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

Comparison of Nilotinib and Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CMLCP): ENESTnd 24-Month Follow-Up
Abstract 6511

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

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

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 in ENESTnd, 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 blastic phases 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 Philadelphia chromosome-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.

Study Design and Endpoints

N = 846 217 centers 35 countries
R A N D O M I Z E D *

Nilotinib 300 mg BID (n = 282)

Nilotinib 400 mg BID (n = 281)

Imatinib 400 mg QD (n = 283) Follow-up; 5 years

MMR at 12 months MMR and CCyR beyond 12 months, time to MMR and CCyR, event-free survival (EFS), progression-free survival (PFS), time to AP/BC, overall survival (OS)

Primary endpoint: Secondary endpoints:

* Stratification by Sokal risk score.

The ENESTnd trial met its primary endpoint of MMR at 12 months in patients treated with nilotinib 300 and 400 mg BID vs imatinib (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.

Patient Disposition
Nilotinib 300 mg BID n = 282
Still on study*, % Still on core or extension treatment, % Still on core treatment, % Discontinued core treatment without entering extension study, % Disease progression Suboptimal response (SoR)/ treatment failure (TF) , Toxicity Death Other reason Discontinued core treatment and entered extension study, % Disease progression# Suboptimal response/ treatment failure# Discontinued extension treatment, % 93 79 74 18 <1 1 9 1 6 7 0 7 2

Nilotinib 400 mg BID n = 281

95 78 78 21 1 1 13 <1 5 <1 0 <1 <1

Imatinib 400 mg QD n = 283

92 75 67 22 4 2 10 0 5 11 <1 10 3

* 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 allowed to enter extension for SoR and/or TF while nilotinib 400 mg BID patients remained on treatment for SoR and allowed to enter extension only for TF.

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

Data cutoff: 20Aug2010

Cumulative Incidence of MMR*

100 90 80 70 60 50 40 30 20 10 0
0 3 6 9 12 15 18 21 24 27 30 33

Patients With MMR, %

n Nilotinib 300 mg BID 282 Nilotinib 400 mg BID 281 Imatinib 400 mg QD 283 By 12 months 55%, P<.0001

By 24 months 71%, P<.0001

67%, P<.0001

23%-27%
51%, P<.0001

24%-28%
27%

44%

Time Since Randomization, months

* Intent-to- treat (ITT) population used for all efficacy analyses. Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.

MMR Rates by 24 Months According to Sokal Risk*

P = .003
P = .002

P<.0001

80
Patients With MMR, %

73

74

74 67

P = .0008

P<.0001
P = .002

70 60

65 56

53 44

50
40

32

30
20 10

n=

Low Sokal

103

103

104

Intermediate Sokal
Nilotinib 400 mg BID

101

100

101

High Sokal

78

78

78

Nilotinib 300 mg BID

Imatinib 400 mg QD

* P values are provided for descriptive purposes only and are not adjusted for multiple comparisons. Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.

MMR Rates by 24 Months According to Age

80
Patients With MMR, %

70 60 50 40 30 20 10 0

71

67

72 61 44 46

71

67

44

n = 246 Age = <

65 years

253

248

36

65 years

28

35

282

Overall

281

283

Nilotinib 300 mg BID

Nilotinib 400 mg BID

Imatinib 400 mg QD
Data cutoff: 20Aug2010

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

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

P<.0001

Patients With Response, %

50 40 30 20 10 0

44

P<.0001 P<.0001

36 26 20

P = .0004

Percentage

21 10

n = 282

n = 281

n = 283

n = 282

n = 281

n = 283

BCR-ABL (IS) 0.01%

(4-log reduction: CMR4)
Nilotinib 300 mg BID
* Most

BCR-ABL (IS) 0.0032%

(4.5-log reduction: CMR4.5)
Imatinib 400 mg QD
Data cutoff: 20Aug2010

Nilotinib 400 mg BID

sensitive measure of leukemic burden available. IS, International Scale Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.

Progression to AP/BC on Treatment*

25
Number of Patients
P = .0059 P = .0196 P = .0003 P = .0089

20 15 10 5 0 2
0.7%

17 12

Percentage

3
1.1% 4.2%

5 2
0.7% 1.8% 6.0%

Including Clonal Evolution

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
Data cutoff: 20Aug2010 as progression to AP/BC or death due to CML while on treatment.

