Patient characteristics
Between October 26, 2016, and October 8, 2019, 165 patients were enrolled: 127 with CML-CP and 38 with CML-AP. A total of 110 (66.7%) patients were men. The median age was 42 (range, 20–74) years (Table 1) and median interval from CML diagnosis to first olverembatinib dose 5.7 (range, 0.3–23.2) years. A total of 90 (54.5%) patients had received 2 prior TKIs and 45 (27.3%) at least 3.
Table 1
|
Total
|
Chronic phase CML
|
Accelerated phase CML
|
Patient number
|
165
|
127
|
38
|
Age (y), median (range)
|
42 (20–74)
|
43 (20–70)
|
38.5 (21–74)
|
Male, n (%)
|
110 (66.7)
|
79 (62.2)
|
31 (81.6)
|
ECOG performance status, n (%)
|
0
|
99 (60.0)
|
82 (64.6)
|
17 (44.7)
|
1
|
64 (38.8)
|
43 (33.9)
|
21 (55.3)
|
Not done
|
2 (1.2)
|
2 (1.6)
|
0
|
Time from diagnosis to olverembatinib treatment (y), median (range)
|
5.7 (0.3–23.2)
|
5.3 (0.6–23.2)
|
6.9 (0.3–14.7)
|
Prior TKIs, n (%)
|
Imatinib
|
22 (13.3)
|
16 (12.6)
|
6 (15.8)
|
Imatinib/dasatinib
|
60 (36.4)
|
47 (37.0)
|
13 (34.2)
|
Imatinib/nilotinib
|
26 (15.8)
|
22 (17.3)
|
4 (10.5)
|
Imatinib/dasatinib/nilotinib
|
45 (27.3)
|
35 (27.6)
|
10 (26.3)
|
Nilotinib
|
6 (3.6)
|
4 (3.1)
|
2 (5.3)
|
Dasatinib
|
2 (1.2)
|
1 (0.8)
|
1 (2.6)
|
Dasatinib/nilotinib
|
4 (2.4)
|
2 (1.6)
|
2 (5.3)
|
Number of lines of prior TKI therapy, n (%)
|
1
|
30 (18.2)
|
21 (16.5)
|
9 (23.7)
|
2
|
90 (54.5)
|
71 (55.9)
|
19 (50.0)
|
≥ 3
|
45 (27.3)
|
35 (27.6)
|
10 (26.3)
|
BCR-ABL1 mutation status by Sanger sequencing, n (%)
|
No mutation
|
24 (14.5)
|
23 (18.1)
|
1 (2.6)
|
T315I single mutation
|
102 (61.8)
|
77 (60.6)
|
25 (65.8)
|
T315I + additional mutations
|
25 (15.2)
|
16 (12.6)
|
9 (23.7)
|
Other mutations
|
14 (8.5)
|
11 (8.7)
|
3 (7.9)
|
BCR-ABL1 mutation status by next-generation sequencing, n (%)
|
No mutation
|
20 (16.9)
|
19 (20.2)
|
1 (4.2)
|
T315I single mutation
|
53 (44.9)
|
41 (43.6)
|
12 (50.0)
|
T315I + additional mutations
|
19 (16.1)
|
15 (16.0)
|
4 (16.7)
|
Other mutations
|
14 (11.9)
|
12 (12.8)
|
2 (8.3)
|
Compound mutations
|
12 (10.2)
|
7 (7.4)
|
5 (20.8)
|
ACA, n (%)
|
Yes
|
28 (17.0)
|
10 (7.9)
|
18 (47.4)
|
No
|
137 (83.0)
|
117 (92.1)
|
20 (52.6)
|
ACA, additional chromosomal abnormalities; CML, chronic myeloid leukemia; ECOG, Eastern Cooperative Oncology Group; TKI, tyrosine kinase inhibitor.
|
Sanger sequencing identified 102 (61.8%) patients with a single T315I mutation, 25 (15.2%) with T315I and additional mutations, 14 (8.5%) with other mutations, and 24 (14.5%) with no BCR-ABL1 mutation. Corresponding data in 118 patients, (94 CML-CP and 24 CML-AP) receiving NGS were 53 (44.9%; single T315I mutation), 19 (16.1%; T315I and additional noncompound mutations), 14 (11.9%; other noncompound mutations), 12 (10.2%; compound mutations), and 20 (16.9%; no BCR-ABL1 mutation).
