New Orleans, LA—Three large randomized phase 3 trials demonstrate the superiority of nilotinib (Tasigna) over imatinib (Gleevec) in achieving molecular response (MR) and complete cytogenetic response (CCyR) across various populations of patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML), including patients who have a suboptimal response to frontline imatinib.
LASOR: Frontline Imatinib Failures
In patients who fail to achieve a CCyR with frontline imatinib, higher rates of MR are achieved by switching to nilotinib compared with escalating the dose of imatinib to 600 mg daily, reported Jorge E. Cortes, MD, Chair, CML and Acute Myeloid Leukemia sections, M.D. Anderson Cancer Center, Houston, TX.
“Patients with suboptimal complete cytogenetic response to imatinib (today classified by ELN [European LeukemiaNet] as warning/failure) represent a significant unmet need in the treatment of CML-CP [chronic phase],” noted Dr Cortes and colleagues. “This important study is the only randomized evaluation of imatinib dose escalation versus switch to the more potent BCR-ABL tyrosine kinase inhibitor nilotinib in this population.”
The study included 191 adults with suboptimal CyR to frontline imatinib 400 mg once daily, who were randomized to nilotinib 400 mg twice daily or to imatinib 600 mg once daily. The primary end point, CCyR at 6 months, was observed in 49% and 42.1% of patients in the nilotinib and imatinib arms, respectively, but this difference failed to achieve significance (P = .384). The high rate of crossover from imatinib to nilotinib confounded the results.
In the imatinib arm, 15 patients crossed over to nilotinib and 6 achieved CCyR; by contrast, none of the 6 patients who crossed over from the nilotinib arm to imatinib achieved CCyR.
The clinical benefit of nilotinib is therefore best evaluated when considering crossover patients as nonresponders, Dr Cortes said. In this type of analysis, 47 (54.7%) patients in the nilotinib arm and 34 (38.6%) in the imatinib arm achieved CCyR at 6 months.
ENESTnd: Newly Diagnosed Disease
Updated 5-year data from the open-label, randomized, multicenter Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) trial support nilotinib as first-line therapy in adults with newly diagnosed Ph+ CML-CP, said Giuseppe Saglio, MD, Director, Department of Molecular Medicine and Targeted Therapy, San Luigi Gonzaga Hospital, University of Turin, Italy. Some 846 patients were randomized to nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily.
The rates of early and deeper sustained MR, including MR4.5, were higher with nilotinib at either dosage compared with imatinib. At 1 year, the rate of MR4.5 was 6% to 19% greater with nilotinib compared with imatinib; by 5 years, this difference reached 21% to 23%, said Dr Saglio.
Furthermore, fewer patients receiving nilotinib progressed to accelerated phase/blast crisis. The estimated rates of patients whose disease did not progress to the accelerated phase or the crisis phase at 5 years were 99.3% and 98.7% in the nilotinib arms (300 mg twice daily and 400 mg twice daily, respectively) versus 95.2% in the imatinib arm.
Of the patients treated with imatinib, 15 had CML-related deaths compared with 10 patients in the nilotinib arms. The estimated overall survival rates at 5 years were 93.6% and 96% in the nilotinib 300-mg twice-daily and 400-mg twice-daily arms, respectively, compared with 91.6% in the imatinib arm.
ENESTcmr: Residual Disease
Three-year data from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) trial, an openlabel, randomized phase 3 study, demonstrate that patients with Ph+ CML and detectable BCR-ABL after long-term treatment with imatinib achieved deeper MRs after switching to nilotinib, reported Brian Leber, MD, Associate Professor of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
In ENESTcmr, 207 patients were randomized to nilotinib 400 mg twice daily or to imatinib 400 mg once daily or 600 mg once daily. Of 32 responders in the imatinib arm, 7 achieved MR4.5 after switching to nilotinib. Among patients without documented MR4.5 at baseline, the cumulative incidence of MR4.5 was higher in patients randomized to nilotinib versus imatinib (46.9% vs 33.3%, respectively; P = .045). MR4.5 was achieved faster with a median time to response of 24 months in the nilotinib arm, and was not reached in the imatinib arm (P = .001). By 36 months, no patients in either arm had progressed to AP/BC.