From the ONI archives: CML patients’ molecular response to nilotinib continues to deepen over time

August 10, 2010

Eighteen-month follow up supports lower-dose nilotinib as the new standard of care for newly diagnosed chronic myeloid leukemia. The ENESTnd trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+CML Patients) enrolled 846 patients at 217 sites in 35 countries. Timothy P. Hughes, MD, MBBS, will present an update to the ENESTnd trial at ASH 2010.

ABSTRACT: Eighteen-month follow up supports lower-dose nilotinib as the new standard of care for newly diagnosed chronic myeloid leukemia.

In the phase III randomized ENESTnd trial, patients treated with nilotinib continued to show superior response after 18 months of follow-up. In addition, these patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia had reduced rates of progression on nilotinib vs imatinib.

Nilotinib (300 mg BID or 400 mg BID twice daily) achieved higher rates of major molecular response and complete cytogenetic response than imatinib (400 mg once daily). Significantly fewer patients on nilotinib progressed to accelerated phase or blast crisis, and there were fewer CML-related deaths on nilotinib.

"Molecular responses continue to deepen over time, and there continue to be fewer progression events and fewer deaths with nilotinib," said ENESTnd lead investigator Richard A. Larson, MD, a professor of medicine and director of the hematologic malignancies program at the University of Chicago. "Longer follow-up supports nilotinib as a new standard of care in patients with newly diagnosed CML."

"The efficacy of nilotinib at 300 mg is equivalent to the 400 mg dose…so we feel [300 mg] is the dose that will go forward in front-line therapy."- RICHARD LARSON, MDD

The ENESTnd trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+CML Patients) enrolled 846 patients at 217 sites in 35 countries; planned follow-up is for five years. At a median follow-up of 18 months, at least 75% of the patients remained in the trial (ASCO 2010 abstract 6501; New Engl J Med 362: 2251-2259, 2010).

Out of 525 evaluable patients at 18 months, significantly more patients on nilotinib (69% at 300 mg and 63% at 400 mg) had a major molecular response than did patients on imatinib 400 mg (36%). Of the 442 patients who had a cytogenetic assessment, 99% on both doses of nilotinib experienced a complete cytogenetic response (CCyR) compared with 89% on imatinib.

Two patients on the nilotinib 300 mg dose and one on the 400 mg dose experienced disease progression vs 12 patients who received imatinib. There were also fewer CML-related deaths with nilotinib (two on the 300 mg dose and one on the 400 mg dose) than with imatinib (eight).

The ENESTnd investigators showed that rates of major molecular response for nilotinib (44% at 300 mg and 43% at 400 mg) were twice the rate for imatinib (22%) after one year. Rates of CCyR at 12 months were also significantly greater for nilotinib (80% at 300 mg and 78% at 400 mg) than for imatinib (65%).

DID YOU KNOW?FDA OKs nilotinib in CMLIn June 2010, the FDA approved nilotinib (150 mg) capsules for patients with newly diagnosed Ph+CML based largely on the results of the ENESTnd trial.

Concerns have been raised about liver function and QT prolongation from imatinib. But in comparison, no patient in the nilotinib arm had prolongation of QT interval greater than 500 milliseconds, and only 1% of patients discontinued nilotinib due to hepatobiliary disorders. Discontinuation rates for adverse events or laboratory abnormalities were lowest in the 300 mg nilotinib group at 7% vs 11% among those who took nilotinib at 400 mg and 9% among patients who received imatinib at 400 mg.

"The efficacy of nilotinib at 300 mg is equivalent to the 400 mg dose, and the side-effect profile favors the lower dose," Dr. Larson said. "So we feel [300 mg] is the dose that will go forward in frontline therapy."

Dr. Larson added that ENESTnd investigators are slated to present data on the durability of major molecular response with nilotinib vs imatinib at 24 months at the 2010 ASH meeting (abstract 207).

VANTAGE POINT


CHARLES L. SAWYERS, MDCapping a 'remarkable' decade in CML therapy

At the time of its FDA approval, imatinib demonstrated outstanding efficacy with minimal toxic effects as initial CML therapy, wrote Dr. Sawyers in a New England Journal of Medicine editorial. However, "by today's standards, imatinib has relatively low potency and inhibits its targets at micromolar rather than nanomolar concentrations…in addition, imatinib is susceptible to resistance through a large number of different mutations in the BCR-ABL target. . . ," he said (362:2314-2315, 2010).

Dasatinib and nilotinib have shown greater potency than imatinib, and both drugs have proved effective in CML patients who fail standard treatment. Dasatinib has proven especially useful in imatinib-resistant mutations in the BCR-ABL, he added.

The dasatinib study and the ENESTnd study "cap a remarkable decade of progress in CML therapy and, for some, may raise the question of whether we have reached the limit of what we can hope to achieve," stated Dr. Sawyers, who is chair of the human oncology and pathogenesis program at Memorial-Sloan Kettering Cancer Center in New York. He is also an investigator with the Howard Hughes Medical Institute.

But these new TKIs are not without their drawbacks, most notably adverse events. Dasatinib has been associated with pleural effusions, while nilotinib has been linked to biochemical changes in liver function and QT prolongation. And, as with imatinib, disease resistance to these newer agents could be a possibility.

Additionally, the findings in both studies were reported after one year of treatment. "Some observers may argue that one year is too early to claim victory in a disease with a long natural history," Dr. Sawyers pointed out.

Despite the superiority of dasatinib and nilotinib in their respective trials, "imatinib may survive the challenge on the basis of economic rather than scientific factors. . . with rising pressure to balance cost and efficacy, patients and payers may be forced to select the cheapest among three excellent treatment options," he wrote.