Roxanne Nelson

December 13, 2010

December 13, 2010 — (Orlando, Florida) Nilotinib (Tasigna) has demonstrated greater efficacy than imatinib (Gleevec) in adult patients with newly diagnosed Philadelphia-chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. Now new data, presented here at the American Society of Hematology 52nd Annual Meeting, show that this efficacy is sustained during 3 years of daily treatment.

Dr. Gianantonio Rosti

"After 3 years of treatment, the number of failures — patients who progressed to blast crisis — is only 1 out of 73," said lead study author Gianantonio Rosti, MD, scientific secretary of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) CML Working Party and professor of hematology and oncology at the University of Bologna in Italy.

Nilotinib rapidly induces a high rate of responses in these patients, Dr. Rosti reported during a press briefing held in advance of his presentation. He noted that 97% of patients achieved a major molecular response, and that "the number of patients achieving a complete molecular response is approaching 72% after 3 years."

The current study was undertaken to evaluate the durability of response to nilotinib. "This was a fear we had a couple of years ago," he said. "We had very good responses in the early period, but we weren't sure about the event-free and overall survival, which is really important for our patients."

Stronger Responses Than Imatinib

Nilotinib received approval from the US Food and Drug Administration in June 2010 as a first-line therapy for Philadelphia-chromosome-positive CML patients. The approval was based on the results of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd) study, an 18-month phase 3 trial in which nilotinib demonstrated superior rates of complete cytogenic and major molecular response to imatinib. Suboptimal responses and treatment failure were also less frequent among patients treated with nilotinib.

The results of the ENESTnd trial were presented at the American Society of Clinical Oncology 2010 Annual Meeting and published concurrently in the New England Journal of Medicine (2010;62:2251-2259). They were reported by Medscape Medical News at that time.

Sustained Responses Observed

The current study is a multicenter phase 2 open-label trial that was conducted by the GIMEMA CML Working Party. The cohort consisted of 73 patients, with a median age of 51 years (range, 18 to 83). Of this group, 45% were classified as low Sokal risk, 41% as intermediate risk, and 14% as high risk.

The primary end point of the study was the complete cytogenetic response rate at 12 months. Secondary end points were overall survival, progression-free survival, treatment-failure-free survival, and event-free survival.

At different key milestones throughout the trial period, the complete cytogenetic response rate was high — 78% at 3 months; 96% at 6, 12, and 18 months; and 92% at 24 months. The cumulative rate at 12 months for study participants was 100%, which indicates that all patients achieved complete cytogenetic response at least once, according to Dr. Rosti.

At a median follow-up of 36 months, overall survival, progression-free survival, and failure-free survival each reached 99%; event-free survival was 92%. The cumulative major molecular response rate was 96% at 12 months; at 3, 6, 12, 18, and 24 months, the rates were 52%, 66%, 85%, 81%, and 82%, respectively. Among patients who achieved a major molecular response, none progressed to accelerated or blast-phase CML. The only patient in the study who progressed to accelerated or blast-phase CML did so because of a T315I mutation.

Adverse events were primarily grade 1 or 2 and manageable with appropriate dose adaptations. Of the 6 patients (8%) who discontinued treatment, 4 did so because of adverse events — 3 after 9, 15, and 27 months on treatment for recurrent episodes of amylase and/or lipase increase (no pancreatitis), and 1 after 25 months because of atrial fibrillation unrelated to the study drug. One patient experienced disease progression and another died of unrelated causes.

Currently, 67 patients (92%) remain on nilotinib therapy, 2 (3%) are receiving second-line imatinib, 2 (3%) are receiving second-line dasatinib, and 2 (3%) have died.

"Each year, we continue to make significant strides in better understanding the underlying role certain genes play in the development of various forms of leukemia," said moderator of the press conference, Peter Emanuel, MD, director of the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock. "These studies underscore the advances we are making in the development of a new generation of treatment options that will improve overall outcomes for our patients."

The study was supported by the GIMEMA Foundation. Dr. Rosti reports financial relationships with Bristol-Myers Squibb, Novartis, and Roche. Other study authors report relationships with Bristol-Myers Squibb, Novartis, Wyeth, and Pfizer.

American Society of Hematology (ASH) 52nd Annual Meeting. Abstract 359. Presented December 6, 2010.

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