Abstract

Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor and is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL. CA180-034 is a randomized, phase III, open-label study in patients with CML-CP (N=670) who have resistance, suboptimal response, or intolerance to prior imatinib 400–800 mg/d. Patients were randomized using a 2×2 factorial design to one of four treatment arms: 100 mg once daily (QD), 70 mg twice daily (BID), 140 mg QD, or 50 mg BID. Time to and duration of response, progressionfree survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Earlier reports demonstrated that dasatinib 100 mg QD (the currently approved dose in CML-CP) maintains efficacy while significantly minimizing adverse events (AEs). This finding was supported by pharmacokinetic analyses, which have demonstrated a correlation between low dasatinib steady-state trough plasma concentration (achieved with 100 mg QD dosing) and less frequent key toxicities and fewer dose interruptions. With a minimum of 2 years of follow-up in all patients, dasatinib 100 mg QD treatment resulted in a MCyR rate of 63% and a CCyR rate of 50%, and rates were similar in the other 3 arms (MCyR: 61%–63%; CCyR 50%–54%) (Table). Rates were similar when 14 patients with Ph-negative BCR-ABL-positive disease were excluded. Among responding patients in the 100 mg QD arm, median time to MCyR was 12.4 weeks and to CCyR was 13.0 weeks, and after 24 months, 87% of patients had maintained their MCyR and 89% had maintained their CCyR, with similar results in other arms. The 24-month PFS rate with 100 mg QD was 80% (vs 75%–76% in other arms) and OS rate was 91% (vs 88%–94%). In all arms, high response rates were achieved in patients with or without a baseline BCR-ABL mutation (CCyR rates for 100 mg QD: 40% vs 54%, respectively). Dasatinib was well tolerated and the incidence of treatment-related AEs after a minimum of 2 years of follow-up was similar to rates after a minimum of 1 year. In the 100 mg QD arm, overall 2-year rates (vs 1 year) were 2% (vs 2%) for grade 3 pleural effusion (grade 4: 0%), 23% (vs 22%) for grade 3/4 thrombocytopenia, and 35% (vs 34%) for grade 3/4 neutropenia. Among the 4 treatment arms, significant differences were observed in the overall incidences of drug-related pleural effusions (all grades: p=0.049) and cytopenias (p=0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. After a minimum of 2 years of 100 mg QD treatment, 12% of patients discontinued therapy following drug toxicity (vs 6% after 1 year), compared with 2-year rates of 16%–21% in other arms. Overall, 2-year data from CA180-034 extend previous findings and demonstrate that dasatinib dose optimization at 100 mg QD is associated with minimal incidence of key grade 3/4 toxicities in Year 2, and maintains long-term efficacy, in patients with CML-CP following resistance, suboptimal response, or intolerance to prior imatinib. Response duration and PFS with dasatinib 100 mg QD are similar to other dose schedules.

Table

 100 mg QD 70 mg BID 140 mg QD 50 mg BID 
All randomized patients n=167 n=168 n=167 n=168 
CHR (%) 92 88 87 92 
MCyR (%) 63 61 63 61 
Median time to MCyR (wks) 12.4 12.3 12.3 12.3 
MCyR maintained at 24 mos (%) 87 88 68 88 
CCyR (%) 50 54 50 50 
Median time to CCyR (wks) 13.0 12.9 13.8 12.9 
CCyR maintained at 24 mos (%) 89 85 78 93 
24-month PFS (%) 80 76 75 76 
24-month OS (%) 91 88 94 90 
Excluding Ph(−) BCR-ABL(+) n=164 n=163 n=163 n=166 
MCyR (%) 63 61 63 61 
CCyR (%) 49 53 50 50 
All treated patients n=165 n=167 n=163 n=167 
Pleural effusion (drug-related), grade 3/4 (%) 
Neutropenia, grade 3/4 (%) 35 45 44 47 
Thrombocytopenia, grade 3/4 (%) 23 38 41 36 
Dose interruption (%) 62 77 79 72 
Dose reduction (%) 39 62 62 46 
 100 mg QD 70 mg BID 140 mg QD 50 mg BID 
All randomized patients n=167 n=168 n=167 n=168 
CHR (%) 92 88 87 92 
MCyR (%) 63 61 63 61 
Median time to MCyR (wks) 12.4 12.3 12.3 12.3 
MCyR maintained at 24 mos (%) 87 88 68 88 
CCyR (%) 50 54 50 50 
Median time to CCyR (wks) 13.0 12.9 13.8 12.9 
CCyR maintained at 24 mos (%) 89 85 78 93 
24-month PFS (%) 80 76 75 76 
24-month OS (%) 91 88 94 90 
Excluding Ph(−) BCR-ABL(+) n=164 n=163 n=163 n=166 
MCyR (%) 63 61 63 61 
CCyR (%) 49 53 50 50 
All treated patients n=165 n=167 n=163 n=167 
Pleural effusion (drug-related), grade 3/4 (%) 
Neutropenia, grade 3/4 (%) 35 45 44 47 
Thrombocytopenia, grade 3/4 (%) 23 38 41 36 
Dose interruption (%) 62 77 79 72 
Dose reduction (%) 39 62 62 46 

Disclosures: Shah:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Kim:Bristol-Myers Squibb: Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding; Merck: Research Funding. Kantarjian:Bristol- Myers Squibb: Research Funding; Novartis: Research Funding. Rousselot:Bristol- Myers Squibb: Consultancy, Research Funding. Milone:Bristol-Myers Squibb: Speakers Bureau. Matloub:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Wyeth: Research Funding; Innovive: Research Funding; Merck: Research Funding.

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