Timothy Hughes, SAHMRI, Adelaide, Australia CML: Current Therapeutic Challenges
Timothy Hughes, SAHMRI, Adelaide, Australia
CML: Current Therapeutic Challenges
Disclosures
Company Research
Support
Honoraria,
Advisory Board
Novartis YES YES
BMS YES YES
Ariad/Takeda YES YES
Celgene YES
Heterogeneity of response to TKI
therapy in CML
6
Years of TKI therapy
1 2 3 4 80
BaselineB
CR
-AB
L%
IS
0.01
0.1
1.0
10
0.001
10% primary resistance
10% secondary resistance
30% plateau response
STOP
25%
25%50% deep mol response
5-10% CML-related death
Heterogeneity of response to TKI
therapy in CML
6
Years of TKI therapy
1 2 3 4 80
BaselineB
CR
-AB
L%
IS
0.01
0.1
1.0
10
0.001
Heterogeneity of response to TKI
therapy in CML
6
Years of TKI therapy
1 2 3 4 80
BaselineB
CR
-AB
L%
IS
0.01
0.1
1.0
10
0.001
1.Kinase inhibition
2. Intrinsic biology
3.Host immunity
Hughes TP, et al. Blood. 2014;123:1353-60.
Lipton JH, et al. Lancet Oncol. 2016;17:612-21.
TKIImatinib
(%)
Nilotinib
(%)
Ponatinib
(%)
ALL CML patients 34 9 6
Kinase inhibition intensity
Probability of EMR failure (>10% BCR-ABL at 3 months) is
dependent on intensity of kinase inhibition
ALL, acute lymphocytic leukaemia; EMR, early molecular response.
Hughes TP, et al. Blood. 2014;123:1353-60.
Lipton JH, et al. Lancet Oncol. 2016;17:612-21.
TKIImatinib
(%)
Nilotinib
(%)
Ponatinib
(%)
ALL CML patients 34 9 6
Divided by
SOKAL score:
High risk 56 14 15
Intermediate risk 30 8 5
Low risk 21 7 2
Kinase inhibition intensity
ALL, acute lymphocytic leukaemia; EMR, early molecular response.
Probability of EMR failure (>10% BCR-ABL at 3 months) is
dependent on intensity of kinase inhibition and risk score
Hughes TP, et al. Blood. 2014;123:1353-60.
Lipton JH, et al. Lancet Oncol. 2016;17:612-21.
TKIImatinib
(%)Nilotinib
(%)Ponatinib
(%)
ALL CML patients 34 9 6
Divided by
SOKAL score:
High risk 56 14 15
Intermediate risk 30 8 5
Low risk 21 7 2
Kinase inhibition intensity
ALL, acute lymphocytic leukaemia; EMR, early molecular response.
Probability of EMR failure (>10% BCR-ABL at 3 months) is
dependent on intensity of kinase inhibition and risk score
For each generation of TKI drugs improved efficacyhas been counterbalanced by increased toxicity
The result – no overall improvement in survival
DASISION: OS and PFS
Cortes JE, et al. Blood. 2014;124:abstract 152.
Dasatinib100 mg OD
(n = 259)
Imatinib400 mg OD
(n = 260)
Hazard ratio
(95% CI)
Total number of deaths, n 26 26 –
CML-related deaths 9 17
Non-CML-related deaths 17 9
Estimated 5-year OS, % (95% CI)
91(87–94)
90(85–93)
1.01 (0.58–1.73)
Estimated 5-year PFS, % (95% CI)
85(80–89)
86(80–89)
1.06 (0.68–1.66)
ENESTnd: Survival and CML-Related Deaths
Nilotinib
300 mg BID
(n = 282)
Imatinib
400 mg QD
(n = 283)
Total deaths, n 18 22
KM-estimated 5-year OS, % 93.7 91.7
Hazard ratio vs imatinib (95% CI)0.80 (0.43-1.50) —
P value vs imatinib .49 —
CML related deaths6 16
Non-CML related deaths12 6
Hazard ratio vs imatinib (95% CI) 0.37 (0.14-0.94) —
P value vs imatinib .03 —
1
0
Parameter
ATE per 100-person yearsP-
ValueTotal Imatinib Nilotinib Dasatinib Ponatinib
N 584 281 132 120 51
Overall 1.1 0.6 1.7 1.8 5.1
Possible responses
• Use more potent (and toxic) TKI where the risk and potential benefit is greatest – a risk-adapted approach
Precision medicine approach in CML – bioassay-directed management
Bioassay-
based
risk
assessment
Imatinib
Experimental
Potent TKIAt
diagnosis
Ph associated fusion
ABL1 kinase domain
