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2011 Oncology Annual Meeting in Chicago

Clinical Spotlight

In Chronic Myeloid Leukemia

Continued Superiority of Nilotinib Over Imatinib:

Updates from ENESTnd and Mutational Analysis

Abstract 6511

Abstract 6502


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Larson RA, Kim D-W, Rosti G, Stenke L, Pasquini R, Hoenekopp A,

Blakesley RE, Gallagher NJ, Hochhaus A, Hughes TP, Saglio G,Kantarjian HM;

on behalf of the ENESTnd Investigators

Comparison of Nilotinib and Imatinib in

Patients with Newly Diagnosed ChronicMyeloid Leukemia in Chronic Phase (CML-

CP): ENESTnd 24-Month Follow-Up

Abstract 6511

Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.


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Background Nilotinib is a highly potent and selective inhibitor of BCR-ABL in

vitro1

Compared with imatinib at 12 months2 and 18 months3,4 follow-up inENESTnd, nilotinib demonstrated:

Significantly higher rates of complete cytogenetic response (CCyR),major molecular response (MMR), and complete molecular response(CMR)

Significant improvement in progression to accelerated or blasticphases of CML (AP/BC)

Fewer deaths related to CML Nilotinib 300 mg BID is now approved in more than 40 countries for

the treatment of adult patients with newly diagnosed Philadelphiachromosome-positive (Ph+) CML-CP

Results reported here represent a minimum follow-up of 24 months(Data cutoff : August 20, 2010)

1. Manley P, et al. Biochim Biophys Acta. 2010;1804(3):445-453. 2. Saglio G, et al. N Engl J Med. 2010;362(24):2251-2259.3. Larson RA, et al. J Clin Oncol. 2010;28(15s): Abstract 6501. 5. Hochhaus A, et al. Haematologica. 2010;95(s2):

Abstract 1113.Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.


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Study Design and Endpoints

Primary endpoint: MMR at 12 monthsSecondary endpoints: MMR and CCyR beyond 12 months, time toMMR and CCyR, event-free survival (EFS),

progression-free survival (PFS), time to AP/BC,overall survival (OS)* Stratification by Sokal risk score.

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)

RA

NDOMI

ZED*

Nilotinib 400 mg BID (n = 281)

N = 846217 centers35 countries

Follow-up;

5 years

The ENESTnd trial met its primary endpoint of MMR at 12 months in patients treated with nilotinib 300 and 400 mg BID vsimatinib (P< .0001).1

1. Saglio G, et al. N Engl J Med. 2010;362(24):2251-2259.Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.


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Nilotinib300 mg BID

n = 282

Nilotinib400 mg BID

n = 281

Imatinib400 mg QD

n = 283

Still on study*, % 93 95 92

Still on core or extension treatment, % 79 78 75

Still on core treatment, % 74 78 67

Discontinued core treatment without enteringextension study, %

18 21 22

Disease progression < 1 1 4

Suboptimal response (SoR)/treatment failure (TF) , 1 1 2

Toxicity 9 13 10

Death 1 < 1 0

Other reason 6 5 5

Discontinued core treatment and entered extensionstudy, %

7 < 1 11

Disease progression# 0 0 < 1

Suboptimal response/treatment failure#

7 < 1 10

Discontinued extension treatment, % 2 < 1 3

Data cutoff: 20Aug2010

* Patients are either on study drug or in follow-up after discontinuation of study drug.Investigator assessment of criteria.Patients with suboptimal response or treatment failure (SoR/TF) were allowed to discontinue core study and enter either into extension

study or follow-up. Imatinib patients were allowed to escalate dose before entering extension. Nilotinib 300 mg BID patients were allowedto enter extension for SoR and/or TF while nilotinib 400 mg BID patients remained on treatment for SoR and allowed to enter extension onlyfor TF.

Patient Disposition



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71%, P


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MMR Rates by 24 MonthsAccording to Sokal Risk*

73 74

65

74

67

5653

44

32

0

10

20

30

40

50

60

70

80

Low Sokal Intermediate Sokal High Sokal

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

PatientsWithM

MR,

%

* Pvalues are provided for descriptive purposes only and are not adjusted for multiple comparisons.

n = 103 103 104 101 100 101 78 78 78

P = .003

P = .002 P


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MMR Rates by 24 MonthsAccording to Age

71 72 7167

6167

4446

44

010

20

30

40

50

60

70

80

< 65 years 65 years Overall


PatientsWith

MMR,

%

n = 246 253 248 36 28 35 282 281 283Age =

Data cutoff: 20Aug2010Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.


