Phase III Clinical Trial (RERISE study) Results of Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Abstract

Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months. Two hundred forty-one patients were randomized to receive radotinib 300 mg ( = 79) or 400 mg twice-daily ( = 81), or imatinib 400 mg daily ( = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; = 0.0044 and = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome-positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289 .

BCR‐ABL1 transcript levels at 4 weeks have prognostic significance for time‐specific responses and for predicting survival in chronic‐phase chronic myeloid leukemia patients treated with various tyrosine kinase inhibitors

“…Of 128 patients administered frontline 2G TKIs, 91% and 83% achieved EMR at 3 and 6 months, respectively. In this study, EMR rates were comparable with those of DASISION, ENESTnd, RERISE, and BFORE studies, indicating the use of homogeneous approaches in terms of molecular analysis and study population. Interestingly, the optimal cutoffs for higher CCyR, MMR, and EFS were similar (approximately 40%), which was albeit as a VEMR.…”

“…In addition, 6-month EMR (BCR-ABL1 transcript level ≤1%) was predicted to be achieved in 49%-58% of imatinib-treated patients and in 69%-82% of 2G TKI-treated patients. 14,27,28 In the present study, of 213 patients eligible for 3-month molecular analysis, 83% (176 patients) achieved EMR at 3 months and 71% (results of molecular analysis available for 131 of 185 patients) achieved EMR at 6 months. Among 130 frontline imatinib-treated patients, the EMR rates at 3 and 6 months were 74% and 59%, respectively.…”

“…Three‐month EMR was previously predicted to be achieved in 50%‐71% of imatinib‐treated new CP patients and in 75%‐91% of frontline 2G TKI‐treated patients. In addition, 6‐month EMR ( BCR‐ABL1 transcript level ≤1%) was predicted to be achieved in 49%‐58% of imatinib‐treated patients and in 69%‐82% of 2G TKI‐treated patients …”

“…Hughes et al reported that patients achieving EMR at 6 months had superior event‐free survival (EFS) and decreased tumor progression. Moreover, numerous studies including those on second‐generation (2G) tyrosine kinase inhibitors (TKIs) revealed that patients achieving EMR had significantly lower overall survival (OS), progression‐free survival (PFS), complete cytogenetic response (CCyR), major molecular response (MMR), and/or complete molecular response (CMR) . The prognostic information from 3‐month vs 6‐month EMR achievement has been analyzed, and earlier achievement of EMR is reported to have superior prognostic value .…”

“…Moreover, numerous studies including those on second-generation (2G) tyrosine kinase inhibitors (TKIs) revealed that patients achieving EMR had significantly lower overall survival (OS), progression-free survival (PFS), complete cytogenetic response (CCyR), major molecular response (MMR), and/or complete molecular response (CMR). 5,[10][11][12][13][14] The prognostic information from 3-month vs 6-month EMR achievement has been analyzed, and earlier achievement of EMR is reported to have superior prognostic value. 6,15,16 In addition, as various factors such as baseline risk score, spleen size, baseline leukocyte count, TKI dose intensity, and blood TKI levels can be associated with EMR achievement, more cautious analyses are warranted.…”