Dose escalation and expansion cohorts
Across 11 dose cohorts (1–60 mg QOD) in 28-day cycles, no DLT was observed at doses below 60 mg. Two of three patients in the 60 mg cohort experienced DLTs, including 1 G4 thrombocytopenia and 1 myocardial injury, which resulted in dose interruption. Among 33 patients in dose escalation, the MTD was 50 mg. Based on preliminary safety and efficacy results, we expanded the 30, 40, and 50 mg QOD dose cohorts. In total, 101 patients were enrolled in the phase 1 trial. The RP2D was established as 40 mg QOD.
Patient disposition
By September 30, 2021, the median follow-up was 34.3 (range, 4.8–58.6) months. A total of 114 (69.0%) patients remained on treatment at doses of 20 (n = 11), 30 (n = 44), 40 (n = 48), or 50 mg (n = 11) QOD (Table 2). Treatment interruptions due to AEs occurred in 86 (52.1%) patients, including 58 (45.7%) with CML-CP and 28 (73.7%) with CML-AP. Median number and duration of treatment interruptions were 2 (range, 1–11) and 56 (range, 1-421) days.
Table 2
|
Total
|
Chronic phase CML
|
Accelerated phase CML
|
Patient number
|
165
|
127
|
38
|
Treatment duration (mo.), median (range)
|
30.7 (1.2–58.6)
|
34.5 (1.2–57.5)
|
25.5 (1.4–58.6)
|
Ongoing, n (%)
|
114 (69.1)
|
96 (75.6)
|
18 (47.4)
|
Olverembatinib 20 mg
|
11 (9.6)
|
8 (8.3)
|
3 (16.7)
|
Olverembatinib 30 mg
|
44 (38.6)
|
38 (39.6)
|
6 (33.3)
|
Olverembatinib 40 mg
|
48 (42.1)
|
41 (42.7)
|
7 (38.9)
|
Olverembatinib 50 mg
|
11 (9.6)
|
9 (9.4)
|
2 (11.1)
|
Discontinuation, n (%)
|
51 (30.9)
|
31 (24.4)
|
20 (52.6)
|
Disease progression
|
15 (9.1)
|
5 (3.9)
|
10 (26.3)
|
Adverse events
|
13 (7.9)
|
9 (7.1)
|
4 (10.5)
|
Treatment failure
|
12 (7.2)
|
8 (6.3)
|
4 (10.5)
|
Withdrawal by subject
|
8 (4.8)
|
8 (6.3)
|
0
|
Death
|
3 (1.8)
|
1 (0.8)
|
2 (5.3)
|
CML, chronic myeloid leukemia.
|
Doses were reduced because of AEs in 50 (30.3%) patients, including 36 (28.3%) with CML-CP and 14 (36.8%) with CML-AP. The most common AE leading to dose reduction was severe thrombocytopenia (n = 26; 15.8%) (Supplementary Table 1). Fifty-one patients permanently discontinued treatment because of either CML progression (n = 15; 9.1%), AEs (n = 13; 7.9%), treatment failure (n = 12; 7.0%), consent withdrawal (n = 8; 4.8%), or death (n = 3; 1.8%) (Table 2).
Safety
The median treatment duration was 30.7 (range, 1.2–58.6) months. All 165 patients experienced at least 1 treatment-related AE (TRAE), of which 131 (79.4%) were G3/4 (Table 3). The most frequent nonhematologic TRAE was skin hyperpigmentation in 139 (84.2%) patients with pathologically confirmed lentiginous nevus in 2 patients, followed by hypertriglyceridemia (57.6%), proteinuria (50.9%), hyperbilirubinemia (41.8%), hypocalcemia (38.8%), and elevated liver transaminases (35.8%). Median time to onset of these TRAEs was 70 (range, 1–1,315) days.
