Nilotinib: a selective choice for resistant and intolerant patients - - PowerPoint PPT Presentation

Nilotinib: a selective choice for resistant and intolerant patients to imatinib

Massimo Breccia

Azienda Policlinico Umberto I° Università Sapienza Roma

Introduction

• Nilotinib is a rationally designed novel tyrosine kinase inhibitor

(TKI); it is highly potent and the most selective of the TKIs used to treat chronic myeloid leukemia (CML)

• Nilotinib binds to ABL with greater affinity and improved

topological fit than imatinib; it inhibits most imatinib-resistant BCR-ABL1 mutants (except T315I)

• Nilotinib is approved for the treatment of patients with

Philadelphia chromosome-positive (Ph+) CML in chronic phase (CML-CP) or accelerated phase (CML-AP) resistant to or intolerant

• f prior therapy, including imatinib

2101 STUDY

Study Design

• Phase 2, open-label, single-treatment arm
• Patient population: adults with imatinib-resistant or -intolerant Ph+ CML-CP
• Standard eligibility criteria
• QTc > 450 msec not eligible
• Nilotinib was given 400 mg orally twice daily (2 hours following meals)
• Primary endpoint: Major cytogenetic response (MCyR)
• Secondary endpoints
• Complete cytogenetic response (CCyR)
• Complete hematologic response (CHR)
• Duration of MCyR
• Progression-free Survival (PFS); progression defined as:

− Progress to AP/BC − Loss of CHR − Loss of MCyR

• OS
• Safety
• MMR: BCR-ABL1 transcript levels ≤ 0.1% according to the international scale

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

Definition of Imatinib Resistance and Intolerance

Imatinib resistance: either treatment with imatinib ≥ 600 mg/day with disease progression

(≥ 50% increase in white blood cell, blast, basophil, or platelet counts), no hematologic response in bone marrow after 4 weeks, or patients receiving < 600 mg/d with any mutations at the following amino acids: L248, G250, Q252, Y253, E255, T315, F317, H396

• Primary resistance
• No CHR at or after 3 months
• No minimal cytogenetic response (minCyR) at or after 6 months
• No MCyR at or after 12 months
• Secondary resistance
• Loss of CHR
• Loss of minCyR, loss of MCyR, loss of CCyR, or cytogenetic relapse
• Development of clonal evolution

Imatinib intolerance with resistance

• Patients without an MCyR* who discontinued for:
• Persistent grade 3/4 imatinib-related adverse event (AE), despite optimal supportive care
• Persistent grade 2 imatinib-related AE, despite optimal supportive care
• Persisting ≥ 1 month, or
• Recurring > 3 times with imatinib dose reduction

* Patients without MCyR were chosen because they were fully and appropriately assessable for the primary study endpoints.

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update

Results

• Median duration of CML was nearly 5 years
• 72% of patients received prior doses of imatinib ≥ 600 mg/day

*Intolerant patients were also resistant and were not allowed to have prior MCyR at study entry. CHR, complete hematologic response; CML, chronic myeloid leukemia; MCyR, major cytogenetic response.

Table 1. Baseline Demographics (N = 321)

Median age, years (range) 58 (21-85) Median duration of CML, months (range) 58 (5-275) Median duration of prior imatinib therapy, months (range) 32 (< 1-94) Active disease prior to therapy, n (%) 206 (64) Imatinib resistant/intolerant (%)* 70/30 Prior highest imatinib dose ≥ 600 mg/day, n (%) 232 (72) Patients with baseline CHR, n (%) 114 (36) Patients ≥ 65 years, n (%) 98 (31) Other prior therapy Hydroxyurea, n (%) 266 (83) Interferon-α, n (%) 134 (42) Cytarabine, n (%) 78 (24)

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

* Includes protocol violation, patient withdrawal of consent, lost to follow-up, reason not stated, and administrative problems.

† Includes only those patients for whom death was reported as primary reason for discontinuation of therapy.

