Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients: 12 Months Result of Phase 3 Clinical Trial
Authors: Kwak Jae-Yong , Kim Hawk , Kim Jeong A , Do Young Rok , Kim Hyeoung Joon , Park Joon Seong , Chung Joo Seop , Shin Ho-Jin , Kim Sung-Hyun , Kim Dae-Young , Bunworasate Udomsak , Choi Chul Won , Comia Narcisa Sonia Cornejo , Zang Dae Young , Oh Sukjoong , Jootar Saengsuree , Reksodiputro Ary Harryanto , Lee Won Sik , Mun Yeung-Chul , Kong Jee Hyun , Caguioa Priscilla B. , Park Jinny , Jung Chul Won , Kim Dong-Wook 
Published: October 2019

Abstract

Background
Radotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm. Co., Ltd (Seoul, South Korea) and approved by the Korea FDA for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients who have failed prior TKIs. We conducted the randomized, open-label, phase 3 study to assess the efficacy and safety of radotinib, as compared with imatinib, for the first-line treatment of newly diagnosed CML-CP.
Methods
Based on baseline demographics and Sokal risk score, 241 patients were randomized 1:1:1 to radotinib 300 mg twice daily (bid) (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81). The primary endpoint was the rate of major molecular response (MMR) by 12 months and molecular response was assessed by RQ-PCR at baseline and every 3 months. Secondary endpoints were the rate of complete cytogenetic response (CCyR), MR4.5 by 12 months, and the rate of progression to accelerate phase or blast crisis.
Results
All three study groups were well balanced with baseline age, gender, race and Sokal risk score. With minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86.3% (69/79) in radotinib 300 mg bid group, 71.6% (58/81) in radotinib 400 mg bid group, and 81.5% (66/81) in imatinib 400 mg qd group. By 12 months, rates of MMR were significantly higher in patients receiving radotinib 300 mg bid (51.9%, P = .0044) and radotinib 400 mg bid (45.7%, P = .0342) compared with imatinib (29.6%). The median time to MMR among responders were shorter on radotinib 300 mg bid (5.7 months) and radotinib 400 mg bid (5.6 months) than imatinib group (8.2 months). The MR4.5 rates by 12 months were also higher for both radotinib 300 mg bid (15.2%) and 400 mg bid (13.6%) compared to imatinib (8.6%). The CCyR rates by 12 months were also higher for radotinib 300 mg bid (91.1%, P = .0120) compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis in all groups by 12 months.
Discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 7 (8.8%), 16 (19.8%), and 5 (6.2%) patients for radotinib 300 mg bid, radotinib 400 mg bid and imatinib, respectively.
Grade 3/4 thrombocytopenia occurred in 16.5% of patients receiving radotinib 300 mg bid, in 13.6% for radotinib 400 mg bid, and in 19.8% receiving imatinib. And grade 3/4 neutropenia occurred in 19.0%, 23.5%, and 29.6% for radotinib 300 mg bid, 400 mg bid and imatinib, respectively. The most common any grade non-laboratory AEs were skin rash (35.4% and 33.3%), nausea/vomiting (22.8% and 23.5%), headache (19.0% and 30.9%), and pruritus (19.0% and 30.0%) in radotinib 300 mg bid and radotinib 400 mg bid, respectively; AEs in the imatinib group were edema (34.6%), myalgia (28.4%), nausea/vomiting (27.2%), and skin rash (22.2%). Overall, grade 3/4 non-laboratory AEs were uncommon in all groups.
Conclusions
With minimum 12 months follow-up, radotinib demonstrated significantly higher and faster rates of CCyR and MMR than imatinib in patients with newly diagnosed CML-CP. The safety profiles of the radotinib and imatinib were different, and most AEs were manageable with optimal dose reduction. The results of this trial support that radotinib can be one of the standard of care in newly diagnosed CML-CP.
Table. Baseline Characteristics, Molecular and Cytogenetic Response Rates Radotinib 300mg BID Radotinib 400mg BID Imatinib 400mg QD (N=79) (N=81) (N=81) Age, median (range), years 45 (20-75) 43 (18-84) 45 (18-83) Gender, n (%) Male 52 (65.8) 47 (58.0) 52 (64.2) Female 27 (34.2) 34 (42.0) 29 (35.8) Sokal risk, n (%) Low 21 (26.6) 22 (27.2) 22 (27.2) Intermediate 38 (48.1) 38 (46.9) 39 (48.2) High 20 (25.3) 21 (25.9) 20 (24.7) MMR by 12 months, % 51.9 45.7 29.6 P = .0044 P = .0342 Cumulative Incidence of MMR by 12 months¢Ó, % 57.0 58.0 35.0 P = .0040 P = .0037 MR4.5 by 12 months, % 15.2 13.6 8.6 CCyR by 12 months, % 91.1 81.5 76.5 ¢Ó Kaplan-Meier estimates of MMR

Disclosures
Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.