Table 3
Treatment-related adverse events (≥ 10%, all grade
|
Total
|
Chronic phase
CML
|
Accelerated phase
CML
|
Patient number
|
165
|
127
|
38
|
Event, n (%)
|
Any grades
|
G 3/4
|
Any grades
|
G 3/4
|
Any grades
|
G 3/4
|
Treatment-related adverse events
|
165 (100.0)
|
131 (79.4)
|
127 (100.0)
|
97 (76.4)
|
38 (100.0)
|
34 (89.5)
|
Nonhematologic
|
165 (100.0)
|
81 (49.1)
|
127 (100.0)
|
61 (48.0)
|
38 (100.0)
|
20 (52.6)
|
Skin pigmentation
|
139 (84.2)
|
0
|
108 (85.0)
|
0
|
31 (81.6)
|
0
|
Hypertriglyceridemia
|
95 (57.6)
|
12 (7.3)
|
72 (56.7)
|
11 (8.7)
|
23 (60.5)
|
1 (2.6)
|
Proteinuria
|
84 (50.9)
|
6 (3.6)
|
65 (51.2)
|
5 (3.9)
|
19 (50.0)
|
1 (2.6)
|
Hyperbilirubinemia
|
69 (41.8)
|
4 (2.4)
|
56 (44.1)
|
3 (2.4)
|
13 (34.2)
|
1 (2.6)
|
Hypocalcemia
|
64 (38.8)
|
0
|
45 (35.4)
|
0
|
19 (50.0)
|
0
|
Increased alanine aminotransferase
|
59 (35.8)
|
4 (2.4)
|
50 (39.4)
|
3 (2.4)
|
9 (23.7)
|
1 (2.6)
|
Increased aspartate aminotransferase
|
59 (35.8)
|
4 (2.4)
|
49 (38.6)
|
2 (1.6)
|
10 (26.3)
|
2 (5.3)
|
Increased creatine phosphokinase
|
48 (29.1)
|
11 (6.7)
|
43 (33.9)
|
10 (7.9)
|
5 (13.2)
|
1 (2.6)
|
Increased γ-glutamyl transferase
|
47 (28.5)
|
5 (3.0)
|
38 (29.9)
|
5 (3.9)
|
9 (23.7)
|
0
|
Hyperglycemia
|
43 (26.1)
|
1 (0.6)
|
33 (26.0)
|
1 (0.8)
|
10 (26.3)
|
0
|
Hypokalemia
|
42 (25.5)
|
2 (1.2)
|
32 (25.2)
|
1 (0.8)
|
10 (26.3)
|
1 (2.6)
|
Hyponatremia
|
38 (23.0)
|
1 (0.6)
|
28 (22.0)
|
1 (0.8)
|
10 (26.3)
|
0
|
Myalgia
|
31 (18.8)
|
0
|
23 (18.1)
|
0
|
8 (21.1)
|
0
|
Pyrexia
|
30 (18.2)
|
9 (5.5)
|
21 (16.5)
|
5 (3.9)
|
9 (23.7)
|
4 (10.5)
|
Sinus tachycardia
|
30 (18.2)
|
0
|
23 (18.1)
|
0
|
7 (18.4)
|
0
|
Rash
|
27 (16.4)
|
1 (0.6)
|
19 (15.0)
|
1 (0.8)
|
8 (21.1)
|
0
|
Hypoalbuminemia
|
26 (15.8)
|
0
|
20 (15.7)
|
0
|
6 (15.8)
|
0
|
Hyperphosphatemia
|
22 (13.3)
|
0
|
11 (8.7)
|
0
|
11 (28.9)
|
0
|
Hypertension
|
22 (13.3)
|
9 (5.5)
|
19 (15.0)
|
7 (5.5)
|
3 (7.9)
|
2 (5.3)
|
Increased lipase
|
22 (13.3)
|
5 (3.0)
|
16 (12.6)
|
5 (3.9)
|
6 (15.8)
|
0
|
Increased alkaline phosphatase
|
21 (12.7)
|
1 (0.6)
|
16 (12.6)
|
1 (0.8)
|
5 (13.2)
|
0
|
Pain in extremity
|
21 (12.7)
|
2 (1.2)
|
14 (11.0)
|
1 (0.8)
|
7 (18.4)
|
1 (2.6)
|
Arthralgia
|
19 (11.5)
|
1 (0.6)
|
11 (8.7)
|
0
|
8 (21.1)
|
1 (2.6)
|
Asthenia
|
18 (10.9)
|
0
|
12 (9.4)
|
0
|
6 (15.8)
|
0
|
Hematologic
|
138 (83.6)
|
93 (56.4)
|
102 (80.3)
|
67 (52.8)
|
36 (94.7)
|
26 (68.4)
|
Thrombocytopenia
|
126 (76.4)
|
85 (51.5)
|
93 (73.2)
|
62 (48.8)
|
33 (86.8)
|
23 (60.5)
|
Anemia
|
90 (54.5)
|
38 (23.0)
|
66 (52.0)
|
26 (20.5)
|
24 (63.2)
|
12 (31.6)
|
Leukopenia
|
56 (33.9)
|
34 (20.6)
|
37 (29.1)
|
21 (16.5)
|
19 (50.0)
|
13 (34.2)
|
Neutropenia
|
26 (15.8)
|
19 (11.5)
|
18 (14.2)
|
11 (8.7)
|
8 (21.1)
|
8 (21.1)
|
Cardiovascular events (CVEs) possibly related to olverembatinib were observed in 53 (32.1%) patients at a median of 11 (range, 0.03-53) months on treatment, including hypertension (13.3%), pericardial effusion (8.5%), ventricular extrasystoles (4.2%), supraventricular extrasystoles or atrial fibrillation (3.0% each), retinal-vein occlusion (1.8%) or palpitations (1.2%); as well as angina pectoris, arrhythmia, atrial tachycardia, cardiomegaly, cerebral ischemia, and/or cerebral infarction in < 1%; of which 11.5% were G3/4 (Supplementary Table 2).