2101 Study 24-Month Update

Patients disposition

Table 2. Patient Disposition (N = 321)

n (%) Ongoing treatment 124 (39) Discontinued treatment 197 (61) Disease progression 88 (27) Adverse event(s) 61 (19) Drug related 50 (16) Non-drug related 11 (3) Abnormal test/laboratory value 6 (2) Other* 39 (12) Death† 3 (< 1)

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update

Median dose intensity

• Median dose delivered was close to the planned dose of 800 mg/day
• Median duration of exposure was long (561 days)
• 62% of patients had nilotinib therapy ≥ 12 months and 42% ≥ 24 months at the

time of data cutoff

• The median duration of dose interruptions was short
• 73% of patients who required treatment interruptions resumed treatment after

interruption at the planned dose

*Dose interruptions defined conservatively as > 1 day of interruption regardless of reason.

Table 3. Nilotinib Exposure (N = 321)

Median duration of nilotinib, days (range) 561 (1-1096) Median dose intensity, mg/day (range) 789 (151-1110) Patients with dose interruption*, n (%) 185 (58) Median cumulative duration of dose interruption, days (range) 20 (1-345) Median percent of dose interruption, % days (range) 4 (< 1-62) Patients with dose reduction, n (%) 125 (39)

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

• Median time to CHR was 1.0 month in patients without CHR at baseline
• Median time to MCyR was 2.8 months (range, 0.9-28)
• Median time to CCyR was 3.3 months (range, 0.9-27)
• MCyR was achieved in 59% of patients, 74% of whom were CCyR

* Patients who achieved (without baseline CHR) or maintained CHR (had CHR at study entry). † Patients with no CHR at baseline. ‡ See definition of imatinib-intolerant with resistance in the Methods sections.

CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response.

2101 Study 24-Month Update

Hematologic and Cytogenetic Response in Patients With a Minimum Follow-Up of 24 Months (N = 321)

95 321 155 321 226 321 226 95 n

M CyR CCyR CH R M CyR M CyR CCyR CCyR CH R CH R

41% 44% 56% 59% 85% 72% 66% 51%

1 0 20 30 40 50 60 70 80 90 1 00

O verall* O verall I matinib R esistant I matinib I ntolerantw/ R esistance‡ O verall I matinib R esistant I matinib I ntolerantw/ R esistance‡ I matinib R esistant

†

I matinib I ntolerantw/ R esistance†,‡

90%

Pa

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update

Cytogenetic Response in Patients With and Without CHR at Baseline

• Patients entering the study with CHR at baseline had higher response rates

(MCyR, CCyR, and MMR) than those without baseline CHR

CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response.

59% 52% 73%

20 40 60 80 1 00

321 n 114 207 A ll Baseline CH R NoBaseline CH R

Patients, %

44% 58% 36%

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

• 44% of patients achieving MCyR achieved MMR
• 56% of patients achieving CCyR achieved MMR

CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response; MMR, major molecular response.

2101 Study 24-Month Update

MMR in Patients With and Without Cytogenetic Response and With and Without CHR at Baseline

44% 58% 56% 51%

W ith M C yR W ith C C yR A llpatients 28% 38% 53% 39% 22% 1 83 62 1 35 78 294 n 1 05 73 1 05 1 89 20 40 60 80 1 00

A ll Baseline CH R No Baseline CH R

Patie

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

CCyR, complete cytogenetic response.

2101 Study 24-Month Update

Duration of CCyR

P t E vt C en P atients with C C yR : 1 41 1 8 1 23 C ensored observations A t-R isk : E vents 1 41 : 0 1 27 : 4 1 1 2 : 9 92 : 1 3 53 : 1 8 0 : 1 8 1 0 20 30 40 50 60 70 80 90 1 00

W ithout ProgressionorD eath, %

3 6 9 1 2 1 5 1 8 21 24 27 30 33

M

• nths Since Complete Cytogenetic R

Pts Without Loss of Response, %

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

• Median PFS has not yet been reached for patients with CHR at baseline
• For all patients, median estimated PFS was 33.6 months
• Estimated PFS rate at 24 months was higher for patients with baseline CHR (75%)

compared with patients without CHR at study entry (48%)

• Only 9 patients (3%) progressed to AP/BC based on actual laboratory values

AP, accelerated phase; BC, blast crisis; Cen, censored; Evt, event; Pt, patient.

