the clinical development of the JAKARTA studies after 8 of 877 patients across 18 studies exposed to the agent experienced neurological symptoms suggestive of Wernicke’s encephalopathy.
When Sanofi abandoned the clinical development of the JAKARTA program, patients returned to standard treatment. The FDA lifted its hold on the drug development of fedratinib following the revelation that the side effects seen in the program were due to a small number of cases of thiamine depletion, which is linked to a high metabolic rate of patients with cancer and malnutrition.
First reported at the 2013 annual meeting of the American Hematologic Society, JAKARTA-1 was a global, double-blind, placebo-controlled phase 3 study that included 289 patients with intermediate-2 or high-risk MF, a platelet count of at least 50 × 109/L, and splenomegaly. Patients were randomly assigned 1:1:1 to receive fedratinib 400 mg (once daily; 96 patients), 500 mg (once daily; 97 patients), or placebo (96 patients) in 4-week cycles.19
The primary end point of at least 35% SVR from baseline at week 24 was achieved in 47% of patients on the 400-mg dose, 49% on the 500-mg dose, and 1% receiving placebo (P < .0001 compared with placebo for both doses).19
JAKARTA-2 was one of the studies that was prematurely terminated.20 The single-arm, nonrandomized, phase 2 study enrolled 97 patients with intermediate- or high-risk MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, who were resistant or intolerant to ruxolitinib. Patients were also required to have palpable splenomegaly. Fedratinib was given at an oral dose of 400 mg once daily every day for 6 consecutive 28-day cycles.
Of 88 assessable patients, 55% achieved the primary response of at least 35% SVR. Grade 3/4 adverse events included anemia (38%) and thrombocytopenia (22%). Seven patients died, but it was determined that none of the deaths were related to treatment with fedratinib.
In January 2018, Celgene acquired Impact Biomedicines and based on the reported benefit risk profile of fedratinib from the JAKARTA-1 and JAKARTA-2 clinical trials, regulatory applications in MF are underway.
NS-018 is another selective JAK2 inhibitor in the early stages of clinical development. Forty-eight patients were enrolled in a phase 1 portion of a phase 1/2 dose escalation study. Patients received increasing doses of NS-018. Thrombocytopenia (27%) and anemia (15%) were the hematologic toxicities reported. Once-daily NS-018 300 mg has been taken into the phase 2 study based on improved tolerability compared with higher doses. A minimum 50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients had prior exposure to a JAK inhibitor), and improvements were observed in myelofibrosis-associated symptoms.21
Currently, ruxolitinib is the treatment of choice for patients with intermediate-2 or higher risk MF. In providing durable spleen volume reduction, symptom improvement, and modest survival, it is still the only go-to drug in this class. The clinical development of pacritinib and fedratinib may provide additional options in the future. In addition, combination trials are underway, evaluating ruxolitinib in combination with other targeted agents.1,22
“It remains to be seen whether other novel non–JAK2-mediated therapies will be the future of progress in MF therapy,” Drs Stahl and Zeidan concluded in their editorial.15
- Bose P, Verstovsek S. Myelofibrosis: an update on drug therapy in 2016. Expert Opin Pharmacother. 2016;17(18):2375-2389.
- National Comprehensive Cancer Network. Myeloproliferative neoplasms. NCCN guidelines Version 2.2018. http://nccn.org. Accessed July 2, 2018.
- Tefferi A, Vaidya R, Caramazza D, et al. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol. 2011;29(10):1356-63.
- Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228:273-287.
- Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673-683.
- Constantinescu SN, Girardot M, Pecquet C. Mining for JAK-STAT mutations in cancer. Trends Biochem Sci. 2008;33:122-131.
- The US Food and Drug Administration. Ruxolitinib. http://wayback.archive-it.org/7993/20161024005358/http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm280155.htm. Accessed July 2, 2018.
- 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.
- Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.
- Jakafi®[package insert]. Wilmington, DE: Incyte Corporation; revised March 2016.
- Porpaczy E, Triplot S, Hoelbl-Kovacic A, et al. Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy [published online June 14, 2018]. Blood. doi: 10.1182/blood-2017-10-810739.
- Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and –II pooled analyses. J Hematol Oncol. 2017;10:156; DOI 10.1186/s13045-017-0527-7.
- Mesa RA, Egyed M, Szoke A, et al. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol. 2015;33:LBA7006. doi: 10.1200/jco.2015.33.18_suppl.lba7006
- Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis. A randomized clinical trial. JAMA Oncol. 2018;2(5):652-59.
- Stahl M, Zeidan AM. Improved JAK inhibition in myelofibrosis—the long road ahead. JAMA Oncol. 2018;2(5):659-60.
- Mesa RA, Egyed M, Szoke A, et al. Pacritinib (PAC) vs best available therapy (BAT) in myelofibrosis (MF): 60 week follow-up of the phase III PERSIST-1 trial. Abstract #7065. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 6, 2016.
- Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase-inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-50.
- Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017 December 20. [Epub ahead of print]
- Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis. A randomized clinical trial. JAMA Oncol. 2015;1(5):643-51.
- Harrison CN, Schaap N, Vannucchi AM, et al. 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. 2017;4(7):e317-e324.
- Verstovsek S, Talpaz M, Ritchie E, et al. A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis. Leukemia. 2017;31:393-402.
- Stahl M, Zeidan AM. Management of myelofibrosis: JAK inhibition and beyond. Expert Rev Hematol. 2017;10(5):459-77.