The median age of patients with CVEs was 43 (range, 20–74) years, including two patients with a history of hypertension and three with prior diabetes. All patients with CVEs were required to have temporary olverembatinib treatment suspension and received disease-specific treatment. Most recovered or improved and received olverembatinib treatment at a reduced dose except for one patient who discontinued because of acute myocardial infarction (MI) and one patient who died of pericardial effusion. None of these patients had a Fridericia-corrected QT interval exceeding 500 ms on treatment. Grade 3/4 hematologic TRAEs included thrombocytopenia (51.5%), neutropenia (11.5%), and anemia (23.0%) (Table 3). Myelosuppression tended to occur early, with a median (range) onset time of 28 (4-676) days and a median (range) duration of 36 (7-718) days. Most resolved after temporary treatment suspension or supportive care, including platelet or erythrocyte transfusion or dose adjustment. Except for skin hyperpigmentation and proteinuria, incidences of TRAEs decreased over time during the follow-up period (Fig. 1). Serious AEs (SAEs; in ≥ 1% of patients) included thrombocytopenia (9.0%), anemia (6.0%), pneumonia (3.0%), pyrexia or atrial fibrillation (2.0% each); as well as acute MI, cholelithiasis, pericardial effusion, upper-respiratory-tract infection, and urinary-tract infection (1% each). Most SAEs resolved after temporary treatment suspension or dose reduction, which was required in 75 (46.0%) patients at a median of 5 (range 1–36) months.
Efficacy
CML-CP
The median follow-up period of 126 evaluable patients with CML-CP since the start of an effective dose (≥ 30 mg QOD) was 37 (range, 7–58) months. All 84 patients without baseline CHR achieved this endpoint. Of 121 patients without MCyR at baseline, 96 (79.3%) and 84 (69.4%) achieved MCyR and CCyR at a median of 3 (range, 3–36) and 3 (range, 3–37) months, respectively. Among 126 patients, 70 (55.6%) achieved MMR, 56 (44.4%) MR4.0, and 49 (38.9%) MR4.5 on olverembatinib therapy. Cytogenetic and molecular response rates increased over time (Fig. 2A). The cumulative 3-year incidences of MCyR, CCyR, MMR, MR4.0, and MR4.5 were 78.6% (95% CI: 70.0%, 85.0%), 69.0% (59·7%, 76·5%), 55.9% (46.5%, 64.4%), 43.5% (34.6%, 52.1%), and 38.6% (30.0%, 47.1%), respectively. The probabilities of sustained MCyR, CCyR, and MMR at 3 years were 77.3% (66.8%, 84.8%), 72.2% (60.4%, 81.1%), and 76.0% (62.1%, 85.3%), respectively. A total of 5 patients progressed to CML-AP (n = 4) or CML-BP (n = 1). Seven patients died of disease progression (n = 3) and one each of either pericardial effusion, gastric cancer, hepatitis E virus infection (with prior autoimmune hepatitis), or an unknown reason. Probabilities of PFS and OS at 3 years were 92.0% (86.0%, 96.0%) and 94.0% (89.0%, 97.0%), respectively (Fig. 3A).
