Fouad Namouni, MD
The European Commission (EC) has approved dasatinib (Sprycel) for the treatment of children and adolescent patients aged 1 to 18 years with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP), according to Bristol-Myers Squibb (BMS), the manufacturer of the tyrosine kinase inhibitor.
With the action, the EC also approved a powder for an oral suspension formulation of dasatinib for use in pediatric patients and adult patients unable to swallow tablets.
The approval, which follows a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use, is based on data from the open-label, nonrandomized, single-arm phase II CA180-226 trial (NCT00777036). The study examined dasatinib in pediatric patients with either newly diagnosed CP-CML or those who had developed resistance or intolerance to imatinib (Gleevec, US; Glivec, EU).
Among newly diagnosed patients receiving dasatinib tablets or as powder for oral suspension, the cumulative complete cytogenetic response (CCyR) rate at ≥2 years’ follow-up was 64% (95% CI, 53-74) at 6 months into treatment and increased to 94% (95% CI, 87-98) at 24 months. The estimated 48-month progression-free survival (PFS) rate for these patients was higher than 90%.
In the cohort of imatinib resistant/intolerant patients, the cumulative major cytogenetic response (MCyR) rate was 55.2% (95% CI, 36-74) at 3 months, and >90% (95% CI, 73-98) at 24 months. The estimated 48-month PFS rate for these patients was >75%.
“Treatment options for pediatric patients with CML are limited, as are formulations that correspond with the unique demands of children with cancer,” Fouad Namouni, MD, head of development, Oncology, BMS, said in a statement.
“Our decision to pursue an expanded indication for Sprycel in this new patient population and as a new formulation is indicative of our commitment to extending the potential of our medicines to address the unmet needs of patients with cancer, regardless of the incidence of the disease,” added Namouni.
BMS noted in a press release that safety data for dasatinib in pediatric patients with CP-CML are similar to results in adult patients with CP-CML. Among imatinib intolerant/resistant patients in CA180-226, the most common adverse events (AEs) included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), and rash (14%). In the newly diagnosed cohort, the most frequent all-grade AEs were nausea/vomiting (20%), rash (19%), and diarrhea (18%). Also of note, there were no cases reported in the study of pleural/pericardial effusion, pulmonary edema/hypertension, or pulmonary arterial hypertension related to treatment with dasatinib.
In its statement, BMS explained that dasatinib powder for oral suspension (PFOS) is indicated for patients who weigh <10 kg or those unable to swallow tablets whole. At least every 3 months, the recommended dose for both the PFOS and tablet formulations should be recalculated. Additionally, the PFOS and tablet formulations are not bioequivalent, and a switch from the tablet to the PFOS formulation should only occur at the recommendation of a medical professional, according to BMS.
In the United States, the FDA approved dasatinib in November 2017 for the treatment of pediatric patients with Ph+ CP-CML. The FDA approval was based on results with dasatinib demonstrated in 97 pediatric patients with CP-CML enrolled across both the CA180-226 trial and the open-label, nonrandomized, dose-ranging phase I CA180-018 trial (NCT00306202). Fifty-one patients (all from the single-arm trial) were newly diagnosed, and the remaining 46 (29 from the single-arm study and 17 from the dose-ranging trial) were intolerant or resistant to prior imatinib.
At a median follow-up of 4.5 years, more than half of the responding patients in the treatment-naïve cohort had not progressed at the time of the data cutoff, and thus, the median duration of CCyR, MCyR, and major molecular response (MMR) could not be estimated. The same was true at the median follow-up time of 5.2 years for the previously treated cohort.
The range of duration of response (DOR) for the newly diagnosed patients was 2.5+ to 66.5+ months for CCyR, 1.4 to 66.5+ months for MCyR, 5.4+ to 72.5+ months for patients who achieved MMR by month 24, and 0.03+ to 72.5+ months for patients who achieved MMR at any time. The ‘+’ denotes a censored observation. Among the imatinib-intolerant cohort, the DOR ranges were 2.4 to 86.9+ months for CCyR, 2.4 to 86.9+ months for MCyR, and 2.6+ to 73.6+ months for MMR.
The 3-, 6-, 12-, and 24-month CCyR rates among newly diagnosed patients were 43.1% (95% CI, 29.3-57.8), 66.7% (95% CI, 52.1-79.2), 96.1% (95% CI, 86.5-99.5), and 96.1% (95% CI, 86.5-99.5), respectively. In the previously treated group, the corresponding rates were 45.7% (95% CI, 30.9-61.0), 71.7% (95% CI, 56.5-84.0), 78.3% (95% CI, 63.6-89.1), and 82.6% (95% CI, 68.6-92.2), respectively.
The 3-, 6-, 12-, and 24-month MCyR rates among treatment-naive patients were 60.8% (95% CI, 46.1-74.2), 90.2% (95% CI, 78.6-96.7), 98.0% (95% CI, 89.6-100), and 98.0% (95% CI, 89.6-100), respectively. The corresponding rates in the imatinib-intolerant group were 60.9% (95% CI, 45.4-74.9), 82.6% (95% CI, 68.6-92.2), 89.1% (95% CI, 76.4-96.4), and 89.1% (95% CI, 76.4-96.4), respectively.
The 3-, 6-, 12-, and 24-month MMR rates among newly diagnosed patients were 7.8% (95% CI, 2.2-18.9), 31.4% (95% CI, 19.1-45.9), 56.9% (95% CI, 42.2-70.7), and 74.5% (95% CI, 60.4-85.7), respectively. The corresponding rates in the previously treated group were 15.2% (95% CI, 6.2-28.9), 26.1% (95% CI, 14.3-41.1), 39.1% (95% CI, 25.1-54.6), and 52.2% (95% CI, 36.9-67.1), respectively.
European Commission Approves Expanded Indication for Sprycel (dasatinib) to Include Treatment of Children with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase. Bristol-Myers Squibb. Posted July 5, 2018. Access July 5, 2018. https://bit.ly/2KNWwzW.