Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP) with T315I Mutation

Abstract

Background BCR-ABL1 T315I, "gatekeeper," mutation can confer a high degree of resistance to many first- and second-generation TKIs. Olverembatinib is a novel, orally active, third-generation BCR-ABL1 TKI with promising efficacy and a preliminary favorable safety profile for the treatment of patients with CML. These phase 2 trials, HQP1351-CC-201 (NCT03883087) and HQP1351-CC-202 (NCT03883100), were conducted based on favorable phase 1 trial results. Methods These open-label, single-arm, multicenter pivotal trials evaluated the efficacy and safety of olverembatinib in Chinese pts with CML-CP (HQP1351-CC-201) or CML-AP (HQP1351-CC-202) with the T315I mutation. Olverembatinib was administered at 40 mg orally on alternate days (QOD) for 28-day cycles. Primary endpoints were major cytogenetic response (MCyR) in pts with CML-CP and major hematologic response (MaHR) in those with CML-AP by the end of Cycle 12. Secondary study endpoints included complete CyR (CCyR), complete hematologic response (CHR), major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety, including treatment-related adverse events (TRAEs) and serious AEs (SAEs). ResultsHQP1351-CC-201 As of the cutoff date of April 30,2022, 41 pts were enrolled, of whom 21 (51.2%) were male, with a median (range) age of 47 (22-70) years. The median (range) interval from CML diagnosis to first olverembatinib dose was 5.31 (0.6-23.2) years, and 32 (78.1%) pts had received ≥ 2 prior TKIs. The median (range) treatment duration was 32.7 (3.1-36.7) months. All pts, 31/31 (100%), achieved CHR (10 others had CHR at baseline), 34/41 (82.9%) MCyR, 29/41 (70.7%) CCyR, and 24/41 (58.5%) MMR (Figure 1). Median time to CHR was 1 (95% CI: 1.0-1.9) month, median time to MCyR was 2.8 (95% CI: 2.8-5.6) months, and median time to MMR was 6.5 (95% CI: 2.8 to not reached [NR]) months. At 36 months, the PFS rate was 86.3% (95% CI: 70.2%-94.1%) and the OS rate was 95.1% (95% CI: 81.9%-98.8%) (Figure 2). A total of 5 pts withdrew because of progressive disease (PD), 4 intolerance, 3 consent withdrawal, and 2 for other reasons. Frequent TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (70.7%; 48.8%; 7.3%), anemia (70.7%; 31.7%; 2.4%), leukopenia (51.2%; 14.6%; 0), and neutropenia (41.4%; 21.9%; 0). Common nonhematologic TRAEs (all grades; grade 3-4) included skin pigmentation (56.1%; 0%) and elevations in creatine kinase (56.1%; 19.5%), ALT (43.9%; 2.4%) and AST (36.6%; 0) levels (Table 1). HQP1351-CC-202 As of the cutoff date of April 30,2022, 23 pts were enrolled, of whom 18 (78.3%) were male, with a median (range) age of 41 (21-74) years. The median (range) interval from CML diagnosis to first olverembatinib dose was 4.96 (0.4-10.2) years, and 19 (82.6%) pts had received ≥ 2 prior TKIs. The median (range) treatment duration was 19.7 (1.4-36.4) months. A total of 18 (78.3%) patients experienced MaHR (73.9% CHR and 4.4% no evidence of leukemia [NEL]); 12 (52.2%) MCyR; 12 (52.2%) CCyR; and 11 (47.8%) MMR (Figure 1). Median time to MaHR was 2.8 (95% CI: 1.0-4.7) months, median time to MCyR was 5.6 (95% CI: 2.00-NR) months, and median time to MMR was 13.1 (95% CI: 5.6-22.4) months. At 36 months, the PFS rate was 57.1% (95% CI: 33.3%-75.1%) and the OS rate was 69.6% (95% CI: 46.6%-84.2%) (Figure 3). Six pts withdrew because of progressive disease (PD), 4 intolerance, and 1 for other reasons; two pts died. Common TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (78.3%; 56.5%; 17.4%), anemia (69.6%; 34.8%; 13.0%), leukopenia (56.5%; 30.4%; 0), and neutropenia (26.1%; 26.1%; 0). Common nonhematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (56.5%), hypertriglyceridemia (60.9%), hyperphosphatemia (47.8%), hyperuricemia (26.1%), and arthralgia (34.8%), of which most were grade 1-2 (Table 2). Conclusions Olverembatinib was efficacious and well tolerated in pts with TKI-resistant CML-CP and CML-AP with the BCR-ABL1T315I mutation. Based on the results of these pivotal trials, the Chinese health authority granted conditional approval for olverembatinib on November 24, 2021. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Topics & Concepts