2101 Study 24-Month Update

Progression-Free Survival

10 20 30 40 50 60 70 80 90 100

Patients W ithout Progressionto A P/ BC, %

3 6 9 1 2 1 5 1 8 21 24 27 30 33 36

M

• nths Since Start of Treatment

P t E vt C en A llpatients: 321 94 227 C ensored

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

• Estimated OS rate at 24 months was 87%

Cen, censored; Evt, event; Pt, patient.

2101 Study 24-Month Update

Overall Survival

A t-R isk : E vents 321 : 0 31 4 : 3 294 : 1 5 274 : 27 223 : 39 0 : 44 1 0 20 30 40 50 60 70 80 90 1 00

Patients A live, %

3 6 9 1 2 1 5 1 8 21 24 27 30 33 36

M

• nths Since Start of Treatment

P t E vt C en A ll patients: 321 44 277 C ensored obse

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update

Non-hematological AEs

• Severe nonhematologic AEs were infrequent on nilotinib therapy

Table 4. Most Frequent (> 10%) Drug-Related Nonhematologic Adverse Events (N = 321)

Adverse Event All Grades (%) Grades 3/4 (%) Rash 31 2 Pruritus 26 < 1 Nausea 25 < 1 Fatigue 20 1 Headache 18 2 Diarrhea 12 2 Vomiting 13 < 1 Constipation 13 < 1

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update

Biochemical abnormalities

* Most frequent newly occurring or worsening, regardless of causality.

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

• Biochemical laboratory abnormalities were generally mild, transient, and

easily managed

• The majority of first episodes of grade 3/4 bilirubin and lipase elevations
• ccurred within the first month of therapy and were brief in duration (median

duration 15 days)

Table 5. Biochemical Laboratory Abnormalities* (N = 321)

Any (%) Grades 3/4 (%) Lipase elevation 47 18 Hypophosphatemia 55 17 Hyperglycemia 70 12 Bilirubin elevation (total) 72 7 ALT elevation 69 4 AST elevation 55 3 Hypocalcemia 51 2 Creatinine elevation 24 1 Hypomagnesemia 17 < 1

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

• Myelosuppression events were predictable and generally easily managed
• The majority of first episodes of grade 3/4 neutropenia and thrombocytopenia occurred

within the first 2 months of therapy and were relatively brief in duration – Median durations of grade 3 or 4 neutropenia and thrombocytopenia were 15 and 22 days, respectively 2101 Study 24-Month Update

Hematologic Laboratory Abnormalities*

* Most frequent newly occurring or worsening, regardless of causality.

20 40 60 80 100

P a t i e n t s , %

42 60 85.5

Grade 3/4 median

• nset (days)

22 15 8

Grade 3/4 median duration (days)

53% 53% 58% 30% 31% 11%

Anemia Neutropenia Thrombocytopenia

All grades Grade 3/4

Patients, %

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update

Safety in long-term follow-up

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

• The incidences of hepatic and pancreatic disorders on nilotinib were

1.3 and 1.7 per 100-patient years of therapy

• No cumulative risk of hepatic and pancreatic events was observed with

longer follow-up

• Discontinuations due to hepatobiliary AEs were uncommon (n = 6; 2%)

Table 6. Laboratory Abnormalities Associated With Treatment Discontinuation (N = 321)

n (%) Discontinuation Myelosuppression 24 (8) AST/ALT elevation 2 (< 1) Hyperbilirubinemia 1 (< 1) Lipase elevation or pancreatitis 4 (1)

Kantarjian HM, et al. Blood. 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update

Fluid retention/bleeding AEs

• Severe fluid retention or bleeding events were rare on nilotinib therapy

CNS, central nervous system; GI, gastrointestinal.

