Introduction

Olverembatinib, a third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), has demonstrated remarkable efficacy and a favorable safety profile in pts with CML resistant and/or intolerant to at least two TKIs or with T315I mutation. The aim of this study was to assess the efficacy and safety of olverembatinib as a second-line treatment for pts with CP-CML without T315I mutation.

Methods

This single-arm, multicenter, open-label study (ChiCTR2200061655) enrolled adult pts with CP-CML resistant/intolerant to first-line TKIs without T315I mutation in China. Eligibility criteria included Eastern Cooperative Oncology Group performance status 0 to 2 and adequate liver and renal function. Olverembatinib 40 mg was administered orally every other day (QOD) in 28-day cycles. The cytogenetic response, molecular response, and safety profile were evaluated every three cycles. The primary endpoint was the complete cytogenetic response (CCyR) rate.

Results

From August 4, 2022, through July 24, 2025, 47 pts were enrolled (91.5% first-line TKI resistant, 8.5% first-line TKI intolerant). The median age was 42.0 (19-70) years (66.0% male). The median (range) interval from diagnosis to initial olverembatinib treatment was 1.03 (0.3-21.1) years. Twelve (25.5%) pts had received imatinib as first-line, and 35 (74.5%) had been treated with a second-generation TKI, including dasatinib (n = 7, 14.9%), nilotinib (n = 13, 27.7%), or flumatinib (n = 15, 31.9%), as first-line. A total of 36/47 (76.6%) pts had no mutations at baseline, while 11 (23.4%) had non-T315I BCR::ABL1 kinase domain mutations. As of the data cutoff date, 33/47 (70.2%) pts continued treatment. Fourteen (29.8%) discontinued because of: adverse events (n = 3; 6.4%, persistently low platelet counts in response to olverembatinib), treatment failure (n = 4; 8.5%), disease progression (n = 2; 4.3%), and other reasons (n = 5; 10.6%, loss to follow-up during the first treatment cycle).

Efficacy

At the cutoff date, 39 (83.0%) pts had at least one, 36 (76.6%) at least two, and 34 (72.3%) at least three efficacy assessments. Two pts had not yet undergone a first efficacy assessment. Up to the cutoff date, 71.8% (28/39) of pts achieved CCyR and 43.6% (17/39) major molecular response (MMR). The CCyR and MMR rates evaluated at the end of cycles 6, 9, 12, 15, 18 ,21, and 24 were 54.3% and 25.7%, 66.7% and 33.3%, 74.2% and 35.5%, 84.6% and 46.2%, 85.7% and 47.6%, 90.0% and 60.0%, and 89.5% and 57.9%, respectively, suggesting that responses deepened with time. Complete hematologic response was achieved in 83.3% (15/18) of pts and major cytogenetic response in 76.9% (30/39). CCyR and MMR responses to olverembatinib tended to improve over time. In 39 efficacy-evaluable pts, 30 were pretreated with second-generation TKIs as first-line treatment, of whom 23/30 (76.7%) achieved CCyR and 13/30 (43.3%) MMR. Five of nine (55.6%) pts pretreated with imatinib achieved CCyR and four of nine (44.4%) achieved MMR.

Safety

A total of 47 safety-evaluable pts received at least one dose of olverembatinib. The median (range) treatment duration was 16.0 (1-18) cycles. A total of 42 (89.4%) pts experienced any-grade treatment-related adverse events (TRAEs), of whom 21 (44.7%) had grade ≥ 3 TRAEs and 6 (12.8%) had olverembatinib-related serious AEs (SAEs). Nonhematologic TRAEs included skin hyperpigmentation (51.1%), hyperuricemia (31.9%), and creatine phosphokinase increased (27.7%). Most of these TRAEs were grade 1 or 2. Grade ≥ 3 hematologic toxicities included platelet count decreased (42.6%), neutropenia (25.5%), and anemia (8.5%). Most hematologic TRAEs were manageable with supportive care. There were only two cardiovascular events possibly related to olverembatinib, all of which were grade 1 hypertension. Olverembatinib-related SAEs included platelet count decreased (6.4%) and anemia, myelosuppression, and pyrexia (2.1% each). No deaths were reported.

Conclusions

Olverembatinib may provide a viable second-line treatment option for pts with CP-CML, especially those with disease failing first-line second-generation TKIs.

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2025
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