CML-AP
The median follow-up was 27 (range, 5–56) months since the onset of an effective dose. Among 37 patients without baseline MaHR, 29 (78.4%) met this endpoint at a median of 3 (range, 1–7) months; and 27 (73%) experienced CHR at a median of 3 (range, 1–14) months. Of the 38 patients without baseline MCyR, 18 (47.4%) achieved MCyR and CCyR at a median of 3 (range, 1–9) months and 4 (range, 1–15) months. MMR and MR4.0 were achieved by 17 (44.7%) and 14 (36.8%) patients, respectively, and MR4.5 by 13 (34.2%) patients. Cytogenetic and molecular response rates increased over time (Fig. 2B). The 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4% (30.7%, 62.4%), 47.4% (30.6%, 62.4%), 44.7% (28.2%, 60.0%), 39.3% (22.3%, 56.0%), and 32.1% (17.6%, 47.6%), respectively. The probabilities of sustained MCyR and CCyR at 3 years were 86.0% (55.0%, 97.0%) and 71% (44.0%, 87.0%). A total of 11 patients had CML that progressed to blast phase, and 4 died. Probabilities of PFS and OS at 3 years were 60.0% (41.0%, 74.0%) and 71% (54.0%, 83.0%), respectively (Fig. 3B).
Responses according to BCR-ABL1 mutation status via Sanger sequencing
Among the four subgroups with CML-CP evaluated by Sanger sequencing, patients with a single T315I mutation had the highest 3-year cumulative incidences of achieving MCyR (85.3%), CCyR (76.0%), MMR (68.7%), MR4.0 (59.3%), and MR4.5 (54.7%); those with no BCR-ABL1 mutation had the lowest cumulative incidences of MCyR (59.1%), CCyR (50.0%), MMR (9.1%), MR4.0 (4.5%), and MR4.5 (0) (all P values among the four subgroups < 0.0001; Fig. 4A). Among patients with CML-AP, those with a single T315I mutation also had the highest 2-year cumulative incidences of MCyR or CCyR (60.0% each), MMR (52.0%), and MR4.0 or MR4.5 (40.0% each); followed by those with T315I and an additional mutation, who had MCyR, CCyR, or MMR (33.3% each), MR4.0 (22.2%), and MR4.5 (11.1%). No cytogenetic or molecular response was observed in patients with no BCR-ABL1 mutation or with other mutations at enrollment (Fig. 4B). We interrogated baseline covariates to evaluate associations with cytogenetic and molecular responses (Table 4).
Table 4
Multivariate analysis results of variables associated with treatment response
|
MCyR
|
CCyR
|
MMR
|
MR4.0
|
MR4.5
|
HR (95% CI)
|
P value
|
HR (95% CI)
|
P value
|
HR (95% CI)
|
P value
|
HR (95% CI)
|
P value
|
HR (95% CI)
|
P value
|
In 164 evaluable patients
|
Baseline BCR-ABL1 mutation status by Sanger sequencing
|
|
0.10
|
|
0.02
|
|
0.006
|
|
0.006
|
|
< 0.001
|
Single T315I mutation (ref.)
