Clinical Spotlight from ASH 2009: eNESTnd

Nilotinib Superior to Imatinib in Patients with Newly Diagnosed CML

December 8, 2009—During the 51st ASH Annual Meeting and Exposition in New Orleans, Giuseppe Saglio, MD (University of Turin, Italy), presented results from ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients), an international randomized phase III trial comparing the efficacy and safety of nilotinib with imatinib in patients with newly diagnosed Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase.

Imatinib is the current standard of care in patients with newly diagnosed CML, but intolerance or development of resistance are limiting factors. Nilotinib, a highly potent and selective inhibitor of BCR-ABL, is currently indicated for adults with Ph+ CML in chronic phase (CP) or accelerated phase (AP) who are resistant or intolerant to imatinib. ENESTnd was designed and conducted to compare the efficacy and safety of nilotinib 300 mg or 400 mg bid with imatinib 400 mg qd in patients with newly diagnosed Ph+ CML-CP. The primary endpoint of ENESTnd was rate of major molecular response (MMR) at 12 months; indeed, molecular monitoring is the most sensitive measure of CML disease burden and achievement of MMR has been shown to be associated with improved long-term outcomes (Hughes T, et al. Blood. 2008;112:Abstract 334). The secondary endpoint of the study was rate of complete cytogenetic response (CCyR) by 12 months based on bone marrow cytogenetics, and other endpoints included time to and duration of MMR and CCyR, event-free survival, progression-free survival, time to AP/blast crisis (BC), and overall survival.

A total of 846 patients with newly diagnosed Ph+ CML-CP who had been diagnosed within 6 months were randomized 1:1:1 to nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib 400 mg qd. Randomization was stratified by Sokal risk score, and all patients had a minimum of 12 months of treatment or discontinued early. Treatment arms were balanced for age, median time since diagnosis, Sokal risk score, and prior therapy.

The following results were obtained from the trial:

Rates of MMR at 12 months were superior for nilotinib compared to imatinib
- Nilotinib 300 mg bid versus imatinib 400 mg qd: 44% versus 22%; P<.0001
- Nilotinib 400 mg bid versus imatinib 400 mg qd: 43% versus 22%; P<.0001

Median time to MMR among patients who achieved MMR was faster for nilotinib compared to imatinib
- Nilotinib 300 mg bid versus imatinib 400 mg qd: 5.7 months versus 8.3 months
- Nilotinib 400 mg bid versus imatinib 400 mg qd: 5.8 months versus 8.3 months

Best molecular response at any time greater for nilotinib compared to imatinib
- BCR-ABL % ≤0.01 (4-log reduction)
  - Nilotinib 300 mg bid: 24% of patients
  - Nilotinib 400 mg bid: 21% of patients
  - Imatinib 400 mg qd: 10% of patients
- BCR-ABL % ≤0.0032 (4.5-log reduction)
  - Nilotinib 300 mg bid: 13% of patients
  - Nilotinib 400 mg bid: 12% of patients
  - Imatinib 400 mg qd: 4% of patients

Rates of CCyR by 12 months were significantly higher for nilotinib compared to imatinib
- Nilotinib 300 mg bid versus imatinib 400 mg qd: 80% versus 65%, P<.0001
- Nilotinib 400 mg bid versus imatinib 400 mg qd: 78% versus 65%, P = .0005

Progression to advanced disease was lower for nilotinib compared to imatinib
- Nilotinib 300 mg bid versus imatinib 400 mg qd: 2 patients versus 11 patients
- Nilotinib 400 mg bid versus imatinib 400 mg qd: 1 patient versus 11 patients

Both nilotinib and imatinib were generally well-tolerated in this study, and rates of discontinuation due to adverse events or laboratory abnormalities were comparable across all treatment arms. In addition, no patients in ENESTnd demonstrated a QTcF interval >500 msec, and there was no decrease from baseline in mean left ventricular ejection fraction during treatment in any arm.

In summary, nilotinib 300 mg bid and nilotinib 400 mg bid demonstrated significant superiority to imatinib 400 mg qd based on improved rates of MMR and CCyR. Fewer patients treated with nilotinib progressed to AP/BC, and the efficacy of nilotinib was observed across all Sokal scores. Trial investigators concluded that nilotinib may replace imatinib as the standard of care in patients with newly diagnosed CML.

Blood. 2009;114(22): Abstract LBA-1.