Among patients with newly diagnosed, Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia (CML), a lower-dose regimen of radotinib demonstrates superior complete cytogenetic response (CCyR) and major molecular response (MMR) rates at 12 months compared to imatinib, according to findings from an open-label, multinational phase III efficacy and safety study in Asia, published in Clinical Cancer Research.
Adverse events, while sometimes severe, were manageable with dose reduction, the authors reported.
Radotinib is a second-generation oral selective BCR-ABL1 tyrosine kinase inhibitor (TKI) that also targets the platelet-derived growth factor receptor. Developed in South Korea by Ilyang Pharmaceutical, where it is co-marketed by Daewoong Pharmaceutical as Supect, radotinib was approved for use in newly diagnosed and salvage settings by the South Korean Ministry of Food & Drug Safety, based on the study’s findings.
“TKI therapy targeting the BCR-ABL1 fusion protein has greatly improved outcomes with patients with CML, but therapy is indefinite and the costs of first- and second-generation TKIs are high,” the authors noted.
Radotinib is less expensive than other TKIs in South Korea. However, it is not yet clear how imatinib losing patent market exclusivity will affect its costs in the United States. Radotinib is not yet approved for use in the United States.
The phase III RERISE study examined its safety and association with CCyR and MMR rates compared to imatinib among 241 newly diagnosed adult patients with Philadelphia chromosome–positive chronic-phase CML treated in South Korea, Thailand, the Philippines, and Indonesia. Patients were randomly assigned 1:1:1 to receive either twice-daily radotinib 300 mg (n = 79) or 400 mg (n = 81), or once-daily imatinib 400 mg (n = 81).
At 12 months, CCyR rates for radotinib 300 mg and imatinib were 91% vs 77% (P = .012). No patient had progressed to accelerated-phase CML or blast crisis at 12 months.
Adverse events were almost universal in all study arms, affecting 96% to 99% of patients. Treatment-related adverse events were reported in 94%, 91%, and 93% of patients receiving radotinib 300 mg, 400 mg, and imatinib 400 mg, respectively. Grade 3/4 hyperbilirubinemia occurred in 27% of patients on 300 mg radotinib and 42% of patients receiving the 400-mg dose of radotinib.
“Dose reduction or interruption due to ALT/AST elevation or hyperbilirubinemia, respectively, occurred in 55% and 78% in radotinib 300 mg bid, 68% and 82% in radotinib 400 mg bid, and 19% and 73% in the imatinib group,” they reported. Grade 3/4 ALT/AST elevations occurred more frequently in the radotinib groups than in the imatinib group.
“More than 80% of these were resolved and controlled, and severe,” the authors reported. “Poorer efficacy and tolerability with the higher dose of radotinib (400 mg bid) highlight the need to consider body size and the potential for weight-based dosing of TKIs, particularly in Asian populations.”
Radotinib 400 mg did not yield statistically significant superiority over imatinib because of the high rate of early toxicity-associated discontinuations.