Table 7. Drug-Related Adverse Events Associated With Fluid Retention and Bleeding (N = 321)

All Grades n (%) Grades 3/4 n (%) Peripheral edema 20 (6) 0 (0) Pericardial effusion 2 (< 1) 1 (< 1) Pleural effusion 4 (1) 1 (< 1) Pulmonary edema 1 (< 1) 1 (< 1) CNS bleeding 1 (< 1) 1 (< 1) GI bleeding 3 (< 1) 1 (< 1)

Radich JP, et al. Blood. 2009;114(22):464-465. Abstract # 1130.

2101 CP/AP Mutations 24-Month Update

Cumulative Incidence of CCyR Achieved Over Time, by Mutation Type (CML-CP)

• Majority of responding patients achieved CCyR within 9 months of therapy
• No patients with Y253H, E255K/V, or F359C/V mutations achieved CCyR within the

first 12 months

• 1 patient with the E255K mutation did achieve CCyR at 16.6 months
• Rate of CCyR achievement over time was similar in patients with no mutations and

patients with all other mutations

5 1 0 1 5 20 25 30 35 40 45 50

Cumulative I ncidence of CCyR, %

3 6 9 1 2 1 8 24

D utationof Therapy( months)

N

• mutation

( n = 91 S ensitive mutations ( n = 78) Y 253H , E 255K / V , F 359C / V mutat

Radich JP, et al. Blood. 2009;114(22):464-465. Abstract # 1130.

2101 CP/AP Mutations 24-Month Update

Cumulative Incidence of MMR Achieved Within Different Durations of Nilotinib Therapy, by Mutation Type (CML-CP)

• Majority of responding patients achieved MMR within 9 months of therapy
• MMR was achieved within 12 months of treatment in 29% of patients with no

mutation, 26% of patients with all other mutations, and no patients with Y253H, E255K/V, or F359C/V mutations

• Median time to MMR was 5.6 months in patients with no mutations and patients with

all other mutations

5 1 0 1 5 20 25 30 35

Cumulative I ncidence of M M R, %

3 6 9 1 2 1 8 24

D utationof Therapy( months)

N

• mutation

( n = 91 ) S ensitive mutations ( n = 78) Y 253H , E 255K / V , F 359C / V mutat

Radich JP, et al. Blood. 2009;114(22):464-465. Abstract # 1130.

• The median EFS was not reached in patients with no mutation
• The median EFS was not reached in patients with all other mutations, while patients with E255K/V,

Y253H, and F359C/V mutations had median EFS of 5.6 months

• At 24 months, the estimated rate of EFS was 62% for patients with no mutations, 55% for patients

with all other mutations, and 7% for patients with E255K/V, Y253H, and F359C/V mutations

2101 CP/AP Mutations 24-Month Update

Event-free Survival in Patients With Imatinib-Resistant CML-CP According to Baseline Mutation Type

1 0 20 30 40 50 60 70 80 90 1 00

W ithoutEvent, %

1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 20 21 22 23 24

M

• nths Since Startof Treatment

N

• mutation (

n = 91 ) S ensitive mutations ( n = 78) Y 253H , E 255K / V , F 359C / V mutations ( n = 27) C ensored observations ( n = 56

Branford S, et al. Blood. 2009;114(22):1275-1276. Abstract # 3292.

2101 3-Month PCR Subanalysis

Time to CCyR by BCR-ABL Ratio at 3 Months in Imatinib-Resistant Patients (ITT Population)

> 1%-10% (n = 30) > 10% (n = 93) P < .001 10 20 30 40 50 60 70 80 90 100 3 6 9 12 15 18 21 24 27 30 33 36 39

Months Since Start of Treatment Patients in CCyR, %

Branford S, et al. Blood. 2009;114(22):1275-1276. Abstract # 3292.

