Olverembatinib As Second-Line (2L) Therapy in Patients (pts) with Chronic Phase-Chronic Myeloid Leukemia (CP-CML)

Introduction Olverembatinib (HQP1351), a third-generation BCR-ABL1 TKI, has demonstrated remarkable efficacy and a favorable safety profile in CML pts resistant and/or intolerant to at least 2 TKIs or with the T315I mutation. The aim of this study was to assess the efficacy and safety of olverembatinib as a 2L treatment for pts with CP-CML without the T315I mutation. Methods This single-arm, multicenter, open-label study (ChiCTR2200061655) planned to enroll adult CP-CML pts who were resistant/intolerant to prior 1L TKIs without the T315I mutation in China. Eligibility criteria included ECOG PS, 0-2; adequate liver and renal function; and life expectancy of ≥ 3 months. Olverembatinib 40 mg was administered orally every other day in 28-day cycles. The cytogenetic response and molecular response and safety profile were evaluated every 3 cycles. The primary endpoint was the complete cytogenetic response (CCyR) rate. Results From August 4, 2022, through July 29, 2024, 42 CP-CML pts were enrolled: 92.9% were 1L TKI-resistant and 7.1% 1L TKI-intolerant. The median (range) age was 45.5 (19-70) years, and 69.0% of pts were male. The median (range) interval from diagnosis to initial olverembatinib treatment was 1.15 (0.3-2.11) years. Twelve (28.6%) pts had received 1L imatinib, and 30 (71.4%) had been treated with a 1L 2G TKI, including dasatinib (n = 5, 11.9%), nilotinib (n = 11, 26.2%), or flumatinib (n = 14, 33.3%). Mutational analyses revealed no mutation in 31/42 (73.8%) pts, while 11 (26.2%) pts had BCR::ABL1 kinase domain mutations (other than T315I) at baseline. As of the data cutoff date, 33/42 (78.6%) pts have continued treatment. Nine (21.4%) pts discontinued because of: loss to follow-up during the first treatment cycle (n = 5), as well as treatment failure and intolerance due to persistently low platelet counts in response to olverembatinib (n = 2 each). Efficacy At the cutoff date (July 29, 2024), 33 (78.6%) pts had at least 1, 28 (66.7%) at least 2, and 23 (54.8%) at least 3 efficacy assessments. Three pts had not yet undergone a first efficacy assessment. Up to the cutoff date, 75.0% (24/32) of pts achieved CCyR and 40.6% (13/32) major molecular response (MMR). The CCyR and MMR rates evaluated at the end of Cycles 6, 9, 12, and 18 were 53.4% and 28.6%, 64.8% and 32.5%, 69.1% and 32.5%, and 77.7% and 43.9%, respectively, suggesting that efficacy improved over time. In 32 efficacy-evaluable pts, 23 pts were pretreated with 2G TKIs as 1L treatment, of whom 19 (82.68%) achieved CCyR and 10 (43.5%) achieved MMR. In 9 pts pretreated with imatinib, 5 pts achieved CCyR (55.6%) and 3 MMR (33.3%). Safety The safety-evaluable population included 42 pts taking at least 1 dose of olverembatinib. The median (range) treatment duration was 16.0 (1-18) months. A total of 37 (88.1%) pts experienced any-grade treatment-related adverse events (TRAEs), of whom 19 (45.2%) had grade ≥ 3 TRAEs and 5 (11.9%) had olverembatinib-related serious AEs (SAEs). Nonhematologic TRAEs included skin hyperpigmentation (38.1%), hyperuricemia (23.8%), and creatine phosphokinase increased (21.4%). Most of these TRAEs were grade 1 or 2. Grade ≥ 3 hematologic toxicities included platelet count decreased (38.1%), neutropenia (21.4%), and anemia (7.1%). Most hematologic TRAEs were manageable with supportive care. Possibly olverembatinib-related any-grade cardiovascular events included hypertension (4.8%) and atrial tachycardia (2.4%), all of which were grade 1 or 2. Olverembatinib-related SAEs included platelet count decreased (7.1%), anemia, myelosuppression, and pyrexia (2.4% each). No deaths were reported. Conclusions This is the first study report of olverembatinib in 2L CP-CML treatment. Olverembatinib may provide an effective and safe 2L treatment option for pts with CP-CML, especially those failing on 1L 2G TKIs.