Novel BCR-ABL1 Tyrosine Kinase Inhibitor (TKI) HQP1351 (Olverembatinib) Is Efficacious and Well Tolerated in Patients with T315I-Mutated Chronic Myeloid Leukemia (CML): Results of Pivotal (Phase II) Trials

Abstract

INTRODUCTION HQP1351 (olverembatinib) is an orally active third-generation BCR-ABL TKI designed for treatment of the patients with CML, harboring T315I mutation, which confers resistance against all first- and second-generation TKIs. METHODS The TKI resistant CML patients harboring T315I mutations either in chronic-phase (CP), or in accelerated-phase (AP), were enrolled into two single-arm, multicenter, open-label pivotal studies: HQP1351-CC201 in and HQP1351-CC202, respectively. The HQP1351 was administered at 40 mg once every other day (QOD) for 28 consecutive days per cycle over 24 months. The primary objective was to evaluate efficacy by major cytogenetic response (MCyR) in patients with CML-CP and major hematologic response (MaHR) in CML-AP. Secondary objectives included safety, tolerability, and pharmacokinetics (PK). RESULTS Baseline characteristics Study CC201 (CML-CP) As of the study cut-off date of March 23, 2020, total 41 patients were enrolled, of whom 38 (92.7%) completed ≥ 6 cycles and 21 (51.2%) were male. Median (range) follow-up was 7.9 (3.1-11.1) months, median age was 47 (22-70) years old. Median (range) interval from CML diagnosis to first HQP1351 treatment was 5.31 (0.6-23.2) years, and 32 (78.1%) patients received ≥ 2 prior lines of TKI. Three patients withdrew from the study-due to progressive disease (PD), intolerance, or consent withdrawal. Study CC202 (CML-AP) As of the cut-off date of February 11, 2020, total 23 patients were enrolled, of whom 18 (78.3%) completed ≥ 6 cycles and 18 (78.3%) were male. Follow-up duration was 8.2 (1.4-9.6) months, median age was 41 (21-74) years old. Median interval from CML diagnosis to first dose of HQP1351 was 4.96 (0.4-10.2) years, and 18 (78.3%) patients received ≥ 2 prior TKIs. Five patients withdrew because of PD or intolerance before Cycle 6. Efficacy Study CC201 (CML-CP) Across a median follow-up of 7.9 months, the mean (95% CI) 3-month progression-free survival (PFS) was 100% (100-100%) and 6-month PFS 96.7% (78.6-99.5%) because of 1 PD. In 31 evaluable patients who did not have a complete hematologic response (CHR) at baseline, 30 (96.8%) achieved CHR. In 41 evaluable patients who did not have a complete CyR (CCyR) at baseline, 31 (75.6%) achieved MCyR, including 27 (65.9%) CCyR and 4 (9.8%) partial CyR (PCyR). Total 20 out of 41 (48.8%) evaluable patients achieved major molecular response (MMR; Figure 1). Study CC202 (CML-AP) Across a median follow-up of 8.2 months, the 3-month PFS was 100% (100-100%) and the 6- month PFS 95.5% (71.9-99.3%) because of 2 PDs. A total of 18 (78.3%) of 23 evaluable patients without MaHR at baseline achieved MaHR, including 14 (60.9%) with CHR. In the 23 evaluable patients without MCyR at baseline, 12 (52.2%) patients achieved MCyR, including 9 (39.1%) CCyR and 3 (13.1%) PCyR. A total of 6 out of 23 (26.1%) evaluable patients achieved MMR (Figure 1). HQP1351 was highly and durably efficacious in the CML patients with T315I mutation; the probability and depth of clinical response may increase with prolonged treatment period. Safety/tolerability Study CC201 Frequent treatment-related adverse events (TRAEs; all grades; G3-4) included thrombocytopenia (65.9%; 48.8%), followed by anemia (48.8%; 24.4%), leukopenia (46.3%; 12.2%), and neutropenia (36.6%; 19.5%). Common non-hematologic TRAEs of any grade included skin pigmentation (53.7%) as well as elevations in creatine kinase (48.8%), ALT (31.7%) and AST (26.8% which most were grade 1 - 2. No death occurred. Study CC202 Common TRAEs (all grades; G3-4; serious AE [SAE]) included thrombocytopenia (73.9%; 52.2%; 17.4%), anemia (65.2%; 39.1%; 13.0%), leukopenia (56.5%; 30.4%; 0%), and neutropenia (26.1%; 21.7%; 0%;). Common non-hematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (52.2%), hypertriglyceridemia (47.8%), hyperphosphatemia (43.5%), arthralgia (34.8%), and fatigue (26.1%), of which most were grade 1- 2. CONCLUSIONS HQP1351 has been shown highly efficacious in heavily TKI-pretreated patients with T315I-mutated CML-CP or CML-AP and was well tolerated. Registration: Clinicaltrials.gov identifier NCT03883087 (Study HQP1351-CC201) NCT03883100 (Study HQP1351-CC202). Disclosures Chen: Ascentage Pharma Group: Current Employment. Niu:Ascentage Pharma Group: Current Employment. Zeng:Ascentage Pharma Group: Current Employment. Men:Ascentage Pharma Group: Current Employment. Lu:Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group: Current Employment. JI:Ascentage Pharma Group: Current Employment. Yue:Ascentage Pharma Group: Current Employment. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