2101 3-Month PCR Subanalysis

Time to MMR by BCR-ABL Ratio at 3 Months for Imatinib-Resistant Patients (ITT Population)

> 0.1%-1% (n = 16) > 1%-10% (n = 40) > 10% (n = 94) = Censored observations P = .011 10 20 30 40 50 60 70 80 90 100

P a t i e n t s W h

• R

e s p

• n

d e d , %

6 12 18 24

Months Since Start of Treatment

P = .002

Patients Who Responded, %

Branford S, et al. J Clin Oncol. 2010;28(15S):490s [abstract 6513]. Hughes TP, et al. Haematologica. 2010;95(s2):54 [abstract 0135].

• There was a significantly improved probability of achieving a CCyR in

patients with BCR-ABL (IS) of ≤ 10% after 1 month of nilotinib treatment

Study 2101 1-Month PCR Analysis

Time to First CCyR for All Patients by BCR-ABL Ratio at 1 Month

Patients Achieving CCyR (%)

100 80 60 40 20 3 6 9 12 15 21 30 39

> 1%-10% (n = 38) > 10% (n = 203)

18 24 27 33 36

Months Since Start of Treatment

90 70 50 30 10

P < .001

ENACT

400 800 Planned Dose CML-CP CML-AP CML-BC

800 783 779 773

Median Dose (mg/day)

ENACT: Final Overall Safety Analysis of 1793 Patients

Median Dose Intensity of Nilotinib Therapy

• Median dose intensity was similar among patients with all phases of CML and was 781 mg/day
• verall
• Median duration of exposure to nilotinib was:
• CML-CP: 266 days (range, 1-807)
• CML-AP: 160 days (range, 6-736)
• CML-BC: 78 days (range, 1-642)
• Patients with duration of exposure ≥12 months: 36.4% in CP, 25.4% in AP and 6.8% in BC
• Patients with duration of exposure < 6months: 36.9% in CP, 54.2% in AP and 78.9% in BC

Nicolini F, et al. Haematologica. 2009;94(s2):255-256.

CML-CP (n = 1422) CML-AP (n = 181) CML-BC (n = 190) Myelosuppression All Grades n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%) Thrombocytopenia 448 (32) 337 (24) 87 (48) 75 (41) 80 (42) 66 (35) Neutropenia 265 (19) 41 (23) 49 (27) 41 (23) 55 (29) 53 (28) Anemia 150 (11) 45 (3) 30 (17) 21 (12) 32 (17) 21 (11)

ENACT: Final Overall Safety Analysis of 1793 Patients

Drug-Related Myelosuppression

Nicolini F, et al. Haematologica. 2009;94(s2):255-256.

• The most frequent grade 3/4 hematologic AEs were thrombocytopenia

and neutropenia

CML-CP (n = 1422) CML-AP (n = 181) CML-BC (n = 190) Adverse Event All Grades n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%) Hyperbilirubinemia 356 (25) 59 (4) 39 (22) 9 (5) 45 (24) 11 (6) ALT elevation 193 (14) 30 (2) 15 (8) 1 (1) 14 (7) 1 (1) Lipase elevation 180 (13) 89 (6) 10 (6) 6 (3) 8 (4) 7 (4) AST elevation 121 (9) 12 (1) 7 (4) 1 (1) 9 (5) 0 (0) Hypophosphatemia 58 (4) 1 (< 1) 7 (4) 3 (2) 5 (3) 0 (0)

ENACT: Final Overall Safety Analysis of 1793 Patients

Top Five Drug-Related Biochemical Laboratory Abnormalities

Nicolini F, et al. Haematologica. 2009;94(s2):255-256. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