RUNX1
BCORL1
CBFB-MYH11
GATA2
IKZF1
TP53 (R248Q-germline)
SETD1B
ASXL1
IDH1 (R132H/C), IDH2 (R140Q)
U2AF1 (Q157R)
KMT2D
UBE2A
SETD2
XPO1 (E571K)
MECOM fusion
BCOR
Novel fusion (not Ph associated)
PHF6
MLL fusion
BCR-ABL1 amplification
HBS1L-MYB intergenic locus del
Chr 17p deletion, 17q amplification
PAX5/CDKN2A whole gene del
IGH locus deletion
TCRA/D loci deletion
IGK locus deletion
TCRB locus deletion
TCRG locus deletion or inversion
Myeloid blast crisis (19) Lymphoid blast crisis (20)
Clinically relevant variants at transformation
Mutation Type
Inversion associated fusion
Fusion
Amplification
Splice site
Frameshift/Nonsense
Missense
Exon deletion
Whole gene or locus deletion
Patient number
Chr 19 amplification
PAX5-ZCCHC7
Chr 8 amplification
57 39 38 60 3 17 23 19 20 18 1 64756
● Variant also present at diagnosis
Variant present at accelerated phase
but not BC
**** * *** *** *** **
* Patients with WES/CNV analysis
Patients with RNA-Seq analysis+
+ + + + + + + + ++ + + + + + + + ++ + + + + + + +58 54 15 2
**+ + + +*21* + + +
44 48 41 52 16 4 10 9 534555 5 42 7 13 1459 22 1211
Poor outcome: 27 patients Good outcome: 19 patients
BCORL1
CBFB-MYH11 fusion
RUNX1
IKZF1
TP53
SETD1B
ASXL1
IDH1
EZH2
KMT2D
Patient number 14 2210 11 139 23 2416 17752 20 251912 153 4 26 27186 8 211 32 33 34 35 36 37 38 39 40 41 42 43 443128 29 30 4645
Mutated genes Mutation Type
Fusion
Frameshift/Nonsense
Missense
Exon deletion
Whole gene deletion
Mutated genes at diagnosis of CML. Shown are mutated cancer genes and SETD1B, which was
a novel recurrently mutated lysine methyltransferase.
Possible responses
• Use more potent (and toxic) TKI where the risk and potential benefit is greatest – a risk-adapted approach
• Develop better targeted inhibitors to break the linkage between potency and toxicity
Asciminib is a potent, specific inhibitor of BCR-ABL1
with a distinct allosteric mechanism of action
ATP, adenosine triphosphate. Hughes TP, et al. Blood. 2016;128:abstract 625.
• Potent BCR-ABL1 inhibition,
maintained against BCR-ABL1
mutations that confer resistance
to TKIs
• High specificity providing the
potency without toxicity
• Potential for combination
therapy
TBCR-ABL1
protein
Nilotinib
(ATP site)
Asciminib
(myristoyl site)
SH2SH2
Kinase
SH2
INACTIVE ACTIVE
SH3
Kinase
SH3
Myristoylated
N-terminus
Regulation of ABL1 enzymatic activity
Wylie A, et al. Blood. 2014:[abstract 398].
SH2SH2
Kinas
e
SH2
INACTIVE ACTIVE
SH3
Kinas
e
SH3
BCR
t(9;22)
Regulation of ABL1 enzymatic activity
Wylie A, et al. Blood. 2014:[abstract
398].
t(9;22)BCR
SH2SH2
Kinas
e
SH2
INACTIVE ACTIVE
SH3
Kinas
e
SH3
BCRASCIMINIB
Regulation of ABL1 enzymatic activity
Wylie A, et al. Blood. 2014:[abstract
398].
Asciminib is quite selective against
BCR-ABL+
cells
IC50, half maximal inhibitory concentration. Wylie AA, et al. Nature. 2017;543:733-7.
0.0001 0.0004 0.01 0.04 0.1 0.4 1 4 10 40
Cell proliferation IC50 (µM)
Asciminib
GNF-2
Imatinib
Bosutinib
Nilotinib
Dasatinib
Ponatinib
Myristoyl-site
inhibitors
ATP-site
inhibitors
BCR-ABL1+
BCR-ABL1−
Cancer cell line panel
Acquired resistance develops to ATP-site and
allosteric inhibitors
WT 1 1
A337V 2 10640
P465S 1 13620
V468F 1 10053
WT 1 1
T315I >30000 55
E255K 1267 4
E255V 268 2
Y253H 132 5
F359V 64 167
Q252H 30 44
G250H 7 2
E459K 4 7
Fold reduction in cell potency (Ba/F3)
due to presence of BCR-ABL mutations
Nilotinib ABL001
Myristoyl-
site
ATP-site
Wylie A, et al. Blood. 2014:[abstract 398].