* Defined

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

PFS on Treatment*
Nilotinib 300 mg BID n = 282 Number of events Estimated 24-month rate of PFS, % P value
* Progression

Nilotinib 400 mg BID n = 281 4 97.7 .0437

Imatinib 400 mg QD n = 283 12 95.2

5 98.0 .0736

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

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

Data cutoff: 20Aug2010

Outcome After Imatinib Dose Escalation to 800 mg/day

Dose escalation* occurred in 82 of 280 patients (29%) treated with imatinib after a median of 14 months (range, 3-31 months)
Median time on treatment after dose escalation, 9 months (range, <1-28 months)

Outcome after dose escalation (n = 82 patients)

21 (26%) achieved MMR 14 (17%) achieved CCyR without MMR 47 (57%) had no improvement in response 36 (44%) required dose reduction/interruption

37 of 82 patients (45%) discontinued after dose escalation

23 (28%) due to SoR/TF 6 (7%) due to intolerance 3 (4%) due to disease progression 5 (6%) due to other reasons
* Dose escalation occurred in patients with SoR/TF on imatinib (according to modified European LeukemiaNet criteria). Among the 47 (57%) patients without any improvement after dose escalation, 6 remained on imatinib 800 mg/day for < 6 months after dose escalation. All 6 patients had CCyR before dose escalation. The remaining 41 patients remained on imatinib 800 mg/day for > 6 months (n = 14) or discontinued without an improvement (n = 27). Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511. Data cutoff: 20Aug2010

Study Drug-Related Adverse Events and Grade 3/4 Myelosuppression

Favors imatinib Favors nilotinib (300 mg BID)

Fluid retention Diarrhea Headache Muscle spasm Any grade Nausea Pruritus Rash Vomiting Anemia Grade 3/4 Neutropenia Thrombocytopenia
-0.5

Rate difference (imatinib - nilotinib) with 95% CI

-0.4 -0.3 -0.2 -0.1 0

0.1

0.2

0.3

0.4

0.5

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

Data cutoff: 20Aug2010

Study Drug-Related Fluid Retention Events (All Grades)

Favors imatinib Favors nilotinib (300 mg BID)

Peripheral edema Eyelid edema Periorbital edema Face edema Pericardial effusion Pleural effusion -0.3 -0.2 -0.1 0 0.1 0.2 0.3
Data cutoff: 20Aug2010

Rate difference (imatinib - nilotinib) with 95% CI

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

Grade 3/4 Myelosuppression and Biochemical Abnormalities by Age

Nilotinib Nilotinib Imatinib 300 mg BID 400 mg BID 400 mg QD < 65 y 65 y < 65 y 65 y < 65 y 65 y (n = 244) (n = 35) (n = 252) (n = 25) (n = 244) (n = 36) Hematologic, % Anemia Neutropenia Thrombocytopenia Selected biochemical abnormalities, % Lipase ALT Total bilirubin Glucose

4 14 12

3 0 0

4 12 13

0 0 4

5 22 9

8 17 6

7 5 4 4

11 0 0 23

7 10 8 4

16 8 12 16

3 2 <1 0

6 3 0 0

Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511. Data cutoff: 20Aug2010

Deaths Unrelated to CML Progression

Nilotinib 300 mg BID n = 282 Deaths unrelated to CML (n = 8) 4 Ileus
on treatment

Nilotinib 400 mg BID n = 281 3 Gastric cancer 6 weeks after stopping nilotinib
in survival follow-up

Imatinib 400 mg QD n = 283 1 Renal failure

in survival follow-up

Suicide
on treatment

Septic shock 9 months after stopping nilotinib

in survival follow-up

Perisurgical myocardial infarction

on treatment

Death (unknown cause)

on treatment

Pneumonia 19 months after stopping nilotinib

in survival follow-up

New cases in second year are in yellow.

Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511. Data cutoff: 20Aug2010

Overall Survival*
Nilotinib 300 mg BID n = 282 Total number of deaths Estimated 24-month rate of OS, % P-value (OS) Unrelated to CML Related to CML Estimated 24-month rate of OS, considering only CML deaths, % P-value (CML deaths)
*Including

Nilotinib 400 mg BID n = 281 6 97.8 .2125 3 3 98.9 .0485

Imatinib 400 mg QD n = 283 11 96.3 1 10 96.7

9 97.4 .6485 4 5 98.9 .1930

deaths after discontinuation of treatment. Data cutoff: 20Aug2010

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

ENESTnd 24-Month Update

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 in all Sokal risk groups Safety and efficacy of nilotinib and imatinib in elderly patients was comparable 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 most patients Longer follow-up continued to demonstrate significantly higher response rates and significantly lower progression rates for nilotinib compared with imatinib for the treatment of patients with newly diagnosed Ph+ CML-CP
Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.

The Incidence of BCR-ABL Mutations in Patients With Newly Diagnosed CML-CP Treated With Nilotinib or Imatinib in ENESTnd: 24-Month Follow-Up
Abstract 6502
Saglio G, Kantarjian HM, Reiffers J, Jootar S, Kalaycio ME, Shibayama H, Fan X, Gallagher NJ, Shou Y, Larson RA, Hughes TP, Hochhaus A

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

1 9

Introduction
Clinical resistance to imatinib frequently results from mutations in the BCR-ABL gene All known mutations are sensitive to nilotinib, with the exception of T315I, E255K/V, Y253H, and F359C/V1 In ENESTnd, nilotinib demonstrated superior efficacy and significantly reduced rates of progression to accelerated phase/blast crisis (AP/BC) over imatinib2,3

Objectives of this analysis: Occurrence of emergent mutations on treatment and their impact on response
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. Saglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502.

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 of BCR-ABL and direct sequencing (sensitivity, 10%-20%) Data reported here are with a minimum follow-up of 24 months
Saglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502.

Polymorphisms Identified at Baseline

Sequence Variants
T83T N96S T117T T204T T240T * Y253Y E499E* ACTACG AATAGT ACGACA ACGACA ACGACA TACTAT GAAGAG c.252TG c.290AG c.344GA c.615GA c.723GA c.762CT c.1500AG

All Patients N = 846

n (%) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 2 (0.2) 1 (0.1) 53 (6.3)

Nilotinib 300 mg BID n = 282

n ---1 1 -21

Nilotinib 400 mg BID n = 281

n 1 1 --1 -17

Imatinib 400 mg QD n = 283

n --1 --1 15

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

Polymorphisms were equally distributed among the 3 arms

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

Mutations Identified During Treatment

Nilotinib 300 mg BID n = 282
Patients with any newly detectable mutations on treatment, n Mutation category: T315I, n Less sensitive to nilotinib,* n Sensitive to nilotinib, n
* Mutations Mutations

Nilotinib 400 mg BID n = 281

8

Imatinib 400 mg QD n = 283

20

10

3 5 2

2 6 0

3 4 13

clinically less sensitive to nilotinib included E255K/V, F359C/V, and Y253H. 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 of T315I was comparable in all arms

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

Mutations Identified During Treatment by Sokal Score

Patients With Any Newly Detectable Mutations on Treatment, n By Sokal score group Low, n Intermediate, n High, n 3 14 21 1 4 5 1 2 5 1 8 11 Nilotinib 300 mg BID n = 10 Nilotinib 400 mg BID n=8 Imatinib 400 mg QD n = 20

Total

The majority of mutations emerged in patients with high and intermediate Sokal score

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

Response Status in Patients With Newly Detectable Mutations

Patients With Any Newly Detectable Mutations on Treatment, n Suboptimal response,* n Treatment failure,* n Unconfirmed loss of response,* n Total 10 25 3 Nilotinib Nilotinib 300 mg 400 mg BID BID n = 10 n=8 5 4 1 1 5 2 Imatinib 400 mg QD n = 20 4 16 0

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

The majority of patients with emergent mutations during treatment had suboptimal response or treatment failure
1. Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051. Saglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502. 2 5

Mutations and Progression to AP/BC*

Nilotinib 300 mg BID
15

Nilotinib 400 mg BID P = .0059 P = .0196

Imatinib 400 mg QD

12

Percentage Patients, n

10

5 2 0
0.7% 1
E459K

3
1.1% 2
Y253H/T315I, E255V

4.2% 7
M244V, Y253H, Y253H/F359I, M351T, F359I, E459K (2)

Patients with mutation at time of progression, n Type of mutation

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
* ITT population. Progression to AP/BC or death due to CML while on treatment. Saglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502.

