The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended changes to the marketing authorization for dasatinib (Sprycel).
The CHMP is recommending approval for dasatinib as a treatment for pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or Ph+ CML-CP that is resistant or intolerant to prior therapy, including imatinib.
The CHMP has also recommended approval of a new formulation of dasatinib—a powder for oral suspension (PFOS)—for use in pediatric patients.
Dasatinib is already approved in the European Union to treat adults with:
- Newly diagnosed Ph+ CML-CP
- Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
- Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.
The CHMP’s opinion on dasatinib for pediatric patients will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s opinion on dasatinib for pediatric patients is supported by 2 studies. Results from the phase 1 study (NCT00306202) were published in the Journal of Clinical Oncology in 2013. Phase 2 (NCT00777036) results were published in the same journal this year.
The phase 1 trial included 17 patients with CML-CP, all of whom had received prior imatinib.
Eleven patients received dasatinib at a starting dose of 60 mg/m2 once daily, and 6 received the drug at a starting dose of 80 mg/m2 once daily. Dose escalation was allowed based on tolerance and response. The median duration of treatment was 24.1 months (range, 2.3 to 50.6 months).
The 60 mg/m2 starting dose appeared more tolerable than 80 mg/m2 dose.
Drug-related adverse events (AEs) occurring in at least 20% of patients included neutropenia (82.4%), anemia (70.6%), thrombocytopenia (64.7%), nausea (29.4%), headache (35.3%), diarrhea (23.5%), and pain in extremity (23.5%). Grade 3-4 AEs included neutropenia (23.5%), thrombocytopenia (11.8%), and headache (5.9%). There were no drug-related deaths.
Ninety-four percent of patients achieved a complete hematologic response (CHR), 88% had a major cytogenetic response (MCyR), 82% had a complete cytogenetic response (CCyR), 47% had a major molecular response (MMR), and 24% had a complete molecular response (CMR).
Patients who received the lower starting dose of dasatinib had lower rates of cumulative CCyR (72.7% vs 100%) and CHR (90.9% vs 100%) but higher rates of cumulative MMR (54.5% vs 33.3%) and CMR (27.3% vs 16.7).
The median progression-free survival (PFS) and overall survival (OS) had not been reached at last follow-up. At 24 months, the estimated PFS was 61%, and the estimated OS was 88%.
The phase 2 trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 with newly diagnosed CML-CP.
The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33). Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.
The average daily dose of dasatinib was 58.18 mg/m2 in the previously treated patients and 59.84 mg/m2 in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.
Rates of confirmed CHR (at any time) were 93% in the previously treated patients and 96% in the newly diagnosed patients.
At 12 months, previously treated patients had an MMR rate of 41% and a CMR rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.
At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.
The rate of MCyR at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.
The rate of CCyR at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.
The median PFS and OS had not been reached at last follow-up. The estimated 48-month PFS was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month OS was 96% and 100%, respectively.
Dasatinib-related AEs occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).
Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).