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A multinational open-label dose-comparison phase III trial has found the optimal dose of dasatinib to be 100 mg once daily in patients with chronic-phase chronic myeloid leukemia.
The trial showed similar levels of hematologic, cytogenetic, and molecular efficacy for dasatinib (Sprycel) at 100 mg and 140 mg, regardles of whether the agent was administered once daily or in divided doses twice daily.
Importantly, the 100-mg once-daily dose was associated with a reduced incidence of thrombocytopenia and pleural effusion.
It also produced significantly better progression-free survival when compared with the current standard dose of 70 mg twice a day (91% vs. 84%, P = .032). No overall survival data were reported.
Dasatinib, a short-acting oral tyrosine kinase inhibitor, mostly targets imatinib-resistant BCR-ABL protein mutations. It is approved at a dose of 70 mg twice daily for adults in all phases of chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib. Its use has been associated with increased pleural effusion, however.
This phase III trial provides the first evidence that transient target inhibition with a tyrosine kinase inhibitor can preserve the efficacy of more continuous inhibition and simultaneously improve tolerability, said the lead investigator, Dr. Neil P. Shah.
"This of course opens the door for consideration of intravenous kinase inhibitors and perhaps even less-frequent dosing as something that should be studied," said Dr. Shah of the University of California, San Francisco.
The trial accrued patients at 139 centers from July 2005 to March 2006. Investigators first randomized 670 patients with late chronic-phase CML to total daily dasatinib doses of 100 mg or 140 mg. They then subdivided the population into four dasatinib arms: 100 mg once daily (165 patients), 50 mg twice daily (167 patients), 140 mg once daily (163 patients), and 70 mg twice daily (170 patients).
Among the 662 patients who received treatment, the median disease duration was 4 years or more before entering the study. Roughly one-third had previously received imatinib at a dose of more than 600 mg/day, and about three-quarters were resistant to imatinib.
Response rates, with a median treatment duration of 11.5 months, were similar across all arms, reported Dr. Shah, who is a consultant for and has received honoraria from Bristol-Myers Squibb Co., which markets dasatinib and sponsored the study.
The numbers of patients who progressed in each arm at a median of 11.5 months were 16 in the 100-mg once-daily arm; 22 in the 50-mg twice-daily arm; 23 in the 140-mg once-daily arm; and 30 in the 70-mg twice-daily arm.
The incidence of thrombocytopenia (22% vs. 38%, P = .004)) and chronic heart failure (0% vs. 4%, P = .015) was significantly reduced when patients received 100 mg once a day as compared with 70 mg twice a day.
The 100-mg once-daily dose was associated with a lower incidence of pleural effusion (10% vs. 18%) and neutropenia (33% vs. 43%) compared to the current standard, but the association was not statistically significant, Dr. Shah reported. Likewise, anemia (17% vs. 23%) and leukopenia (34% vs. 43%) were reduced but not significantly.
Treatment interruption (58% vs. 71%, P = .047), dose reduction (33% vs. 57%, P less than .001), discontinuation (22% vs. 32%, P = .049), and discontinuation because of toxicity (6% vs. 15%, P = .012) were significantly lowered in patients receiving 100 mg once daily rather than 70 mg twice daily, Dr. Shah said. Fewer patients had dose interruptions (66%) and reductions (45%) on 50 mg twice a day than with the standard dose, but the benefit was greater with 100 mg once a day.
The median daily dose was 99 mg in the 100-mg once daily cohort, 90 mg in the 50-mg twice daily cohort, 121 mg in the 140-mg once daily cohort, and 102 mg in the standard 70-mg twice-a-day cohort.
The rationale for the trial came from pharmacokinetic and pharmacodynamic data showing that, unlike most tyrosine kinase inhibitors, dasatinib has a relatively short biologic half-life of only 3-5 hours and does not appear to have a significant long-acting metabolite.
Surprisingly, phase I data demonstrated that dasatinib induces complete hematologic and major cytogenetic responses at total daily doses of 100 mg and 140 mg given once or twice daily, despite achieving only transient inhibition of the BCR-ABL kinase domain when administered once daily (N. Engl. J. Med. 2006;354:2531-41).
Shah N.P. et al. Dasatinib 50 mg or 70 mg BID, compared with 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: 1-year results of CA180034. Abstract 7004.
Commentary |
The treatment options for patients with chronic myeloid leukemia continue to expand. Although imatinib remains the only tyrosine kinase inhibitor indicated for initial treatment of CML, results of a phase II trial using dasatinib as initial treatment highlight the possibilities for the future. In that study from the M.D. Anderson Cancer Center in Houston (abstract 70 on the following page), rates of both cytogenetic and molecular responses with dasatinib were similar to those expected with imatinib, but the responses were more rapid than previously reported with imatinib. Several other studies of dasatinib as initial therapy are ongoing. These include a Southwest Oncology Group trial that randomizes patients between two different starting doses of imatinib or dasatinib. Ultimately, the benefit of earlier responses, whether cytogenetic or molecular, will need to be confirmed by other end points, primarily progression-free survival. Dasatinib is an approved treatment option for patients who are intolerant or resistant to imatinib. A second-generation kinase inhibitor, it is approved for dosing at 70 mg twice daily. Results of a randomized study have demonstrated that transient inhibition of BCR-ABL achieved with once-daily 100-mg dasatinib dosing was equally efficacious and associated with less toxicity than the approved dosing schedule. The study on this page confirms that patients receiving dasatinib for imatinib-resistant or -intolerant chronic-phase CML should be started at a dose of 100 mg once daily. Finally, two additional second-generation kinase inhibitors, bosutinib and nilotinib, are active against imatinib-resistant CML, with results very similar to those reported for dasatinib. These oral drugs also seem to be well tolerated. Mutation analysis should be obtained prior to starting dasatinib or the two new second-generation tyrosine kinase inhibitors, since none of them have activity against the T315I mutation, which which remains a concern. That physicians soon may be faced with a wealth of choices in treating CML emphasizes the need for vigilance to ensure that our patients are achieving optimal responses, including not only complete cytogenetic remissions but also major molecular responses. — Steven E. Coutré, M.D.
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