|
|
|
|
|
|
|
|
|
|
|
T315I + additional mutations
|
0.6 (0.3-1.0)
|
0.05
|
0.6 (0.3–1.1)
|
0.10
|
0.8 (0.4–1.3)
|
0.32
|
0.4 (0.2-1.0)
|
0.05
|
0.5 (0.2–1.1)
|
0.10
|
Other mutations
|
0.7 (0.5–1.2)
|
0.21
|
0.6 (0.3-1.0)
|
0.06
|
1.0 (0.5–1.8)
|
0.80
|
0.6 (0.3–1.3)
|
0.23
|
0.4 (0.1–1.6)
|
0.22
|
No mutation
|
0.6 (0.4–1.1)
|
0.13
|
0.5 (0.3–0.8)
|
0.009
|
1.0 (0.0-0.4)
|
< 0.001
|
0.1 (0.0-0.4)
|
0.005
|
0.0 (0.0–0.0)
|
< 0.001
|
Accelerated phase (ref. chronic phase)
|
0.5 (0.3-1.0)
|
0.04
|
0.5 (0.3–0.9)
|
0.03
|
0.6 (0.4-1.0)
|
0.06
|
0.7 (0.4–1.3)
|
0.29
|
0.8 (0.4–1.5)
|
0.51
|
Additional chromosomal abnormalities (ref. none)
|
0.7 (0.4–1.2)
|
0.18
|
0.7 (0.4–1.3)
|
0.23
|
0.7 (0.4–1.3)
|
0.24
|
0.8 (0.4–1.6)
|
0.49
|
0.6 (0.3–1.6)
|
0.33
|
Time from diagnosis to olverembatinib treatment, years (continuous)
|
0.9 (0. 9 − 1.0)
|
0.002
|
1.0 (0.9-1.0)
|
0.003
|
1.0 (0.9-1.0)
|
< 0.001
|
1.0 (0.9-1.0)
|
0.002
|
0.9 (0.8-1.0)
|
< 0.001
|
Number of prior TKIs (continuous)
|
0.8 (0.6–1.1)
|
0.16
|
0.7 (0.5–1.1)
|
0.10
|
0.7 (0.5-1.0)
|
0.03
|
0.7 (0.5–1.1)
|
0.12
|
0.8 (0.5–1.2)
|
0.27
|
Age (10 years)
|
0.9 (0.8–1.1)
|
0.36
|
0.8 (0.7-1.0)
|
0.07
|
0.9 (0.8–1.1)
|
0.30
|
0.9 (0.8–1.1)
|
0.44
|
1.0 (0.8–1.2)
|
0.90
|
In 118 evaluable patients
|
Baseline BCR-ABL1 mutation status by next-generation sequencing
|
|
0.31
|
|
0.13
|
|
0.002
|
|
< 0.001
|
|
< 0.001
|
Single T315I mutation (ref.)
|
|
|
|
|
|
|
|
|
|
|
T315I + additional mutations
|
0.6 (0.3–1.2)
|
0.15
|
0.7 (0.3–1.4)
|
0.26
|
0.4 (0.1–0.9)
|
0.03
|
0.5 (0.2–1.2)
|
0.13
|
0.7 (0.3–1.5)
|
0.35
|
Other mutations
|
0.7 (0.4–1.5)
|
0.40
|
0.6 (0.3–1.2)
|
0.14
|
0.8 (0.4–1.9)
|
0.67
|
0.7 (0.3–1.6)
|
0.42
|
0.5 (0.1–1.9)
|
0.29
|
Compound mutations
|
0.6 (0.3–1.2)
|
0.13
|
0.7 (0.3–1.4)
|
0.26
|
0.6 (0.3–1.2)
|
0.16
|
0.3 (0.1–1.1)
|
0.07
|
0.4 (0.1–1.2)
|
0.11
|
No mutation
|
0.7 (0.3–1.2)
|
0.15
|
0.5 (0.3–0.9)
|
0.02
|
0.0 (0.0-0.2)
|
< 0.001
|
0.0 (0.0–0.0)
|
< 0.001
|
0.0 (0.0–0.0)
|
< 0.001
|
Accelerated phase (ref. chronic phase)
|
0.8 (0.7-1.0)
|
0.10
|
0.8 (0.6-1.0)
|
0.03
|
0.9 (0.7–1.1)
|
0.21
|
0.9 (0.7–1.1)
|
0.45
|
1.0 (0.8–1.3)
|
0.82
|
Additional chromosomal abnormalities (ref. none)
|
0.3 (0.2–0.7)
|
0.004
|
0.4 (0.2–0.8)
|
0.007
|
0.4 (0.2–0.8)
|
0.009
|
0.7 (0.3–1.4)
|
0.32
|
0.8 (0.4–1.7)
|
0.59
|
Time from diagnosis to olverembatinib treatment, years (continuous)
|
0.9 (0.8-1.0)
|
0.003
|
1.0 (0.8-1.0)
|
0.004
|
0.9 (0.8-1.0)
|
< 0.001
|
0.9 (0.8-1.0)
|
0.003
|
0.9 (0.8-1.0)
|
0.002
|
Number of prior TKIs (continuous)
|
0.7 (0.4-1.0)
|
0.03
|
0.6 (0.4-1.0)
|