Mutations and Loss of CCyR*

Nilotinib 300 mg BID Nilotinib 400 mg BID P = .0018 Patients With CCyR, %
100 90 80 70 60 50 40 30 20 10 0
Patients with CCyR, n Patients with confirmed loss of CCyR, n Patients with mutations at loss of CCyR, n Type of mutation

Imatinib 400 mg QD

87

85

P = .016
77

n = 282 245 2 0

n = 281 238 2 2
Y253H/T315I, E255V

n = 283 218 5 3
Y253H/F359I, M351T, E459K

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

Mutations and Loss of MMR*

Nilotinib 300 mg BID Nilotinib 400 mg BID
P<.0001
68

Imatinib 400 mg QD

P<.0001
80

Patients With MMR, %

72

70 60 50 40 30 20 10 0

Percentage

46

n = 282 203 7 0

n = 281 192 6 2 Y253H/T315, E255V

n = 283 131 7 3 M244V, T315I, H396R/M351T

Patients with MMR, n Patients with confirmed loss of MMR, n Patients with mutations at loss of MMR, n Type of mutation

Of patients who achieved MMR, 3% treated with nilotinib and 5% treated with imatinib lost MMR In most cases (12/20, 60%), patients who lost MMR regained response
* 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 later discontinued due to suboptimal response.

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

BCR-ABL Transcript Levels Over Time in Patients With T315I Mutations on Imatinib and Nilotinib*
100 10 1 0.1 0.01 0.001 0 6 Patient ID A1 A2 A3 B1 B2 12 Treatment Nilotinib 300 mg BID Nilotinib 300 mg BID Nilotinib 300 mg BID Nilotinib 400 mg BID Nilotinib 400 mg BID 18 24 Patient ID C1 C2 C3 30 Treatment Imatinib 400 mg QD Imatinib 400 mg QD Imatinib 400 mg QD 36

BCR-ABL, % (IS)

MMR

Treatment Duration, months

* Time of first detected mutation based on mutational analysis triggered per protocol. Red diamonds indicate the T315I mutation. Saglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502.

BCR-ABL Transcript Levels Over Time in Patients With T315I Mutations on Imatinib and Nilotinib*
100 10 1 0.1 0.01 0.001 0 6 12 18 24 30 36

BCR-ABL, % (IS)

MMR

Treatment Duration, months

All but 1 patient with the T315I mutation discontinued due to suboptimal response or treatment failure
* Time of first detected mutation based on mutational analysis triggered per protocol. Red diamonds indicate the T315I mutation.

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

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
Rates of CMR4 and CMR4.5 at any Time
Nilotinib 300 mg BID
Percentage Patients With Response, %

Nilotinib 400 mg BID

Imatinib 400 mg QD

P<.0001

50 40 30 20 10 0

44

P<.0001 36

P<.0001 P = .0004

26 20 21 10

n = 282

n = 281 n = 283 CMR4)

n = 282 n = 281

n = 283

BCR-ABL (IS) 0.01%

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

BCR-ABL (IS) 0.0032%

(4.5-log reduction: CMR4.5)

Conclusions
Twice as many patients with newly-detectable mutations were identified in the imatinib arm compared with each nilotinib arm Most patients who developed mutations had an intermediate or high Sokal risk score at diagnosis Nilotinib was effective in preventing the emergence of clones with nilotinib-sensitive mutations Incidence of the T315I mutation was similar with nilotinib and imatinib Almost all patients with emergent mutations during treatment had suboptimal response or treatment failure Deeper molecular responses with nilotinib protect from the development of emerging mutations and progression to AP/BC
Saglio G, et al. J Clin Oncol. 2011;29(suppl): Abstract 6502.