• Most biochemical lab abnormalities were mild, manageable, and not clinically relevant
• Grade 3/4 lipase elevation occurred in 5.7% of patients, but only 5 patients (0.3%)

discontinued therapy because of lipase elevation

• There was no difference between proportion of AEs between patients with imatinib

resistance and those with imatinib intolerance

CML-CP (n = 1422) CML-AP (n = 181) CML-BC (n = 190) Abnormality, n (%) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Rash 349 (25) 38 (3) 37 (20) 3 (2) 40 (21) 2 (1) Headache 233 (16) 27 (2) 20 (11) 2 (1) 16 (8) 3 (2) Nausea 165 (12) 12 (1) 23 (13) 0 (0) 16 (8) 0 (0) Myalgia 133 (9) 11 (1) 12 (7) 1 (1) 14 (7) 1 (1) Fatigue 121 (9) 14 (1) 12 (7) 1 (1) 9 (5) 0 (0) Vomiting 105 (7) 11 (1) 11 (6) 1 (1) 11 (6) 1 (1)

ENACT: Final Overall Safety Analysis of 1793 Patients

Most Frequent Nonhematologic Drug- Related AEs (≥ 5% in All Groups)

• Nonhematologic AEs were mostly grade 1/2
• Grade 3/4 AEs were infrequent and included rash, headache, and nausea
• Dose interruptions or reductions were sufficient to manage most AEs
• There was no difference in the proportion of AEs between patients with imatinib resistance and those with

imatinib intolerance

• Pleural or pericardial effusions were reported in 1.89% of all patients (34 out of 1793); 0.2% were grade 3

and 4

• Pancreatitis was reported in 1.3% of all patients (24 out of 1893); 0.5% were grade 3/4 (9 patients),

but only 4 patients discontinued treatment because of this AE

Nicolini F, et al. Haematologica. 2009;94(s2):255-256.

le Coutre PD, et al. Blood. 2009;114(22):457. .Abstract # 1115.

ENACT AEs

Successful Nilotinib Dose Re-Escalation Following Resolution of AEs

• Per protocol, if the reason for dose reduction was an AE, patients were allowed to re-

escalate the dose to 400 mg twice daily once the AE was resolved to grade ≤ 1

• The majority (87%) of patients who attempted to re-escalate after a dose decrease did

so successfully

• In 13% of patients where dose re-escalation was not successful, the reason for

subsequent dose modifications could be the same or a different AE

*Successful dose re-escalation defined as maintenance of 800 mg/day nilotinib for at least a month with no subsequent treatment reductions or interruptions > 5 days.

87% 13%

S uccessful re-escalation* D

• se re-escalation not successfu

le Coutre PD, et al. Blood. 2009;114(22):1272-1273. Abstract # 3286.

ENACT Elderly

Elderly patients

Table 1. Patient Demographics and Baseline Disease Characteristics

< 60 Years n = 970 ≥ 60 Years n = 452 ≥ 70 Years n = 165 Percentage from total patients, % 68 32 12 Median age, years (range) 46 (17-59) 67 (60-85) 74 (70-85) Male, n (%) 484 (50) 212 (47) 88 (53) Median duration of CML, months (range) 51 (2-256) 69 (4-328) 67 (4-328) < 6 months, % 2 3 4 ≥ 6 months - < 1 year, % 7 5 5 ≥ 1 - < 2 years, % 16 13 14 ≥ 2 - < 5 years, % 31 24 25 ≥ 5 years, % 43 56 52 Imatinib resistant/intolerant, % 63/36 50/49 48/51

le Coutre PD, et al. Blood. 2009;114(22):1272-1273. Abstract # 3286.

ENACT Elderly

Efficacy in elderly patients

• Efficacy was similar in all patients regardless of age
• 77% of patients ≥ 60 years who achieved MCyR also achieved CCyR

(141 of 183)

• 84% of patients ≥ 70 years who achieved MCyR also achieved CCyR

(54 of 64)

CCyR, complete cytogenetic response; MCyR, major cytogenetic response.

Table 6. Cytogenetic Responses

< 60 Years n = 970 n (%) ≥ 60 Years n = 452 n (%) ≥ 70 Years n = 165 n (%) MCyR 458 (47) 183 (40) 64 (39) CCyR 345 (36) 141 (31) 54 (33)

le Coutre PD, et al. Blood. 2009;114(22):1272-1273. Abstract # 3286.