0.02
|
0.6 (0.4–0.9)
|
0.01
|
0.7 (0.4-1.0)
|
0.08
|
0.8 (0.5–1.3)
|
0.33
|
Age (10 years)
|
0.8 (0.7-1.0)
|
0.10
|
0.8 (0.6-1.0)
|
0.03
|
0.9 (0.7–1.1)
|
0.21
|
0.9 (0.7–1.1)
|
0.45
|
1.0 (0.8–1.3)
|
0.82
|
MCyR, major cytogenetic response; CCyR, complete cytogenetic response; CI, confidential interval; HR, hazard ratio; MMR, major molecular response;
MR4.0, molecular response 4; MR4.5, molecular response 4.5; ref., reference; TKI, tyrosine kinase inhibitor.
|
In multivariate analyses, BCR-ABL1 mutation status before study entry was independently associated with higher cumulative incidences of achieving CCyR (P = 0.02), MMR (P = 0.006), MR4.0 (P = 0.006), and MR4.5 (P < 0.0001). Compared to no mutation or other mutation status, a single T315I mutation showed higher responses (or a trend in this direction). In addition, a longer interval from CML diagnosis to olverembatinib treatment onset, CML-AP rather than CML-CP, and more prior TKIs were significantly associated with lower rates of cytogenetic and molecular responses.
Responses according to BCR-ABL1 mutation status via NGS
Findings on treatment responses stratified by BCR-ABL1 mutation status with NGS paralleled those with Sanger sequencing (Fig. 5). Among 12 patients (7 with CML-CP and 5 with CML-AP) with compound mutations (Table 5), 8 (67.0%) had T315I-inclusive compound mutations; and 9 (75.0%), 2 (17.0%), and 1 (8.0%) had 1, 2, and 3 compound mutations, respectively. A total of 7 (58.0%) achieved MMR and 3 (25.0%) MR.4.5 By the last follow-up date, 3 patients had progressed to CML-AP or CML-BP and died, and 7 remained on treatment with olverembatinib, of whom one had CCyR and two each had CHR, MMR, or MR.4.5
Table 5
Characteristics of 12 patients harboring compound mutations at baseline
Pt
ID
|
Disease phase
|
Prior TKI
|
Dose, mg
|
Baseline SS
|
Baseline NGS
(frequency)
|
Best response
|
Time to response (mo.)
|
Response duration (mo.)
|
Outcome
|
0401
|
CP
|
I
D
N
|
40
|
V299L;
F317;
F359V
|
V299L/F359V (60%); V299L/F317L/F359V (3.8%);
F317L (33.4%);
F359V (3.6%)
|
MMR
|
6*
|
41
|
Loss of MMR at 36 mo.,
ongoing in CCyR
|
0601
|
CP
|
I
N
|
40
|
G250E;
T315I;
F317L
|
G250E/F317L (79.1%);
G250E (7.9%);
T315I (17.5%);
|
MR4.5
|
3*
|
47
|
Ongoing in MR4.5
|
0705
|
CP
|
I
N
|
50
|
T315I; F359V
|
T315I/F359V (7.1%);
T315I (73.0%);
F359V (10.4%)
|
MMR
|
9**
|
35
|
Ongoing in MMR
|
0722
|
CP
|
I
|
30
|
K247R; G250E; Y253F;
T315I;
F359I
|
K247R/Y253F (55.4%);
K247R/T315I (5.5%); K247R/F359I (3.7%);
G250E (9.64%);
T315I (11.6%);
F359I (7.45%)
|
CHR
|
|
|
Progression to AP and died at 21 mo.