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BCR-ABL 0.01% (CMR4) and BCR-ABL 0.0032% (CMR4.5) at Any Time*

44

26

36

2120

10

0

10

20

30

40

50

PatientsWithRe

sponse,%


P


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2 2

3

5

12

17

0

5

10

15

20

25

Progression to AP/BC on Treatment*

N

umberofPatients

0.7% 0.7%


P = .0059

P = .0196

P = .0003

P = .0089

Including Clonal Evolution

* Defined as progression to AP/BC or death due to CML while on treatment.

1.1% 4.2% 1.8% 6.0%



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PFS on Treatment*

Nilotinib300 mg BID

n = 282

Nilotinib400 mg BID

n = 281

Imatinib400 mg QD

n = 283

Number of events 5 4 12

Estimated 24-month

rate of PFS, %98.0 97.7 95.2

Pvalue .0736 .0437

*

Progression to AP/BC or death due to any cause while on treatment.



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Outcome After Imatinib DoseEscalation to 800 mg/day

Dose escalation* occurred in 82 of 280 patients (29%) treated withimatinib after a median of 14 months (range, 3-31 months)

Median time on treatment after dose escalation, 9 months (range, 6 months (n = 14) or discontinued without an improvement (n = 27).



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Study Drug-Related Adverse Eventsand Grade 3/4 Myelosuppression


Fluid retention

Diarrhea

Headache

Muscle spasm

Nausea

Pruritus

Rash

Vomiting

Anemia

Neutropenia

Thrombocytopenia

Any grade

Grade 3/4

0.10 0.2 0.3 0.4 0.5-0.1-0.2-0.3-0.4-0.5

Rate difference (imatinib - nilotinib) with 95% CI

Favors imatinib Favors nilotinib (300 mg BID)



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Study Drug-Related FluidRetention Events (All Grades)

Peripheral edema

Eyelid edema

Periorbital edema

Face edema

Pericardial effusion

Pleural effusion

0 0.30.20.1-0.1-0.2-0.3

Rate difference (imatinib - nilotinib) with 95% CI

Favors imatinib Favors nilotinib (300 mg BID)



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Grade 3/4 Myelosuppression andBiochemical Abnormalities by Age

Nilotinib

300 mg BID

Nilotinib

400 mg BID

Imatinib

400 mg QD< 65 y

(n = 244) 65 y

(n = 35)< 65 y

(n = 252) 65 y

(n = 25)< 65 y

(n = 244) 65 y

(n = 36)

Hematologic, %

Anemia 4 3 4 0 5 8

Neutropenia 14 0 12 0 22 17Thrombocytopenia 12 0 13 4 9 6

Selected biochemicalabnormalities, %

Lipase 7 11 7 16 3 6

ALT 5 0 10 8 2 3Total bilirubin 4 0 8 12 < 1 0

Glucose 4 23 4 16 0 0




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Deaths Unrelated to CML ProgressionNilotinib

300 mg BID

n = 282

Nilotinib400 mg BID

n = 281

Imatinib400 mg QD

n = 283

Deaths unrelated to

CML (n = 8)4 3 1

Ileuson treatment

Gastric cancer

6 weeks after

stopping nilotinibin survival follow-up

Renal failurein survival follow-up

Suicideon treatment

Septic shock

9 months after

stopping nilotinibin survival follow-up

Perisurgical

myocardial infarctionon treatment

Death (unknown

cause)on treatment

Pneumonia 19 months

after stopping

nilotinibin survival follow-up


New cases in second year are in yellow.Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.


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Overall Survival*Nilotinib

300 mg BIDn = 282

Nilotinib

400 mg BIDn = 281

Imatinib

400 mg QDn = 283

Total number of deaths 9 6 11

Estimated 24-monthrate of OS, %

97.4 97.8 96.3

P-value (OS) .6485 .2125

Unrelated to CML 4 3 1

Related to CML 5 3 10

Estimated 24-month

rate of OS, consideringonly CML deaths, %

98.9 98.9 96.7

P-value (CML deaths) .1930 .0485

*Including deaths after discontinuation of treatment.



