cml: current therapeutic challenges · 2019. 2. 13. · all, acute lymphocytic leukaemia; emr,...

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


therapy in CML

6


1 2 3 4 80

BaselineB

CR

-AB

L%

IS

0.01

0.1

1.0

10

0.001


therapy in CML

6


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.



TKIImatinib

(%)

Nilotinib

(%)

Ponatinib

(%)


Divided by

SOKAL score:

High risk 56 14 15

Intermediate risk 30 8 5

Low risk 21 7 2




dependent on intensity of kinase inhibition and risk score



TKIImatinib

(%)Nilotinib

(%)Ponatinib

(%)


Divided by

SOKAL score:

High risk 56 14 15

Intermediate risk 30 8 5

Low risk 21 7 2




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)


Wylie A, et al. Blood. 2014:[abstract

398].

t(9;22)BCR

SH2SH2

Kinas

e

SH2

INACTIVE ACTIVE

SH3

Kinas

e

SH3

BCRASCIMINIB



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


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


CML

ABL001+imatinib

Expansion


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:


asciminib + IMA 400 mg QD

40, 60, and 80 mg QD; 40 mg BID

Dose Expansion:


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)

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]

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cml: current therapeutic challenges · 2019. 2. 13. · all, acute lymphocytic leukaemia; emr,...

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