|
0728
|
CP
|
I
|
30
|
T315I;
E459K
|
T315I/E459K (7.9%);
T315I (56.3%);
E459K ( 27.7%)
|
MMR
|
3**
|
1
|
Consent withdrawal because of breast cancer at 4 mo.
|
1028
|
CP
|
I
N
D
|
30
|
L248V; T315I; F359C; E459K
|
T315I/E459K (6.9%);
L248V (6.51%);
T315I (13.6%);
F359C (5.26%);
E459K (59.1%);
|
MMR
|
6*
|
31
|
Ongoing in MMR
|
1110
|
CP
|
I
N
|
50
|
T315I; M351T; F359V
|
M351T/F359V (35.2%);
Y253H (5.41%);
T315I (4.57%);
M351T (8.6%);
F359V (22.6% );
|
CHR
|
|
|
Consent withdrawal at 27 mo.
|
0701
|
AP
|
I
|
30
|
T315I;
F359C
|
T315I/F359C (4.7%);
T315I (24.1%);
F359V (51.4%)
|
MR4.5
|
9**
|
39
|
Ongoing in MR4.5
|
0706
|
AP
|
I
D
N
|
30
|
E255K; E279A; T315I;
F317L
|
E279A/T315I (4.3%);
E279A/F317L (3.4%);
E255K (47.1%);
F359C (3.09%)
|
CHR
|
|
|
Progression to AP at 6 mo., to BP at 16 mo., and died at 18 mo.
|
0718
|
AP
|
I
D
|
30
|
T315I;
F359I
|
T315I/F359I (4.4%);
T315I (38.1%);
F359I (51.3%);
|
CHR
|
|
|
Ongoing in CHR
|
1101
|
AP
|
I
|
50
|
E255K;
T315I
|
E255K/T315I (2.0%);
T315I (95.1%);
|
MR4.5
|
3**
|
10
|
Loss of MR4.5 at 6 mo., progression to BP and died at 13 mo.
|
1106
|
AP
|
I N
|
50
|
M244V; H396R
|
M244V/H396R (60.3%);
M244V (39.4%)
|
CHR
|
|
|
Ongoing in CHR
|
AP, accelerated phase; BP, blast phase; CP, chronic phase; CHR, complete hematologic response; CCyR, complete cytogenetic response; D, dasatinib;
I, imatinib; MMR, major molecular response; MR, molecular response; NGS, next-generation sequencing; N, nilotinib; SS, Sanger sequencing.
*, achieving PCyR; **, achieving CCyR·
|
In multivariate analyses, BCR-ABL1 mutation status before study entry was independently associated with cumulative incidences of achieving MMR (P = 0.002), MR4.0 (P < 0.0001), and MR4.5 (P < 0.0001; Table 4). A single T315I mutation was also significantly associated with higher molecular response rates; compound mutation was comparable to other mutation status except no mutations; and no mutation was associated with lower response rates. In addition, longer intervals from CML diagnosis to olverembatinib treatment onset, CML-AP (rather than CML-CP), more prior TKIs, and increasing age were significantly associated with lower rates of cytogenetic and/or molecular responses.
Pharmacokinetics and pharmacodynamics
Based on plasma concentration-time curves on treatment Days 1 and 27, olverembatinib pharmacokinetics were linear, with mean terminal elimination half-life values (17.5–36.5 hours) that are well suited to QOD administration (Fig. 6). Systemic exposure and maximum concentration were approximately dose proportional across olverembatinib doses (1–60 mg QOD). With multiple dosing, slight to moderate accumulation of olverembatinib was observed on C1D27. Significant dose- and time-dependent reductions in pCRKL levels (indicative of BCR-ABL1 inhibition) were observed within 8 hours after olverembatinib dosing (30–50 mg QOD) on C1D1 and maintained at steady state on C1D15 and C1D27 (Fig. 7).