FREEDOM trial: Primary analysis

Fedratinib, an oral Janus kinase 2 (JAK2) inhibitor previously reviewed on the MPN Hub, is currently under investigation for the treatment of patients diagnosed with myelofibrosis (MF) and with prior ruxolitinib exposure.¹ Long-term data regarding fedratinib in the setting are currently limited due to early treatment termination.¹

In order to address this, Gupta et al.¹ recently published a preliminary analysis from the single-arm phase IIIb FREEDOM trial (NCT03755518) investigating the safety and efficacy of fedratinib in patients with MF previously treated with ruxolitinib. The authors also discussed strategies to mitigate gastrointestinal adverse events (AE), thiamine level reductions, and potential encephalopathy.¹ We summarize the key findings in the article below. For more information on how to manage AEs associated with fedratinib, watch our previous interview with Ruben Mesa.

Study design

• Key eligibility criteria:
  • Confirmed primary MF diagnosis, post-polycythemia vera MF, or post-essential thrombocythemia MF with ≥3 months prior ruxolitinib treatment
  • Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2
  • Intermediate or high-risk
  • Baseline platelet count ≥50 x 10⁹/L
• Fedratinib 400 mg once daily in 28-day cycles
• Strategies for AE mitigation:
  • Antiemetics
  • Antidiarrheals
  • Thiamine supplementation
  • Surveillance for potential encephalopathy

Results

• A total of 38 patients were included in the analysis.
• Baseline patient characteristics are shown in Table 1.

Table 1. Baseline patient characteristics*

DIPSS, Dynamic International Prognostic Scoring System; ET, essential thrombocythemia; MF, myelofibrosis; PMF, primary myelofibrosis; PV, polycythemia vera. *Data from Gupta, et al.1
Characteristic, % (unless otherwise stated)	All patients (N = 38)
Median age, years	68.5
Median treatment duration, weeks	38
Diagnosis
PMF	60.5
Post-PV MF	23.7
Post-ET MF	15.8
DIPSS classification
Intermediate-1	34.2
Intermediate-2	47.4
High risk	18.4
Median spleen volume, mL	1,831.6

• At the end of Cycle 6, 25.7 patients achieved ≥35% spleen volume reduction (SVR)
  • 62.9% of patients achieved a best overall response of ≥35% SVR.
• Of the patients who achieved ≥35% SVR, 86.4% maintained a response at cutoff.
• At the end of Cycle 3, 58.3% of patients achieved ≥50% reduction in total symptom score
• At the end of Cycle 6, 44.4% of patients achieved ≥50% reduction in total symptom score.
• A total of 89.5% of patients had one treatment-emergent AE; 7.9% of which were serious.

Common AEs are shown in Figure 1.

*Data from Gupta, et al.¹

• Most gastrointestinal AEs were of Grade 1 or 2 severity.
• Reduction in thiamine levels were also of Grade 1 or 2 severity.
  • There were no treatment discontinuations due to thiamine levels.
• A total of two deaths occurred during treatment and seven occurred during follow-up.
  • None of the deaths were deemed to be study related.

Conclusion

Primary analysis from the FREEDOM study highlights durable spleen and symptom responses as well as SVR. Gastrointestinal AEs were easily mitigated, and no cases of encephalopathy were reported. Although the sample size for the analysis was small, the overall safety and efficacy data collected support the use of fedratinib in patients with MF and prior ruxolitinib exposure.