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Compared with imatinib, nilotinib continued to demonstrate: Significantly higher rates of MMR, CMR4, and CMR4.5 Significantly fewer progressions to AP/BC on treatment

Nilotinib demonstrated significantly higher MMR rates vs imatinib inall Sokal risk groups

Safety and efficacy of nilotinib and imatinib in elderly patients wascomparable to that in younger patients Nilotinib at both doses was generally well tolerated, and fewer

adverse events led to discontinuation in the nilotinib 300 mg BID arm

Imatinib dose escalation was not an effective strategy in mostpatients

Longer follow-up continued to demonstrate significantly higherresponse rates and significantly lower progression rates for nilotinibcompared with imatinib for the treatment of patients with newlydiagnosed Ph+ CML-CP

ENESTnd 24-Month Update



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The Incidence of BCR-ABL Mutationsin Patients With Newly DiagnosedCML-CP Treated With Nilotinib or

Imatinib in ENESTnd:

24-Month Follow-Up

Saglio G, Kantarjian HM, Reiffers J, Jootar S, Kalaycio ME,Shibayama H, Fan X, Gallagher NJ, Shou Y, Larson RA,

Hughes TP, Hochhaus A

19

Saglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502.

Abstract 6502


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Introduction

Clinical resistance to imatinib frequently results frommutations in the BCR-ABL gene All known mutations are sensitive to nilotinib, with the

exception ofT315I, E255K/V, Y253H, and F359C/V1

In ENESTnd, nilotinib demonstrated superior efficacyand significantly reduced rates of progression toaccelerated phase/blast crisis (AP/BC) over imatinib2,3

1. Hughes T, et al. J Clin Oncol. 2009;27(25):4204-4210.2. Saglio G, et al. N Engl J Med. 2010;362(24):2251-2259.3. Hughes TP, et al. Blood. 2010;116: Abstract 207.

Objectives of this analysis: Occurrence of emergent mutations ontreatment and their impact on response



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Mutational Analysis

Mutation testing schedule: Prior to the start of therapy for all patients For patients who failed to achieve MMR at 12

months

For patients with loss of MMR during study For patients with a 5-fold increase in BCR-ABL from

the lowest levels achieved on study

At end of treatment (including discontinuation)

Mutation testing was long-range PCR amplification ofBCR-ABL and direct sequencing (sensitivity, 10%-20%)

Data reported here are with a minimum follow-up of 24months



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Polymorphisms Identified at Baseline

Polymorphisms were equally distributed among the 3 arms

Sequence Variants

AllPatientsN = 846

Nilotinib

300 mgBID

n = 282

Nilotinib

400 mgBID

n = 281

Imatinib

400 mgQD

n = 283

n (%) n n n

T83T ACTACG c.252TG 1 (0.1) -- 1 --

N96S AATAGT c.290AG 1 (0.1) -- 1 --

T117T ACGACA c.344GA 1 (0.1) -- -- 1

T204T ACGACA c.615GA 1 (0.1) 1 -- --

T240T* ACGACA c.723GA 2 (0.2) 1 1 --

Y253Y TACTAT c.762CT 1 (0.1) -- -- 1

E499E* GAAGAG c.1500AG 53 (6.3) 21 17 15

All sequence variants were verified to be present in nontranslocated ABL; therefore they are polymorphisms.* T240T and E499E are previously reported polymorphisms.



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Mutations Identified During TreatmentNilotinib

300 mgBIDn = 282

Nilotinib

400 mgBIDn = 281

Imatinib

400 mgQDn = 283

Patients with any newlydetectable mutations

on treatment, n

10 8 20

Mutation category:

T315I, n 3 2 3

Less sensitive to nilotinib,* n 5 6 4

Sensitive to nilotinib, n 2 0 13

* Mutations clinically less sensitive to nilotinib included E255K/V, F359C/V, and Y253H. Mutations sensitive to nilotinib included all mutations other than less-sensitive mutations and T315I.

Twice as many patients with mutations were detected in imatinib arm during treatment The incidence of emerging mutations was comparable in both nilotinib arms Approximately 2/3 of the mutations emerging on imatinib were nilotinib-sensitive The incidence ofT315Iwas comparable in all armsSaglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502.


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Mutations Identified During Treatmentby Sokal Score

Patients With Any

Newly Detectable

Mutations on

Treatment, n Total

Nilotinib300 mg

BIDn = 10

Nilotinib400 mg

BIDn = 8

Imatinib400 mg

QDn = 20

By Sokal score group

Low, n 3 1 1 1

Intermediate, n 14 4 2 8

High, n 21 5 5 11

The majority of mutations emerged in patients with high andintermediate Sokal score



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Response Status in Patients WithNewly Detectable Mutations

*Patients were only counted once under the worst-case response category.

1. Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051.

The majority of patients with emergent mutations during treatment hadsuboptimal response or treatment failure

25

Patients With Any

Newly Detectable Mutations

on Treatment, n Total

Nilotinib300 mg

BIDn = 10

Nilotinib400 mg

BIDn = 8

Imatinib400 mg

QDn = 20

Suboptimal response,* n 10 5 1 4

Treatment failure,* n 25 4 5 16

Unconfirmed loss of

response,* n 3 1 2 0



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23

12

0

5

10

15

Mutations and Progression to AP/BC*

P

atients,n

0.7%

P = .0059 P = .0196

1.1% 4.2%

* ITT population.

Progression to AP/BC or death due to CML while on treatment.


Nilotinib significantly decreased the rate of progression to AP/BC vs imatinib Mutations account for the majority of, but not all, cases of progression

suggesting the presence of alternative mechanisms of resistance

Patients with mutation at time of

progression, n1 2 7

Type of mutation E459K Y253H/T315I, E255V M244V, Y253H,Y253H/F359I,

M351T, F359I, E459K (2)



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Mutations and Loss of CCyR*

87 85

77

0

10

20

30

40

50

60

70

80

90

100

PatientsWithCCyR,% P = .016

P = .0018


Patients with CCyR, n 245 238 218

Patients with confirmed loss ofCCyR, n

2 2 5

Patients with mutationsat loss of CCyR, n

0 2 3

Type of mutation Y253H/T315I,E255V

Y253H/F359I,M351T, E459K

n = 282 n = 281 n = 283

* ITT population. Patients later progressed to AP/BC.Saglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502.


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Mutations and Loss of MMR*

7268

46

0

10

20

30

40

50

60

70

80

PatientsWithMMR,%

* ITT population; Loss of MMR was defined as a BCR-ABL ratio > 0.1% in association with a 5-fold rise in BCR-ABL ratio, confirmed by another

PCR sample 4 weeks apart; unconfirmed loss of MMR was considered confirmed if associated with confirmed loss of CHR or CCyR; CML-related

death, or progression to AP/BC was considered confirmed loss of MMR in any case.

Patients later progressed to AP/BC.

Patients laterdiscontinued due to suboptimal response.

P


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BCR-ABL Transcript Levels Over Time in PatientsWith T315IMutations on Imatinib and Nilotinib*

0.001

0.01

0.1

1

10

100

0 12 24 36

BCR-ABL,%(IS)

Treatment Duration, months

6 18 30

C1C2

C3

Patient ID Treatment

Imatinib 400 mg QDImatinib 400 mg QD

Imatinib 400 mg QD

* Time of first detected mutation based on mutational analysis triggered per protocol.Red diamonds indicate the T315Imutation.

A1

B1

A2

A3

B2

Patient ID Treatment

Nilotinib 300 mg BIDNilotinib 300 mg BID

Nilotinib 300 mg BID



MMR



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BCR-ABL Transcript Levels Over Time in PatientsWith T315IMutations on Imatinib and Nilotinib*

0.001

0.01

0.1

1

10

100

0 12 24 36

BCR-ABL,%(IS)

Treatment Duration, months

6 18 30

MMR

All but 1 patient with the T315I mutation discontinued due tosuboptimal response or treatment failure

* Time of first detected mutation based on mutational analysis triggered per protocol.Red diamonds indicate the T315Imutation.



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Mutations and Achievement of CMR No patient with CMR4.5 exhibited a mutation and progressed to AP/

BC at any time during treatment

One patient with CMR4 exhibited a double mutation (Y253H/T315I)and progressed to AP/BC

44

26

36

2120

10

0

10

20

30

40

50

PatientsWit

hResponse,%

P


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Conclusions Twice as many patients with newly-detectable mutations were

identified in the imatinib arm compared with each nilotinibarm

Most patients who developed mutations had an intermediateor high Sokal risk score at diagnosis

Nilotinib was effective in preventing the emergence of cloneswith nilotinib-sensitive mutations Incidence of the T315Imutation was similar with nilotinib

and imatinib

Almost all patients with emergent mutations during treatmenthad suboptimal response or treatment failure Deeper molecular responses with nilotinib protect from

the development of emerging mutations and progressionto AP/BC

S G C O 2011 29( ) 6 02

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