Acquired resistance develops to ATP-site and
allosteric inhibitors
WT 1 1
A337V 2 10640
P465S 1 13620
V468F 1 10053
WT 1 1
T315I >30000 55
E255K 1267 4
E255V 268 2
Y253H 132 5
F359V 64 167
Q252H 30 44
G250H 7 2
E459K 4 7
Fold reduction in cell potency (Ba/F3)
due to presence of BCR-ABL mutations
Nilotinib ABL001
Myristoyl-
site
ATP-site
Wylie A, et al. Blood. 2014:[abstract
398].
Dose Escalation
Bayesian Logistic Regression
CML—completed
ABL001, po, BID
Dose Expansion
CML (20 mg, 40 mg)–completed
T315I mutation (150 mg)–ongoing
Dose Escalation
Ph+ ALL/CML-BP
Combo Dose Escalation
CML
ABL001+nilotinib
MT
DR
DE
Expansion
Dose Expansion
Ph+ ALL/CML-BP
Combo Dose Escalation
CML
ABL001+imatinib
Expansion
Combo Dose Escalation
CML
ABL001+dasatinib
Expansion
Dose Escalation
CML
ABL001, po, QD
Dose Expansion
CMLMT
DR
DE
MT
DR
DE
MT
DR
DE
MT
DR
DE
MT
DR
DE
ABL001X2101: Study DesignA multicenter, phase 1, first-in-human study
• Primary outcome: estimation of MTD/RDE
• Secondary outcomes: safety, tolerability, preliminary anti-CML
activity, pharmacodynamics,
pharmacokinetic profile
ALL, acute lymphocytic leukemia; BID, twice daily; BP, blast phase; CML, chronic myeloid leukemia; MTD, maximum tolerated dose;
Ph+, Philadelphia chromosome–positive; po, peroral; QD, once daily; RDE, recommended dose for expansion.
Asciminib, a Specific Allosteric BCR-ABL1 Inhibitor,
in Patients with Chronic Myeloid Leukemia
Carrying the T315I Mutation in a Phase 1 Trial
Delphine Rea, MD, PhD
First-in-human phase 1 study design
Dose Escalation: CML
asciminib BID completed
10 – 200 mg BID
Dose Expansion:
CML (20 mg and 40 mg BID) completed
Dose Escalation: CMLasciminib QD
80 – 200 mg
Dose Expansion: CML
Dose Expansion:
Ph+ ALL/CML-BP
Dose Escalation: Ph+ ALL/CML-BPasciminib BID
40 – 280 mg
MTD
RDE
MTD
RDE
MTD
RDE
MTD
RDE
MTD
RDE
MTD
RDE
Dose Expansion:
CMLCombo Dose Escalation: CML
asciminib + NIL 300 mg BID
20 and 40 mg BID
Dose Expansion:
CMLCombo Dose Escalation: CML
asciminib + IMA 400 mg QD
40, 60, and 80 mg QD; 40 mg BID
Dose Expansion:
CMLCombo Dose Escalation: CML
asciminib + DAS 100 mg QD
80 mg QD; 40 mg BID
Dose Escalation: CML T315I
asciminib BID and QD completed
Asciminib BID20 – 200 mg BID
80 – 200 mg QD
Dose Expansion:
T315I mutation (200 mg BID) ongoing MTD
RDE
ALL, acute lymphoblastic leukemia; BID, twice daily; BP, blast phase; DAS, dasatinib; IMA, imatinib; MTD, maximum tolerated dose; NIL, nilotinib; QD, once daily; RDE, recommended dose for expansion.
Baseline disease characteristicsDemographics and Prior Therapy N = 32Age, median, years (range) 54.0 (29-77)
Male, n (%) 25 (78.1)
ECOG performance status, n (%)
0 26 (81.3)
1 6 (18.8)
Number of prior TKIs, n (%)
1 3 (9.4)
2 11 (34.4)
3 11 (34.4)
≥ 4 7 (21.9)
Prior ponatinib treatment, n (%) 19 (59.4)
Ponatinib resistanta 12 (37.5)
Ponatinib intolerantb 7 (21.9)
AP, accelerated phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; MMR, major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale [IS]).a Patients who discontinued due to disease progression, completed prescribed regimen, or showed lack of efficacy at their last ponatinib regimen. b Patients who discontinued due to toxicity or adverse events (AEs) at their last ponatinib regimen. c Insufficient number of metaphases available to evaluate for CCyR. d One patient had atypical BCR-ABL1 transcript.
