Will Nilotinib Supplant Imatinib as First-line Therapy for CML?
New Orleans, LA – Even though imatinib (Gleevec) is a highly effective drug for chronic myeloid leukemia (CML) and the standard of care for newly diagnosed patients, a phase III study presented at a late-breaking news session showed that nilotinib (Tasigna) was superior as first-line therapy. This conclusion was based on rates of molecular and cytogenetic response.
Results of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd) trial presented by Giuseppe Saglio, MD, University of Turin, Italy, showed that nilotinib was superior to imatinib in achieving major molecular response (MMR), complete cytogenetic response (CCyR), and prevention of progression to accelerated or blastic phase. The study was funded by Novartis and conducted at 220 international sites. These results could be practice changing, with nilotinib replacing imatinib as first-line therapy, Dr Saglio said.
Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) FDA-approved for the treatment of CML patients who have failed on or are intolerant to imatinib. Imatinib is the only TKI approved as first-line therapy. Nilotinib has the same targets at imatinib but is significantly more selectively for the Abl gene associated with CML.
ENESTnd enrolled 846 patients with newly diagnosed Philadelphia chromosome-positive (Ph+) CML and randomized them 1:1:1 to 300 mg of nilotinib twice daily, 400 mg of nilotinib twice daily, or 400 mg of imatinib daily. Patients were treated for a minimum of 12 months; median follow-up was 14 months.
No difference was seen between the two doses of nilotinib for the primary endpoint of MMR (the deepest level of remission) at 1 year: 44% for the 300-mg dose and 43% for the 400-mg dose; 1-year MMR with imatinib was 22% (P <.0001). Overall, MMR was observed in 57% of patients in the low-dose nilotinib group, 54% in the high-dose nilotinib arm, and 30% who received imatinib before data cutoff. Looking at the subset of patients who were high-risk (n = 230), MMR at 1 year was 41% in the 300-mg nilotinib group, 32% in the 400-mg nilotinib group, and 17% in the imatinib group, respectively.
Rates for the secondary endpoints of CCyR and rates of transformation to acute phase/blast crisis were nearly equal with both doses of nilotinib. Overall, approximately 79% of patients receiving nilotinib achieved CCyR at 1 year compared with 65% of patients treated with imatinib (P <.0001). Only 2 patients on low-dose nilotinib and 1 on high-dose nilotinib progressed to advanced disease compared with 11 patients taking imatinib.
Both nilotinib and imatinib were well tolerated. Discontinuation was only slightly higher in the imatinib group, at 21%, compared with 16% in the low-dose nilotinib group and 18% in the high-dose group. Patients taking the lower dose of nilotinib were least likely to discontinue due to adverse events (7%) compared with patients receiving the higher dose (11%) or taking imatinib (9%). Imatinib was associated with higher rates of grade 3-4 neutropenia (20%) compared with low-dose nilotinib (12%) and high-dose nilotinib (10%). Gastrointestinal events occurred twice as frequently in the imatinib group, in about 30% of patients compared with 10% to 20% taking nilotinib. The number of patients who developed skin rash, however, was nearly double with nilotinib. Patients in the nilotinib arms were also more likely to experience elevated liver enzymes compared with those taking imatinib, although the rates in all treatment arms were low.
Dr Saglio said planned follow-up is in 5 years. Patients with failed/suboptimal response to imatinib will be allowed to escalate the imatinib dose or cross over to nilotinib.
A Press Release from Novartis stated that ENESTnd is the largest global randomized trial to compare two oral therapies in newly diagnosed Ph+ CML patients. It is also the first registration study in which MMR, considered a surrogate endpoint, is being used to indicate patient outcomes for regulatory review. During the question-and-answer session following the presentation, some experts said that more data on progression-free survival and other hard endpoints are needed before nilotinib replaces imatinib. ASH Abstract LBA-1.