Olverembatinib (HQP1351) demonstrates efficacy vs. best available therapy (BAT) in patients (pts) with tyrosine kinase inhibitor (TKI)-resistant chronic-Phase chronic myeloid leukemia (CML-CP) in a registrational randomized Phase 2 trial: Up to 4-yea

Abstract Introduction This was a multicenter, randomized, registrational phase 2 study to assess efficacy and safety of olverembatinib vs. BAT in pts with CML-CP resistant and/or intolerant to three TKIs (imatinib [I]), dasatinib [D], nilotinib [N]) in China. This report updates an oral presentation at the 2023 American Society of Hematology Annual Meeting (data cutoff date of October 17, 2023), with median (range) follow-up 21.40 (0.6-54.7) months in the olverembatinib and 2.91 (0-48.9) months in the BAT arm. Methods Eligible CP-CML pts were adults resistant or intolerant to three TKIs and in ECOG PS 0-2 with adequate organ function. Pts were randomized 2:1 to olverembatinib (40 mg QOD) or the BAT arm: TKIs (I, D, or N), interferon, hydroxyurea, and/or homoharringtonine by investigator choice. The primary endpoint was event-free survival (EFS), including time from randomization to CML progression; all-cause mortality; relapse; treatment failure; loss of complete hematologic response; and treatment intolerance as per investigator and study sponsor. Efficacy was analyzed in the intention-to-treat (ITT) efficacy population and safety in pts receiving ≥1 dose of olverembatinib. Results As of January 13, 2025, a total of 144 pts (96, olverembatinib; 48, BAT) were enrolled (69.4% male), with a median (range) age of 49.0 (18-77) years. Pts without the T315I mutation included a somewhat lower proportion of males (68/105; 64.8%) and had the same median age. A total of 129/144 pts (89.6%) were previously treated with ≥ 3 TKIs (I, D, N), including all 105 (100.0%) of those without the T315I mutation. Sixty-six (45.8%) of all pts (27/105; 25.7% of those without the T315I mutation) had ≥1 BCR::ABL1 mutation and 39 (27.1%) BCR::ABL1T315I. A total of 96 (66.7%) of all pts discontinued therapies (54 [56.3%] olverembatinib, 42 [91.3%] BAT) due to disease progression/treatment failure, adverse event (AE), consent withdrawal, poor compliance, or death. Median EFS was significantly longer with olverembatinib (vs. BAT) in pts without T315I mutations: 11.96 (95% CI 8.28-22.11) vs. 3.14 (95% CI, 2.53-12.98) (P = 0.0159; HR, 0.550; 95% CI, 0.335-0.901). Median EFS was also significantly longer in the olverembatinib (vs. BAT) group in all pts: 21.22 (95% CI, 10.15-not reached [NR]) months vs. 2.86 (95% CI 2.53-4.73) months (P < .0001; HR, 0.355; 95% CI, 0.230-0.549). In pts without T315I mutations, estimated EFS at 6, 12, and 24 months was 68.5% (95% CI, 55.5%-78.4%), 49.7% (95% CI, 36.7%-61.5%), and 36.9% (95% CI, 24.7%-49.1%), respectively, in the olverembatinib arm and 41.2% (24.8%-56.9%), 35.3% (19.9%-51.0%), and 22.9% (10.5%-38.1%) in the BAT arm. In the olverembatinib arm in all pts, respective data were 73.0% (95% CI, 62.5%-81.0%), 58.7% (95% CI, 47.5%-68.2%), and 47.0% (95% CI, 35.9%-57.2%). In the BAT group, it was 32.6% (95% CI, 19.7%-46.2%), 26.1% (14.5%-39.3%), and 16.9% (7.7%-29.2%), respectively. Median OS was not reached in both treatment groups (P = 0.21 in those without the T315I mutation and P = 0.17 in all patients). In pts without T315I mutations who were treated with olverembatinib, 32 of 39 (82.1%) achieved complete hematologic response (CHR); 16 of 62 (25.8%) complete cytogenetic response (CCyR); and 10 of 62 (16.1%) major molecular response (MMR). Among those without T315I mutations treated with BAT, these data were 8/16 (50.0%) CHR; 6/29 (20.7%) CCyR; and 3/29 (10.3%) MMR. In the ITT efficacy group, 51 of 60 (85.0%) of all evaluable patients treated with olverembatinib achieved CHR; 33/88 (37.5%), CCyR; and 26/88 (29.5%) MMR. In the BAT group, these values were 8/23 (34.8%) for CHR; 7/37 (18.9%), CCyR; and 3/37 (8.1%) MMR. In the safety population, 85/96 (88.5%) of all pts receiving olverembatinib (60/69; 87.0% in the non-T315I mutation group) and 31/46 (67.4%) BAT (27/35; 77.1% non-T315I) experienced grade ≥ 3 AEs. In all pts and those without T315I mutations, frequent any-grade TEAEs in pts treated with olverembatinib included thrombocytopenia, leukopenia, neutropenia, and CPK increased. Serious AEs (SAEs) (>15%) included thrombocytopenia and leukopenia. Conclusions This study represents the largest population of pts with CML-CP resistant to or intolerant of both 1G and 2G TKIs, who have now been monitored for up to 4 years. Olverembatinib was more efficacious and better tolerated than BAT in treating these pts (including those without T315I mutations). Internal study (CT.gov) numbers: HQP1351CC203 (NCT04126681).