Disease Characteristics N = 32Disease phase, n (%)
CML-CP 30 (93.8)CML-AP 2 (6.3)
CHR at screening, n (%)No 15 (46.9)Yes 17 (53.1)
CCyR at screening, n (%)No 22 (68.8)Yes 7 (21.9)Incompletec 3 (9.4)
MMR at screening, n (%)No 30 (93.8)Yes 1 (3.1)Not assessabled 1 (3.1)
Baseline disease characteristicsDemographics and Prior Therapy N = 32Age, median, years (range) 54.0 (29-77)
Male, n (%) 25 (78.1)
ECOG performance status, n (%)
0 26 (81.3)
1 6 (18.8)
Number of prior TKIs, n (%)
1 3 (9.4)
2 11 (34.4)
3 11 (34.4)
≥ 4 7 (21.9)
Prior ponatinib treatment, n (%) 19 (59.4)
Ponatinib resistanta 12 (37.5)
Ponatinib intolerantb 7 (21.9)
AP, accelerated phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; MMR, major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale [IS]).a Patients who discontinued due to disease progression, completed prescribed regimen, or showed lack of efficacy at their last ponatinib regimen. b Patients who discontinued due to toxicity or adverse events (AEs) at their last ponatinib regimen. c Insufficient number of metaphases available to evaluate for CCyR. d One patient had atypical BCR-ABL1 transcript.
Disease Characteristics N = 32Disease phase, n (%)
CML-CP 30 (93.8)CML-AP 2 (6.3)
CHR at screening, n (%)No 15 (46.9)Yes 17 (53.1)
CCyR at screening, n (%)No 22 (68.8)Yes 7 (21.9)Incompletec 3 (9.4)
MMR at screening, n (%)No 30 (93.8)Yes 1 (3.1)Not assessabled 1 (3.1)
Baseline disease characteristicsDemographics and Prior Therapy N = 32Age, median, years (range) 54.0 (29-77)
Male, n (%) 25 (78.1)
ECOG performance status, n (%)
0 26 (81.3)
1 6 (18.8)
Number of prior TKIs, n (%)
1 3 (9.4)
2 11 (34.4)
3 11 (34.4)
≥ 4 7 (21.9)
Prior ponatinib treatment, n (%) 19 (59.4)
Ponatinib resistanta 12 (37.5)
Ponatinib intolerantb 7 (21.9)
AP, accelerated phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; MMR, major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale [IS]).a Patients who discontinued due to disease progression, completed prescribed regimen, or showed lack of efficacy at their last ponatinib regimen. b Patients who discontinued due to toxicity or adverse events (AEs) at their last ponatinib regimen. c Insufficient number of metaphases available to evaluate for CCyR. d One patient had atypical BCR-ABL1 transcript.
Disease Characteristics N = 32Disease phase, n (%)
CML-CP 30 (93.8)CML-AP 2 (6.3)
CHR at screening, n (%)No 15 (46.9)Yes 17 (53.1)
CCyR at screening, n (%)No 22 (68.8)Yes 7 (21.9)Incompletec 3 (9.4)
MMR at screening, n (%)No 30 (93.8)Yes 1 (3.1)Not assessabled 1 (3.1)
Patient disposition
Patients, n (%) 200 mg BID (N = 32)Treatment ongoing 29 (90.6)
Treatment ended 3 (9.4)
Lack of responsea 2 (6.3)
Adverse event 1 (3.1)
a One patient had BCR-ABL1IS > 10% and thrombocytosis at screening, and discontinued after continued BCR-ABL1IS > 10% and grade 1 thrombocytosis. The other patient had CML-CP at study entry and persistent thrombocytosis with no progression to AP on study.
• Analysis is based on a data cutoff date of July 15, 2018• Median duration of exposure: 27.6 weeks (range, 1.0-85.6 weeks)
Hematologic and cytogenetic responses
a Maintenance or achievement of CHR by the data cutoff, based on clinical review of laboratory parameters. b One patient with persistent thrombocytosis was in CHR at screening (platelets 395K) and not in CHR during follow-up due to thrombocytosis (platelets 539K). c Evaluable patients had a cytogenetic evaluation within the specified time window or achieved a CCyR or discontinued treatment before that time window. d Maintenance or achievement of CCyR.
