At 5 Years, Nilotinib Offers Benefit Over Imatinib in CML

Five-year results of the randomized phase III ENESTnd trial show a positive risk-benefit profile for nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), as compared to imatinib. Cardiovascular risk does seem to be slightly raised with nilotinib, but improvements in CML disease control likely outweigh those risks.

“Through the first 4 years of ENESTnd, nilotinib resulted in earlier and higher rates of molecular response than imatinib and was associated with a lower risk of progression to accelerated phase or blast crisis,” wrote study authors led by Andreas Hochhaus, MD, of Universitätsklinikum Jena in Germany. However, because tyrosine kinase inhibitors such as nilotinib are taken indefinitely, long-term safety is an important issue.

The new analysis includes a minimum follow-up of 5 years, which was the full duration specified in the original study protocol. The study initially included 846 patients, randomized to nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily. The 5-year results were published online ahead of print in Leukemia.

By 5 years, 217 patients in the lower dose nilotinib group (77%), 217 patients in the higher dose nilotinib group (77.2%), and 171 imatinib patients (60.4%) achieved a major molecular response (MMR). Deep molecular responses were more frequent in the nilotinib patients, with 65.6%, 63%, and 57.1% of the three groups achieving MR⁴. MR^4.5 was achieved by 53.5%, 52.3%, and 31.4% of the two nilotinib and imatinib patients, respectively. The differences between cumulative rates of deep molecular response grew each year of the study’s follow-up period.

Progression to accelerated or blast phase was also more likely with imatinib than with nilotinib. In total, 18 nilotinib 300 mg patients, 10 nilotinib 400 mg patients, and 22 imatinib patients died during follow-up. Sixteen of the imatinib patients’ cause of death was CML, compared to only six and four of the nilotinib patients.

Grade 3/4 adverse events (AEs) , serious AEs, and AEs leading to treatment discontinuation were similar between the lower-dose nilotinib arm and the imatinib arm, and slightly higher in the nilotinib 400-mg group.

Some cardiovascular events were numerically more common with nilotinib. Hypertension was reported in 10.4% and 8.3% of the nilotinib groups, compared with 4.3% of the imatinib patients. Two patients in the higher-dose nilotinib group developed pulmonary hypertension, and venous thromboembolism or embolism was very rare in all groups.

Events including ischemic heart disease, ischemic cerebrovascular events, and/or peripheral artery disease were seen in 7.5% and 13.4% of nilotinib patients, compared with only 2.1% of imatinib patients. Cholesterol elevations were also more frequent with nilotinib. Very few patients died within 3 months of a cardiovascular event-two in the nilotinib 300 mg arm, none in the 400 mg arm, and one in the imatinib arm.

“Avoiding disease progression is a primary goal of therapy for patients with CML-CP because median survival following progression is poor” at about 10.5 months, the authors wrote. “Viewed as a whole, the combined efficacy and safety results from ENESTnd demonstrate that nilotinib provided patients with meaningful long-term clinical benefits over imatinib, with a positive balance of benefit and risk, particularly with the 300-mg twice-daily dose, as frontline therapy for patients with CML.”