Dose-Optimized Nilotinib in Patients with Newly Diagnosed CML-CP: Final Results from ENESTxtnd Study
The pivotal ENESTnd study demonstrated that frontline nilotinib (300 mg and 400 mg twice daily [BID]) treatment resulted in higher rates of deep molecular response and lower rates of disease progression compared with imatinib in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP).1 The ENEST–Extending Molecular Responses (ENESTxtnd) study was a 24-month phase 3b study that evaluated the kinetics of molecular response to frontline nilotinib 300 mg BID and novel dose-optimization strategies in de novo patients with CML-CP; the results of the study were reported by Hughes and colleagues.2
A total of 421 patients enrolled in the study, of which 93 (22.1%) discontinued early, mainly due to adverse events (AEs; n = 43). Dose escalation from a starting dose of 300 mg BID to 400 mg BID was permitted in patients with suboptimal response or treatment failure; dose reduction to 450 mg once daily as defined in the protocol with subsequent re-escalation was permitted after AE improvement. Patients who were unable to tolerate nilotinib 450 mg daily were discontinued from the study. Overall, 88 (20.9%) patients dose-escalated; 144 patients (34.2%) underwent dose reductions, of which 92 patients (64%) re-escalated to nilotinib 300 mg BID. Median duration of exposure was 23.2 months, and median actual dose intensity was 599 mg/day. At 12 months, 306 patients were on a 300-mg BID dose, 33 on 400 mg BID, 16 on 450 mg once daily, and 7 on other doses.
At 12 months, the cumulative major molecular response (MMR) rate was 70.8%, and at 24 months it was 81.0%. In patients who dose-escalated (n = 88), MMR by 24 months was 63.6%; of the 144 patients who dose-reduced, 75.7% achieved MMR by 24 months, including 78 of 92 patients (85%) who subsequently re-escalated to 300 mg BID. The cumulative rate of complete cytogenetic response by 24 months was 74.1%. At 24 months, the estimated progression-free survival rate was 97.0%, and the estimated overall survival rate was 97.6%. Predominant all-grade nonhematologic drug-related AEs were headache (18.5%), rash (18.3%), and nausea (14.5%); grade 3/4 laboratory abnormalities included lipase abnormalities (14.5%), neutropenia (11.9%), and thrombocytopenia (10.5%). Cardiovascular events were reported in 19 patients (4.5%) and were characterized mainly by ischemic heart disease. The authors concluded that the frontline use of the nilotinib 300-mg BID dose, with dose optimization as necessary, was a viable treatment approach in patients with newly diagnosed CML-CP and resulted in a high rate of MMR at 1 and 2 years.
- Larson RA, et al. ASCO 2014. Abstract 7073.
- Hughes TP, et al. ASH 2015. Abstract 344.