NILOTINIB APPROVED FOR FIRST LINE THERAPY IN CML

June 21, 2010 — The US Food and Drug Administration has approved nilotinib (Tasigna, Novartis) as a first-line treatment for chronic-phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML).

Approval was based on results from ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients), in which nilotinib was found to be superior to imatinib in achieving major molecular and complete cytogenetic responses.

The data showed that patients who received nilotinib, either 300 mg or 400 mg twice daily, had a significant improvement in time to progression to the accelerate phase (P = .01) or blast crisis (P = .004), compared with imatinib.

The results of the study were presented at the recent American Society of Clinical Oncology (ASCO) 2010 Annual Meeting, simultaneously published in the New England Journal of Medicine, and reported by Medscape Oncology at that time.

"With the faster and deeper responses we are seeing with [nilotinib], newly diagnosed CML patients will have a new and more effective treatment option," said Herve Hoppenot, president of Novartis Oncology, in a statement.

More Potent Than Imatinib

Nilotinib is a second-generation tyrosine kinase inhibitor and is a more potent and selective inhibitor of the BCR-ABL protein than imatinib. It is also active against a broad spectrum of BCR-ABL mutations associated with resistance to imatinib, and received regulatory approval in 2007 as a second-line treatment for CML.

ENESTnd is a phase 3 randomized open-label multicenter trial of 846 patients with Ph+ CML in the chronic phase. The cohort was randomized to nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281), or imatinib 400 mg once daily (n = 283). The primary end point was major molecular response (≤0.1% BCR-ABL) rate at 12 months.

At 12 months, the rates of major molecular response for nilotinib (44% for 300 mg and 43% for 400 mg) were nearly twice those for imatinib (22%; P < .001 for both comparisons). The rates of complete cytogenic response were significantly higher for patients receiving nilotinib (80% for 300 mg and 78% for 400 mg) than for those receiving imatinib (65%; P < .001 for both comparisons).

At both doses, those receiving nilotinib had a significant improvement in time to progression to accelerated phase or blast crisis, compared with those receiving imatinib.

Suboptimal responses and treatment failure were less frequent among patients treated with nilotinib, said study author coauthor Richard A. Larson, MD, during his presentation at ASCO. Dr. Larson is director of the Hematologic Malignancies Clinical Research Program at the University of Chicago in Illinois.

"There continue to be fewer progression events and CML-related deaths with nilotinib vs imatinib," said Dr. Larson. "With longer follow-up, rates of major molecular response and complete cytogenic response remain superior for nilotinib vs imatinib."

The study is ongoing and further data will be required to determine long-term outcome, he pointed out. "Molecular responses are continuing to deepen over time," he added. "There continue to be fewer progression events and CML-related deaths with nilotinib vs imatinib."

High-grade nonhematologic events were uncommon in both groups, and discontinuation of therapy because of adverse events or abnormal laboratory values was lowest for patients in the nilotinib 300 mg group (7%). Grade 3/4 neutropenia and anemia were more common in the imatinib group, whereas thrombocytopenia was more frequent in the 2 nilotinib groups.

Longer Follow-Up Needed

Nilotinib has been approved in more than 80 countries for the treatment of chronic- and accelerated-phase Ph+ CML in adult patients who are either resistant or intolerant to at least 1 previous therapy, including imatinib. Novartis reports that regulatory submissions are under way worldwide, with applications for a first-line indication currently filed in the European Union, Switzerland, and Japan.

The study authors note that additional follow-up will provide information about the potential long-term benefits or disadvantages of nilotinib therapy and that "further follow-up will provide information on the durability of responses, the development of treatment resistance, and the side-effect profile of nilotinib in the front-line setting."