Four-year update shows nilotinib induces significantly deeper molecular responses than imatinib

July 4, 2013

The 4-year data from the landmark ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) trial continues to demonstrate the improved clinical benefit of front-line nilotinib (Tasigna) versus imatinib (Gleevec) in patients with newly diagnosed, Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase

The 4-year data from the landmark ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) trial continues to demonstrate the improved clinical benefit of front-line nilotinib (Tasigna) versus imatinib (Gleevec) in patients with newly diagnosed, Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase.

“Front-line nilotinib compared with imatinib affords a higher proportion of patients the opportunity to achieve deep molecular responses, a key eligibility criterion for participation in studies of treatment-free remission,” said lead author Richard A. Larson, MD, of the University of Chicago, at the American Society of Clinical Oncology annual meeting in Chicago.

Dr Larson

ENESTnd is a phase 3 randomized, open-label, multicenter trial comparing the efficacy and safety of the two tyrosine kinase inhibitors. The study enrolled 846 CML patients, who were randomly assigned to receive nilotinib 300 mg twice daily (282 patients), nilotinib 400 mg twice daily (281 patients), or imatinib 400 mg once daily (283 patients). The primary end point was major molecular response (MMR) at 12 months. Patients in the imatinib arm who had suboptimal response or treatment failure were allowed to escalate dose and/or switch to nilotinib in a separate extension study.

An update of data from years 3 to 4 of the study found significantly higher rates of molecular response and deep molecular responses were achieved in the nilotinib versus the imatinib arms. “The difference in the rates of deep molecular response continued to be significantly higher for nilotinib, with the difference in favor of nilotinib increasing from year 1 to year 4,” said Dr Larson. Among patients who achieved MMR, more patients achieved deep molecular responses on the nilotinib 300-mg arm (76%) and nilotinib 400-mg arm (73%) compared with the imatinib arm (56%) (P<.0001 for both nilotinib arms versus imatinib). No patient in any arm progressed after achieving deep molecular response.

Significantly fewer patients progressed to accelerated phase/blast crisis on nilotinib versus imatinib, he said. No new progressions (excluding clonal evolution) occurred between years 3 and 4. All progressions on core treatment occurred before the 2-year data cutoff. Including clonal evolution, 3 (1.1%), 5 (1.8%), and 17 (6.0%) progressions occurred on core treatment in the nilotinib 300 mg, nilotinib 400 mg, and imatinib arms, respectively (P=.0009 and .0085 for nilotinib 300-mg arm and nilotinib 400-mg arm versus imatinib, respectively).

Between years 3 and 4 of the study, in the nilotinib 300-mg arm there was 1 new case of clonal evolution on core treatment and 2 patients had newly emergent BCR-ABL mutations, and 1 patient on imatinib had a new BCR-ABL mutation.

“Nilotinib displayed good tolerability, with a safety profile consistent with that of previous reports and no new safety signals observed,” Dr Larson said, noting that few new patients experienced selected cardiac and vascular events on nilotinib (3 on the nilotinib 300-mg arm and 6 on nilotinib 400-mg arm) between years 3 and 4.

In conclusion, Dr Larson said “nilotinib provided greater protection from progression to advanced phase and induced more rapid, deeper molecular responses. Treatment-emergent mutations were less frequent on nilotinib.”

Dr Larson is a consultant for Novartis Pharmaceuticals and has received research funding from Novartis Pharmaceuticals. Several of his co-authors are consultant/advisers for Novartis Pharmaceuticals, Bristol-Myers Squibb, Ariad, and Pfizer.