Efficacy and Safety of Nilotinib Compared with Imatinib in Patients with Chronic Myeloid Leukemia

New Orleans—During a late breaking abstract session at the ASH conference, Giuseppe Saglio of the University of Turin, San Luigi Hospital, Orbassano, Italy, presented results of the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial, a phase 3, randomized open-label, multicenter study that compared the efficacy and safety of 300 or 400 mg twice a day of nilotinib with 400 mg imatinib daily in patients with newly diagnosed Philadelphia chromosome chronic myeloid leukemia (Ph + CML) in chronic phase (CMP-CP).

Nilotinib is the most selective inhibitor of the BCR-ABL fusion gene, the only proven molecular target for CMP therapy. The ENESTnd trial included 846 patients whose Ph + CMP had been diagnosed within 6 months. The trial participants were randomized 1:1:1 to receive 300 mg of nilotinib twice a day (n=282), 400 mg of nilotinib twice a day (n=281), or 400 mg imatinib once a day (n=283).

The primary end point was the rate of major molecular response (MMR) at 12 months. The researchers defined MMR as a value of ≤0.1% of BCR-ABL/ABL ratio on the International Scale. Molecular response was assessed by real-time quantitative polymerase chain reaction at baseline, every month for 3 months, and every 3 months after that. The secondary end point was the rate of complete cytogenetic response (CCyR) at 12 months based on bone marrow cytogenetics.

Patients in all 3 arms were well matched in baseline demographics, disease characteristics, and Sokal scores. In each of the 3 arms, 28% of patients had high-risk Sokal scores. Median dose intensities of nilotinib were 592 mg/day for 300 mg twice a day and 779 mg/day for 400 twice a day; for imatinib, dose intensity was 400 mg/day. Throughout the study, 84% of patients remained on the study drug for 300 mg of nilotinib twice a day, 82% for 300 mg of nilotinib twice a day, and 79% for 400 mg of imatinib once a day.

Rates of MMR at 12 months were superior for nilotinib 300 mg twice a day compared with imatinib 400 mg once a day (44% vs. 22%, P<.0001) and also for nilotinib 400 mg twice a day compared with imatinib 400 mg once a day (43% vs. 22%, P<.0001). Median time to MMR among patients who achieved MMR was faster for nilotinib 300 mg twice a day (5.7 months) and nilotinib 400 mg twice a day (5.8 months) compared with imatinib 400 mg once a day (8.3 months).

Rates of CCyR by 12 months were significantly higher for both nilotinib at either 300 mg twice a day compared with imatinib 400 mg once a day (80% vs 65%, P<.0001) and for nilotinib 400 mg twice a day compared with imatinib 400 mg once a day (78% vs 65%, P=.0005). Overall, progression to advanced disease was lower for nilotinib 300 mg twice a day (2 pts) and nilotinib 400 mg twice a day (1 pt) compared with imatinib 400 mg once a day (11 pts).

Both drugs were well tolerated. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for nilotinib 300 mg twice a day, 11% for nilotinib 400 mg twice a day, and 9% for imatinib 400 mg once a day. Patients were monitored for QT prolongation and left ventricular ejection fraction (LVEF). No patients in any treatment arm showed a QTcF interval >500 msec. There was no decrease from baseline in mean LVEF anytime during treatment in any arm. The study is ongoing.

In summary, the researchers stated that “Nilotinib at both 300 mg twice a day and 400 mg twice a day induced significantly higher and faster rates of MMR and CCyR compared with imatinib 400 mg once a day, the current standard of care in patients with newly diagnosed CML. Nilotinib was effective across all Sokal scores. After only 1 year of treatment, both nilotinib arms resulted in a meaningful clinical benefit compared to imatinib, with reduction of transformation to AP/BC stages. Nilotinib exhibited a favorable safety and tolerability profile. The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML.—Tori Socha