Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial

Abstract

Background: BCR-ABL1T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP).

Methods: In the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses.

Results: A total of 165 patients (> 80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0, and MR4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia.

Conclusions: Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation.

Trial registration: The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).

Trial registration: ClinicalTrials.gov NCT03883087 NCT03883100 NCT04126681 NCT04260022.

Keywords: Accelerated phase; Chronic myeloid leukemia; Chronic phase; T315I mutation; Tyrosine kinase inhibitor.

Conflict of interest statement

ZC, QN, SZ, LM, ML, HW, CY, DY, and YZ: Employees of, and shareholders in, Ascentage Pharma. DY and YZ: Hold positions of leadership within Ascentage. All other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Prevalence of treatment-related adverse events over time

Fig. 2

Cumulative incidence of responses in the chronic phase (A) and accelerated phase (B) MCyR, major cytogenetic response; CCyR, complete cytogenetic response; MMR, major molecular response; MR4.0, molecular response 4; MR4.5, molecular response 4.5.

Fig. 3

Progression-free survival (PFS) and overall survival (OS) in the chronic phase (A) or accelerated phase (B)

Fig. 4

Responses by baseline BCR-ABL1 mutation status in the chronic phase (A) or accelerated phase (B) using Sanger sequencing. CCyR, complete cytogenetic response; MCyR, major cytogenetic response; MMR, major molecular response; MR4.0, molecular response 4; MR4.5, molecular response 4.5

Fig. 5

Responses by baseline BCR-ABL1 mutation status in the chronic phase (A) or accelerated phase (B) using next-generation sequencing. CCyR, complete cytogenetic response; MCyR, major cytogenetic response; MMR, major molecular response; MR4.0, molecular response 4; MR4.5, molecular response 4.5

Fig. 6

Pharmacokinetics, mean plasma concentration–time curves on treatment Days 1 (A) and 27 (B)

Fig. 7

Pharmacodynamics by dose cohorts on Cycle 1 (A) and on Day 1 of Cycle 1 (B)