Short-term results from two phase III clinical trials suggest that patients with chronic myeloid leukemia (CML) may have new options for the initial treatment of their cancer. It’s still unclear, though, whether there will be a longer-term survival benefit from the drugs compared with the standard first-line treatment , imatinib (Gleevec®). Some researchers said this information will be important in determining the optimal treatment for patients with newly diagnosed CML. Data from both trials were presented in June 2010 at the ASCO annual meeting in Chicago and published online June 5, 2010, in the New England Journal of Medicine.
The trials compared the drugs dasatinib (Sprycel®) and nilotinib (Tasigna®), respectively, with imatinib. Both drugs are second-generation agents that, like imatinib, target the molecular driver of CML, a fusion of the genes BCR and ABL . This fusion gene produces a protein that spurs the overdevelopment of white blood cells that is the hallmark of CML. In both trials, patients who received one of the new drugs had higher rates of complete cytogenetic response, meaning a complete disappearance of cells that contain the chromosome (known as the Philadelphia chromosome ) that harbors the BCR-ABL fusion gene, than patients who received imatinib. They also had higher rates of major molecular response, a disappearance of virtually all cancerous cells.
In the 519-patient trial that pitted dasatinib against imatinib, dubbed DASISION , at the 12-month follow-up point the confirmed complete cytogenetic response rate was 77 percent for patients treated with dasatinib compared with 66 percent for patients who received imatinib. The rates of major molecular response were 46 and 28 percent, respectively.
The 846-patient trial involving nilotinib, dubbed ENESTnd , compared two different doses of nilotinib with imatinib. The confirmed complete cytogenetic response and major molecular response rates for patients who received either nilotinib dose or imatinib were very similar to what was seen in the DASISION trial. In both trials, the side effects were considered minimal and manageable.
Both drugs—which are already approved by the FDA to treat CML that no longer responds to or is resistant to imatinib—are more potent than imatinib. In addition, fewer mutations in the BCR-ABL target appear capable of conferring resistance to these drugs than to imatinib, explained Charles Sawyers, M.D., whose research helped lead to the development of imatinib, one of the first and most successful molecularly targeted cancer therapies.
“The data regarding response and side effects in the two studies certainly make a strong case for dasatinib or nilotinib as first-line therapy over imatinib,” Dr. Sawyers wrote in an accompanying editorial in NEJM. But because imatinib will be available as a generic drug in several years and given “the rising pressure to balance cost and efficacy,” he noted, imatinib may remain a first-line option.
In February 2010, FDA granted “priority review” for nilotinib, which is manufactured by Novartis, as a first-line CML treatment. In a news release, Bristol-Myers Squibb, which manufactures dasatinib, said the company is “in the process of submitting the DASISION data to worldwide health authorities this year” for approval of the drug as a first-line CML treatment.