Therapy for patients with chronic phase-chronic myeloid leukemia previously treated with ⩾2 tyrosine kinase inhibitors: a systematic literature review

“…The CCyR rate ranged from 16.1% with omacetaxine to 64.8% with ponatinib at 6 months, and the corresponding values at 12 months were 16.2% to as high as 83.9% with bosutinib. 28–31 Among the included interventions, the CCyR rates ranged from 38.7% at 6 months to 66% at 10.2 months for asciminib, 20,32 16.2% at 12 months to 83.9% at 12 months for bosutinib, 30,31 6% at 15 months to 69.6% at 40.8 months for ponatinib, 33,34 4% at 19.1 months to 16.1% at 6 months for omacetaxine, 28,35 36.8% at 12.8 months to 65.9 at 7.9 months for olverembatinib, 36,37 24% at 12 months to 31% at 16 months for nilotinib, 19,38 and 11% at 16 months to 46.2% at 12 months for dasatinib. 19,39 The median time to CCyR was reported as 4.8 months in a study of ponatinib-treated patients.…”

“…The MMR rate ranged from 10.5% with omacetaxine to as high as 66.7% with ponatinib at 6 months of follow-up and was 14–35% with ponatinib at 12 months of follow-up. 26,27,29,35,42 Among the included interventions, the MMR rates ranged from 23.3% at 6 months to 41% at 10.2 months for asciminib, 20,32 13.2% at 6 months to 76.4% at 24 months for bosutinib, 25,30 14% at 6 months to 66.7% at 6 months for ponatinib, 27,29 10.5–19.2% at 6 months for omacetaxine, 28,35 14.7% at 12.8 months to 48.8% at 7.9 months for olverembatinib, 36,37,55 13% at 16 months to 33.3% at 12 months for nilotinib, 19,22 and 20.8% at 12 months to 33.3% at 16 months for dasatinib. 19,39…”

Chronic myeloid leukemia stem cells: targeting therapeutic implications

“…However, some BCR-ABL1 or compound mutations (for example, T315M, T315V, and Y253H/T315I or E255V/T315I) can create ponatinib resistance [ 168 ]. Olverembatinib (HQP1351), a novel orally administered 3G-TKI, was found to be highly effective in CML patients who were resistant to existing TKI treatments, including some with T315I mutations in a phase II trial [ 169 ]. Vodobatinib (K0706) is another new orally bioavailable 3G-TKI with promising in vitro action against majority of BCR-ABL mutations, but not T315I.…”

B-Lymphoid Blast Phase–Chronic Myeloid Leukemia: Current Therapeutics

“…Additionally, preclinical studies have shown that there is synergistic activity when combining Asciminib and ponatinib [ 44 ] Olverembatinib is a third-generation BCR-ABL TKI which is highly effective in CML patients with T315I mutation. In a phase II study (CC 202) of 23 patients with CML-AP, Olverembatinib achieved a CHR of 60.9% and CCyR of 39.1% [ 45 ]. PF114 is an oral TKI similar to ponatinib and was studied in a phase I/II study of 51 patients with CP/AP CML resistant to two or more TKIs.…”

“…Olverembatinib is a third-generation BCR-ABL TKI which is highly effective in CML patients with T315I mutation. In a phase II study (CC 202) of 23 patients with CML-AP, Olverembatinib achieved a CHR of 60.9% and CCyR of 39.1% [ 45 ].…”