First-line dasatinib, nilotinib sustain their edge over imatinib

2010 Dec 21,

JS MacNeil

ORLANDO (EGMN) - Second-generation tyrosine kinase inhibitors dasatinib and nilotinib maintained their separate advantages over imatinib in updates of pivotal phase III trials that won them first-line indications in chronic myeloid leukemia.

The deeper, faster responses seen in the experimental arms of the multinational DASISION and ENESTnd trials are being sustained with longer follow-up in both studies, investigators reported at the annual meeting of the American Society of Hematology.

Cost could be the key issue in determining which drug to use for newly diagnosed patients in chronic phase, observers agreed. The new drugs may be better, but imatinib (Gleevec) is effective in most patients and its cost is expected to go down when it goes off patent.

Most patients do "extremely well" with the first-generation drug, Dr. Kimmo Porkka, a professor of hematology at Helsinki University, noted in an interview after moderating the oral session at which the new data were presented.

"The current problem is we cannot predict which patients will need the better drugs. It is a very small group of patients, but we don't know which patients they are," he said.

Already in the United States, even as practitioners move to the second-generation drugs, cost can be a factor, Dr. Charles A. Schiffer, head of the malignant hematology multidisciplinary team at the Karmanos Cancer Center in Detroit, said in an interview after the same oral session.

"In the United States, most doctors are choosing to use either nilotinib or dasatinib, and the data certainly justify that. ... But for certain people, there may be issues with copays," he said, adding that the Medicare "doughnut hole" that forces older patients to pay out of pocket when they reach a coverage gap also can influence which drug gets chosen.

Dasatinib. Dr. Neil Shah of the Diller Family Comprehensive Cancer Center at the University of California, San Francisco, presented 18-month follow-up data on DASISION (Dasatinib vs. Imatinib Study in Treatment Naive CML Patients) comparing 100 mg daily of dasatinib (Sprycel) to a 400-mg daily dose of imatinib in two cohorts of 258 patients each. The 12-month data were previously published (N. Engl. J. Med. 2010;362:2260-70).

Intent-to-treat analyses show confirmed complete cytogenetic response (CCyR) rates of 78% and 70%, respectively (P = .0366) at 18 months. All told, 85% and 80%, respectively, had a CCyR at some point during treatment. "The likelihood of achieving a complete cytogenetic response at any time was 1.5-fold higher with dasatinib than with imatinib [stratified log rank P less than .0001]," Dr. Shah said.

Similarly, the likelihood of achieving a major molecular response (MMR) was 1.8-fold greater with dasatinib than with imatinib (stratified log rank P less than .0001). Rates of achieving MMR at any time were 57% vs. 41% (P = .0002), and time to MMR was faster, at 8.3 months with dasatinib vs. 11.8 months with imatinib.

More patients on imatinib converted to accelerated or blast-phase chronic myeloid leukemia (CML): 9 vs. 6 in the dasatinib arm. More deaths have occurred in the dasatinib arm (11 vs. 6), however; Dr. Shah said the excess was not drug related.

Nilotinib. Dr. Timothy P. Hughes, head of hematology at the Royal Adelaide Hospital, Australia, presented intent-to-treat data from the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial comparing two doses of nilotinib (Tasigna) - 300 mg and 400 mg twice a day - to 400 mg of imatinib daily at a minimum follow-up of 24 months, with about 280 patients in each study arm. Twelve-month data also were published in June (N. Engl. J. Med. 2010;362:2251-9).

At 2 years, durable MMR was seen in 62% of the 300-mg group, 59% of the 400-mg group, and 37% of the imatinib group (P less than .001 in both comparisons). In all three arms, the responses were durable, with less than 2% losing response between 12 and 24 months.

The differences in cumulative MMR that were seen at 12 months continued to be seen at 24 months, he said; rates were 71% in the 300-mg arm and 67% in the 400-mg arm vs. 44% with imatinib (again P less than .001 for both comparisons). Complete CCyR rates were closer but also remained significantly different at 87% and 85%, respectively, in the nilotinib arms vs. 75% in the imatinib arm.

Conversely, suboptimal response rates and treatment failure rates were higher in the imatinib arm, and more patients on imatinib had progressed to accelerated or blast phase: 12 vs. 2 in the nilotinib 300-mg group and 3 in the nilotinib 400-mg group. There were more CML-related deaths in the imatinib group: 10 vs. 5 and 3, respectively.

Dr. Shah and Dr. Hughes each disclosed relationships with Novartis, Bristol-Myers Squibb, and Ariad Pharmaceuticals, and Dr. Porkka disclosed relationships with Novartis.

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