CHICAGO—Among patients with chronic myeloid leukemia (CML) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, major molecular response (MMR) rates with nilotinib remain superior to those with imatinib after follow-up extended to a median of 18.5 months. The finding suggests that nilotinib should be “a new standard of care” in this population, according to lead investigator Richard Larson, MD, director of the leukemia program at the University of Chicago Medical Center in Chicago, Illinois. He noted that although nilotinib is the most selective inhibitor of BCR-ABL, imatinib is the current standard of care for CML.
ENESTnd included 846 patients, all diagnosed with Philadelphia chromosome–positive (Ph+ CML) in chronic phase within the previous 6 months. They were randomized to receive nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281), or imatinib 400 mg once daily (n = 283), with planned 5-year follow-up and a primary end point of MMR response (MMR, ≤ 0.1% BCR-ABLIS) at 12 months and 24 months.
In prior reporting of 12-month follow-up, MMRs were achieved by 44% of patients taking nilotinib 300 mg twice daily, 43% of patients taking nilotinib 400 mg twice daily, and 22% of patients taking imatinib 400 mg once daily (P <.0001 for both nilotinib groups vs imatinib). After median follow-up of 18.5 months in 525 patients, MMRs were achieved by 69% of those taking nilotinib 300 mg twice daily (n = 178), 63% of those taking nilotinib 400 mg twice daily (n = 175), and 36% of those taking imatinib 400 mg once daily (n = 172). Among 145 patients with follow-up out to 24 months, MMR rates were 86% for nilotinib 300 mg twice daily (n = 49), 88% for nilotinib 400 mg twice daily (n = 48), and 48% for imatinib 400 mg once daily (n = 48).
Similar percentages of patients remain on treatment in all groups (80% nilotinib 300 mg twice daily; 81% nilotinib 400 mg twice daily; 75% imatinib 400 mg once daily). Although dose escalation was not permitted
in the nilotinib arms, imatinib dose escalation to 800 mg/day for suboptimal response or treatment failure was allowed and occurred in 24%.
Progression to accelerated phase or blast crisis was reported in <1% of nilotinib patients (0.7% nilotinib 300 mg twice daily; 0.4% nilotinib 400 mg twice daily) and in 4.2% of imatinib 400-mg once-daily patients (P = .006/.003 for nilotinib 300/400 mg twice daily versus imatinib 400-mg once-daily).
Edema was more common among patients receiving imatinib. Grade 3 to 4 adverse events were rare (<1%) across all treatments. No clinically relevant prolongations of QT interval or left ventricular ejection fraction were reported.
CML-related deaths were significantly (P = .03) less common for nilotinib 400 mg twice daily compared with imatinib (1 vs 8; 2 with nilotinib 300 mg twice daily, P = .28). Larson concluded, “With longer follow-up, rates of MMR and CCyR [complete cytogenetic response] remain superior for nilotinib versus imatinib.
Molecular responses are continuing to deepen over time.” He added, “Longer follow-up supports nilotinib as a new standard of care in patients with newly diagnosed CML.”
In response to a question about the implications of the dose findings, Larson commented, “The data from this trial show that while the efficacy of the 300-mg twice-daily dose is equivalent to that of the 400-mg, the side effect profile favors the lower dose—so that is probably the dose that will go forward.”
The US Food and Drug Administration granted nilotinib priority review status for newly diagnosed CML in February 2010, and, based on the ENESTnd results, approved the drug for adults with newly diagnosed Ph+ CML in chronic phase in June 2010.