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

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