The European Commission (EC) has approved nilotinib (Tasigna) for the treatment of pediatric patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in the chronic phase (CML-CP), both in the frontline setting and for those with resistance or intolerance to prior therapy including imatinib.
The approval follows a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use, which was issued on September 14. The second-generation tyrosine kinase inhibitor is now approved for these indications in all EU member states, Novartis, the manufacturer of the treatment, noted in a press release.
"Treatment options for children with CML have historically been limited, and with this new indication, an unmet need has been addressed," said Bruno Strigini, CEO, Novartis Oncology. "Data from 2 prospective studies demonstrated Tasigna is safe and effective in patients as young as 2 years old, which is consistent with the established safety profile of Tasigna in adults."
The EC based the approval on 2 prospective studies of nilotinib in children with Ph+ CML-CP. The trials were part of a formal "pediatric investigation plan" agreed upon with the EMA, according to Novartis.
Overall, nilotinib was administered to 69 pediatric patients aged 2 to 18 years with either newly diagnosed disease, or Ph+ CML-CP resistant/intolerance to prior treatment, including imatinib.
The rate of major molecular response (MMR; BCR ABL/ABL ≤0.1% International Scale) in patients with newly diagnosed CML was 60.0% (95% CI, 38.7-78.9) at 12 cycles. Fifteen patients achieved MMR.
The MMR rate at 12 cycles was 40.9% (95% CI, 26.3-56.8) in previously treated patients, comprising 18 patients who achieved MMR.
By cycle 12, the cumulative MMR rates were 64.0% and 47.7% among the newly diagnosed and previously treated patients, respectively.
Adverse events in the pediatric population were mostly similar to results previously reported for adult patients. Exceptions included hyperbilirubinemia (grade 3/4, 13.0%), elevated AST (grade 3/4, 1.4%) and elevated ALT (grade 3/4, 8.7%), which were more commonly reported than in adult patients. There were no deaths in either study reported during treatment or following discontinuation.
This is the second recent major regulatory development in this patient population. On November 10, the FDA approved dasatinib (Sprycel) for the treatment of pediatric patients with Ph+ CML-CP.
The approval was based on results with dasatinib demonstrated in 97 pediatric patients with CP-CML enrolled across 2 studies, an open-label, nonrandomized, single-arm phase II trial (CA180-226; NCT00777036) and an open-label, nonrandomized, dose-ranging phase I trial (CA180-018; 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 complete cytogenetic response (CCyR), major cytogenetic response (MCyR), and 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.