Phase 3 ENDURE Trial Shows No Benefit of Ropeginterferon Alfa-2b Maintenance After TKI Cessation in CML
Key Insights
The phase 3 ENDURE trial demonstrated that ropeginterferon alfa-2b maintenance therapy provides no additional benefit over observation alone after tyrosine kinase inhibitor cessation in chronic myeloid leukemia (search) patients.
At 25 months follow-up, molecular relapse-free survival rates were similar between ropeginterferon alfa-2b and observation groups at 56% and 59% respectively, with no statistically significant difference.
Among patients who lost major molecular remission after TKI (search) cessation, 95% regained remission within 12 months after restarting TKI therapy, highlighting the reversibility of molecular relapse.
The phase 3 ENDURE trial has definitively shown that ropeginterferon alfa-2b maintenance therapy offers no clinical advantage over observation alone following tyrosine kinase inhibitor (TKI (search)) discontinuation in patients with chronic myeloid leukemia (search) (CML (search)). The results, published in Leukemia, challenge previous biological hypotheses suggesting interferon-based strategies could improve treatment-free remission outcomes.
Primary Efficacy Results
At a median follow-up of 36 months, the molecular relapse-free survival (MRFS) at 25 months was virtually identical between treatment arms. Patients receiving ropeginterferon alfa-2b achieved 56% MRFS (95% CI, 45%-66%) compared to 59% (95% CI, 49%-68%) in the observation group (HR, 1.02; 95% CI, 0.68-1.55; P = 0.91).
The lack of benefit was consistent across multiple time points. At 6 months, MRFS rates were 73% versus 67% for ropeginterferon alfa-2b and observation groups respectively. At 12 months, the rates were 64% versus 60%, demonstrating no clinically meaningful improvement in treatment-free remission probability.
Molecular Relapse Recovery
Despite 90 patients losing major molecular remission (MMR) after TKI (search) cessation, the study revealed encouraging recovery data. Among 83 patients with available molecular data after restarting TKI therapy, an impressive 95% regained MMR within 12 months, with a median time to re-achievement of just 3 months. These findings underscore the reversibility of molecular relapse and emphasize the critical importance of close molecular monitoring during treatment-free remission attempts.
Safety and Tolerability Profile
Ropeginterferon alfa-2b demonstrated a favorable safety profile throughout the 15-month maintenance period. The median administered dose was 92 μg, and 86.1% of the safety population experienced at least one adverse event, with toxicities generally consistent with known interferon profiles and primarily low-grade regardless of treatment arm.
Importantly, no CML (search)-specific deaths occurred during the study period. Among 21 patients with 29 reported serious adverse events, only 7 serious adverse events in 6 patients were potentially related to ropeginterferon alfa-2b treatment. The authors noted that the toxicity profile was favorable compared with other interferon formulations.
Study Design and Patient Population
The ENDURE trial was a randomized, multicenter, open-label study conducted across centers in France and Germany between May 2017 and June 2021. The study enrolled 203 adult patients with BCR::ABL1 (search)-positive chronic phase CML (search) who had been on TKI (search) monotherapy for a minimum of 3 years and maintained deep molecular remission for at least 1 year.
Patients were randomized 1:1 to receive either ropeginterferon alfa-2b maintenance therapy (n = 95) or surveillance only (n = 108). The treatment arm received ropeginterferon alfa-2b at 50 μg subcutaneously every 2 weeks, followed by 100 μg every 2 weeks thereafter up to month 15. The primary endpoint was MRFS, defined as loss of MMR.
Clinical Implications
Study authors Andreas Burchert and colleagues acknowledged that while the ENDURE trial failed to confirm benefit in its primary endpoint, it served a crucial role in objectively testing previous non-randomized or translational evidence that had suggested interferon-related improvements in treatment-free remission rates.
"In this sense, the ENDURE trial may be regarded as concluding the long-standing exploration of interferon-α-based strategies in CML (search), pending a clearer mechanistic distinction between IFN- and TKI (search)-associated pathways to TFR," the authors wrote.
The study's findings provide definitive evidence that maintenance interferon therapy does not enhance the probability of sustained treatment-free remission after TKI (search) discontinuation, while confirming that molecular relapses remain highly reversible with TKI reinitiation.