0
20
40
60
80
100
CHRa CCyR
CHR at screening(n = 17)
No CHR at screening(n = 15)
Pati
ents
, % 94.1% (16/17)
maintained
CHR
100%
(15/15)
achieved
CHR
5.9% (1/17)b
without CHR
0
20
40
60
80
100
By 24 weeks By 48 weeksPa
tien
ts W
ith
Res
po
nse
, %
75.0%
(15/20)
62.5%
(5/8)
80.0%
(16/20)
66.7%
(6/9)
All evaluable patientsc,d
Evaluable patientsc with > 35% Ph+ at screening
Cumulative molecular response rates
MR4, BCR-ABL1IS ≤ 0.01%; MR4.5, BCR-ABL1IS ≤ 0.0032%. a One patient with atypical BCR-ABL1 transcript and no molecular data was excluded from analyses of cumulative molecular responses; 1 patient with MMR at screening was excluded from analysis of cumulative MMR. b Among patients who achieved MMR.
Median time to MMRa,b:
12.2 weeks (range, 4.1-60.0 weeks)
MMR % (N = 30): 0.0 26.7 33.3 33.3 33.3 36.7 36.7 36.7MR4 % (N = 31): 0.0 6.5 16.1 19.4 19.4 19.4 19.4 19.4
MR4.5 % (N = 31): 0.0 0.0 12.9 12.9 16.1 16.1 16.1 16.1
200 mg BID (N = 32)a
Time (28-day cycles)
Pati
ents
Wit
h R
esp
on
se (
%)
MMR: 36.7%
MR4: 19.4%
MR4.5: 16.1%
MMRMR4MR4.5
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21
Summary and conclusions
• Asciminib at 200 mg BID shows promising efficacy and a favorable safety profile in patients with T315I-mutated CML-CP or -AP
• Clinical benefit is observed in ponatinib-naive and ponatinib-resistant/intolerant patients
• Asciminib is a promising treatment option in these patients with high unmet medical need
Current asciminib trials
Frontline add-on therapy (phase 2; NCT03578367)1
• Enrolling patients without DMR on long-term frontline imatinib
• Patients randomized to:
o Asciminib 40 mg QD + imatinib 400 mg QD
o Asciminib 60 mg QD + imatinib 400 mg QD
o Continue imatinib 400 mg QD
o Switch to nilotinib 300 mg BID
• Primary endpoint: MR4.5 rate at 48 weeks
Third- or later-line therapy (phase 3; NCT03106779)2
• Enrolling patients previously treated with ≥ 2 ATP binding–site TKIs
• Patients randomized to asciminib 40 mg BID or bosutinib 500 mg QD
• Primary endpoint: MMR rate at 24 weeks
65%
57%
39%
15 YRS:
Adelaide Cohort: Cumulative Incidence of TFR
Multivariate Analysis of Factors
Predicting TFR
Forest plot of multivariate analysis of factors predicting TFR success at 12 months
Variable p-value
Hazard ratio
[LCL,UCL]Favouring TFR
Bioassay-Based Risk Assessment
AND
Molecular Dynamics
ATDiagnosis
STABLEDMR
IMATINIB
Experimental
CONTINUE
POTENT TKI
Intensify/immunomodify
STOP
Future of CML Management: Precision Medicine ApproachBioassay Directed Management
Current therapeutic challenges in
CML
• Rational selection of frontline therapy– based on risk profile, comorbidities and TFR priority
– Future prospect of risk-adapted therapy based on biomarker algorithm
• Break the linkage between potency of kinase inhibition and toxicity– Asciminib shows great potential
• Majority of CML patients eventually eligible for TFR attempt
Bordeaux, FranceSEPTEMBER 12-15, 2019
21st Annual John Goldman Conference on CHRONIC MYELOID LEUKEMIA: BIOLOGY AND THERAPY
Chairs: J. Cortes, T. P. Hughes, D. S. KrauseOrganizers: R. Bhatia, T. Brümmendorf, M. Copland, M. Deininger, O. Hantschel, F.X. Mahon, D. Perrotti, J. Radich, D. RéaAdvisory Committee: J. Apperley, S. Branford, C. Gambacorti-Passerini, F. Guilhot, R. Hehlmann, P. Laneuville, G. Saglio,
C. Schiffer, S. Soverini, P. Valent, R. Van Etten
DEADLINE FOR ABSTRACTS: MAY 8th, 2019
For further information: www.esh.orgor contact [email protected]
Mount Kilimanjaro can be climbed
CML can be cured