Olverembatinib (HQP1351) Overcomes Resistance/Intolerance to Asciminib and Ponatinib in Patients (pts) with Heavily Pretreated Chronic-Phase Chronic Myeloid Leukemia (CP-CML): A 1.5-Year Follow-up Update with Comprehensive Exposure-Response (E-R) Analyses

Introduction New treatment options are needed for pts with CP-CML resistant/intolerant to third-generation (3G) TKI ponatinib and/or asciminib, a specifically targeting the ABL myristoyl pocket (STAMP) inhibitor. Olverembatinib is a well-tolerated TKI with potential to overcome resistance. This update presents efficacy and safety data from a phase 1b study of olverembatinib in pts with heavily pretreated CP-CML. Methods Adults with CP-CML previously treated with ≥2 TKIs and/or a STAMP inhibitor, adequate organ function, and no major molecular response (MMR) were eligible. Pts were randomly allocated to receive olverembatinib at doses of 30, 40, or 50 mg orally every other day (QOD) in 28-day cycles, with stratification based on T315I mutation status. Comprehensive E-R analyses were performed. Results As of July 28, 2024, 67 pts with CP-CML were enrolled; median (range) follow-up was 74.3 (0.1-217.1) weeks; median (range) age, 50 (21-80) years; and 38 (56.7%) were male. At baseline, 19 (28.4%) pts had the T315I mutation; 34 (50.7%) had cardiovascular comorbidities; and BCR::ABL1 IS levels were ≥10% in 49 (73.1%) pts, 1% to 10% in 13 (19.4%), and <1% in 4 (6%); data for 1 pt were missing. The median (range) time from CML diagnosis to first olverembatinib dose was 6.3 (0.4-24.0) years. A total of 21 (31.3%) and 34 (50.7%) pts had received 3 or ≥4 TKIs, respectively. In pts treated with ponatinib (n = 32; 47.8%), 23 (71.9%) were resistant; 8 (25%), intolerant; and 1 (3.1%), uncategorized. In pts treated with asciminib (n = 20; 29.9%), 15 (75%) had resistance; 4 (20%), intolerance; and 1 (5%), uncategorized; 12 pts with CP-CML were resistant to both ponatinib and asciminib. Among 66 dosed subjects, a total of 62 (93.9%) reported TEAEs of any grade, with 44 (66.7%) experiencing ≥G3 TEAEs and 30 (45.5%) serious TEAEs. In addition, 60 (90.9%) pts reported TRAEs of any grade, with 30 (45.5%) experiencing ≥G3 TRAEs and 11 (16.7%) SAEs; 4 (6.1%) pts discontinued olverembatinib due to TRAEs (none fatal). Common TRAEs (≥20%) were elevated CPK (37.9%), thrombocytopenia (24.2%), and increased ALT (22.7%). Common ≥G3 TRAEs (≥10% incidence) included thrombocytopenia (16.7%), neutropenia (13.6%), and elevated CPK (12.1%). Treatment-related SAEs occurring in ≥2 (3%) pts included anemia, febrile neutropenia, and increased troponin (in 2 pts each). There was no report of treatment-related SAEs associated with arterial occlusive events. After a median (range) treatment duration of 59.4 (0.1-190.6) weeks, 30 (45.5%) pts required dose reductions, 42 (63.6%) had dose interruptions, and 22 (33.3%) discontinued treatment. Reasons for discontinuation included intolerance (n = 6), disease progression (n = 3), and other factors (n = 13), such as noncompliance, withdrawal, lack of response, and/or switching to transplantation. Thirty-five of 60 (58.3%) evaluable pts achieved CCyR and 29/64 (45.3%) MMR. The median (range) time to MMR was 91 (29-489) days. At 12 months, the MMR rate was 61.4% (27/44). Comparable response rates were observed regardless of T315I mutation status, with CCyR achieved by 66.7% of pts with the T315I mutation vs 54.8% without it, and MMR achieved by 50.0% vs 43.5%, respectively. MMR rates for pts treated with 2, 3, or ≥4 TKIs were 66.7%, 40.0%, and 40.6%, respectively. Of 28 cytogenetic response-evaluable pts with ponatinib-failed CP-CML, 15 (53.6%) achieved CCyR, including 12/23 (52.2%) with prior ponatinib resistance and 3/4 (75.0%) with intolerance. A total of 12/30 (40.0%) evaluable pts previously treated with ponatinib achieved MMR, including those with prior resistance (11/23 [47.8%]) or intolerance (1/6 [16.7%]). In evaluable pts with asciminib treatment failure, 37.5% (6/16) achieved CCyR and 30% (6/20) MMR, including those with prior resistance (4/13 [30.8%] in CCyR, 4/15 [26.7%] in MMR) or intolerance (1/2 [50.0%] in CCyR, 1/4 [25.0%] in MMR). CCyR and MMR rates in pts previously treated with both ponatinib and asciminib were 30% and 25%, respectively. The comprehensive E-R analyses show a positive exposure-efficacy correlation with no significant exposure-safety relationship for Grade 3+ TRAEs or TEAEs, serious TEAE, serious TRAEs, and neutropenia. Conclusions Olverembatinib was well tolerated and showed strong and durable antileukemic activity in pts with heavily pretreated CP-CML. The registrational study (POLARIS-2, NCT06423911) is recruiting.

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