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【medical-news】 Intermittent Target Inhibition With Dasati
J Clin Oncol. 2008 Jul 1;26(19):3204 -3212 , NP Shah, HM Kantarjian, DW Kim, D Réa, PE Dorlhiac-Llacer, JH Milone, J Vela-Ojeda, RT Silver, HJ Khoury, A Charbonnier, N Khoroshko, RL Paquette, M Deininger, RH Collins, I Otero, T Hughes, E Bleickardt, L Strauss, S Francis , A Hochhaus
For most patients who are diagnosed with chronic myeloid leukemia (CML) during the initial chronic phase (CP), first-line treatment consists of imatinib mesylate, which inhibits BCR-ABL tyrosine kinase activity. Phase II studies showed that dasatinib is an even more potent inhibitor than imatinib. Therefore, the agent was approved at a dosage of 70 mg twice daily for imatinib-resistant and -intolerant patients with CML. For these patients, dasatinib may be a life-saving therapy. After dasatinib’s approval, attention turned to how its dosing might be adjusted to optimize efficacy and safety in practice. The basis for this interest was 2-fold: (1) the relatively short half-life of dasatinib (3 to 5 hours) as compared with the half-lives of imatinib (18 hours) and various other tyrosine kinase inhibitors (20 to 48 hours); and (2) the fact that during phase I studies, intermittent BCR-ABL inhibition was efficacious, and a reduced incidence of pleural effusions was noted with once- vs twice-daily dosing.
To evaluate the effect of various doses and schedules of dasatinib, a randomized, international, multicenter, open-label, phase III trial with a 2 x 2 factorial design was conducted. A total of 662 Ph-positive patients with CML and imatinib resistance (n = 491) or intolerance (n = 171) (primary or acquired) were enrolled and randomized to receive oral dasatinib at 1 of the following 4 doses/schedules: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily; if response was deemed inadequate, the dosing in the 4 treatment arms was increased to 140 mg once daily, 70 mg twice daily, 180 mg once daily, or 90 mg twice daily, respectively. Dose interruptions or reductions were permitted if grade 2 or higher nonhematologic toxicity or grade 3 or higher hematologic toxicity developed. Treatment continued until disease progressed or toxicity became intolerable. Efficacy was based on hematologic assessments and bone marrow cytogenic analyses.
Median treatment duration was 8 months (range, <1-15 months). The primary objective of the study (ie, to show that once-daily dosing of dasatinib was noninferior to twice-daily dosing in terms of minimum cytogenic response [MCyR] in imatinib-resistant patients) was realized. McyR rate for the once-daily schedule was 52% (95% confidence interval [CI], 45.4%-58.2%) vs a rate of 49% for the twice-daily schedule (95% CI, 42.7%-55.4%), a treatment difference of 2.8% (95% CI, –6.0%-11.6%). The secondary objective (ie, to show that the 100-mg total daily dose was noninferior to the 140-mg total daily dose in imatinib-resistant patients) was also achieved: MCyR rates for the 100- and 140-mg doses were 50% (95% CI, 43.6%-56.4%) and 51% (95% CI, 44.4%-57.2%), a –0.8% difference (95% CI, –9.6%-8.0%).
Response depth was greater among imatinib-intolerant patients (MCyR, 68%-74%; complete cytogenic response [CCyR], 61%-68%) than among imatinib-resistant patients (MCyR, 47%-53%; CCyR, 34%-39%). At the minimum follow-up of 6 months, only minimal disease progression was seen in patients who had a MCyR regardless of treatment assignment. Progression-free survival (PFS) rates did not vary across treatment groups, and disease progression or death occurred in few patients (100 mg once daily, 50 mg twice daily, and 140 mg once daily, all 8%; 70 mg twice daily, 11%). Similarly, overall survival rates did not vary much across the treatment groups (100 mg once daily, 2% [n = 3]; 50 mg twice daily, 4% [n = 6]; 140 mg once daily, 2% [n = 4]; and 70 mg twice daily, 5% [n = 8]).
Treatment-related adverse events (AEs) occurred less often in the 100-mg once-daily cohort than in the other groups. Grade 3 to 4 AEs occurred in fewer patients who received the 100-mg once-daily dosage than in those who received the currently approved 70-mg twice-daily dosage (30% vs 48%, P = .001); differences between these 2 groups were most pronounced for rates of grade 3/4 thrombocytopenia (22% vs 37%; P = .004). Pleural effusions also occurred less often in patients receiving dasatinib 100 mg once daily than in those receiving 70 mg twice daily (7% vs 16%, P = .024). Dose reduction or interruption occurred less often in the 100-mg once-daily group compared with the 70-mg twice-daily group. Most notably, hematologic toxicity led to treatment interruption in 27% vs 35% of the 2 respective groups of patients, and to dose reduction in 22% vs 32% of patients.
This study’s findings have several implications. First, 100-mg once-daily dosing is more effective and better tolerated by patients with chronic-phase CML who are beginning dasatinib treatment. Second, the results indicate that tyrosine kinase inhibitor development should not be discontinued when newer compounds under development are found to have short half-lives. Third, high-dose intermittent kinase inhibitor therapy should be explored further for patients with resistant malignancies.
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作者:admin@医学,生命科学 2011-07-04 18:05
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