ENACT Elderly

Non-hematological toxicity in elderly

• Grade 3/4 nonhematologic AEs were similar in elderly patients

compared with younger patients

• 7 out of 8 elderly patients with pleural effusion on dasatinib no longer

had it on nilotinib

Table 7. Most Frequent Grade 3/4 Nonhematologic Drug-Related Adverse Events

Grade 3/4 Adverse Event, % < 60 Years n = 970 ≥ 60 Years n = 452 ≥ 70 Years n = 165 Headache 2.2 1.3 1.8 Rash 2.5 3.1 3.0 Fatigue 1.4 2.0 1.8 Vomiting 0.9 0.4 1.2 Myalgia 0.9 0.9 0.6 Nausea 0.7 1.1 1.2

le Coutre PD, et al. Blood. 2009;114(22):1272-1273. Abstract # 3286.

ENACT Elderly

Drug-Related Myelosuppression

• The occurrence of grade 3/4 drug-related myelosupression was similar

between the elderly and younger patients

4 4 15 14 11

≥ 60 Y rs ( n = 452) ≥ 70 Y rs ( n = 1 65) < 60 Y rs ( n = 970) 3 24 21 21

A nemia Neutropenia Thrombocytopenia

1 0 30 20 40 50

% of Patients

le Coutre PD, et al. Blood. 2009;114(22):1272-1273. Abstract # 3286.

• The median dose of nilotinib treatment delivered was close to the planned dose of

800 mg/day in all patients regardless of age

• This was achieved despite the fact that dose escalation above 400 mg twice daily

was not permitted in the protocol ENACT Elderly

Dose Intensity in elderly patients

200 1 00 300 400 500 800 700 600

<60 ( n=970) ≥60 ( n=452) Planneddose 800 mg/ day ≥70 ( n=165)

789 749 775

Nilot

le Coutre PD, et al. Blood. 2009;114(22):1272-1273. Abstract # 3286.

1 0 20 30 40 50 60 70 80 90 1 00

Progression-Free Survival, %

5 1 0 1 5 20 25

M

• nths Since FirstD

ayof StudyD rug

< 60 Y ears ≥ 60 Y e

• PFS was 85% at 12 months and 81% at 24 months in patients ≥ 60 years

ENACT Elderly

Progression-Free Survival in Elderly Patients

• 1. The Kaplan-Meier curve displays the proportion of patients without progression to AP/BC or death among patients at risk of progression to

AP/BC or death (survival rate). The number of patients at risk of progression to AP/BC or death at a given time point decreases as patients progress, die or were censored.

• 2. The KM estimates of progression-free survival may be subject to bias due to curtailed follow-up of patients who discontinued the study drug

early and variable lengths of study drug administration for patients who completed the study.

le Coutre PD, et al. Blood. 2009;114(22):1272-1273. Abstract # 3286.

1 0 20 30 40 50 60 70 80 90 1 00

O verallSurvival, %

5 1 0 1 5 20 25

M

• nths Since FirstD

ayof StudyD rug

< 60 Y ears ≥ 60 Y ear

• OS was 98% at 12 months and 96% at 24 months in patients ≥ 60 years

ENACT Elderly

Overall Survival in Elderly Patients

• 1. The Kaplan-Meier curve displays the proportion of patients without death (survival rate). The number of patients at risk of death at a given time

point decreases as patients progress, die or were censored.

• 2. The KM estimates of overall survival may be subject to bias due to curtailed follow-up of patients who discontinued the study drug early and

variable lengths of study drug administration for patients who completed the study.

• The response and outcomes of patients treated with nilotinib was higher

in patients with CHR at baseline, suggesting these patients may have a more favorable response to second-generation tyrosine kinase inhibitors (TKIs)

• Long-term safety profile of nilotinib remains consistent with phase 2

studies and nilotinib therapy continued to be well-tolerated with long-term follow-up

• Resistant patients with mutations (excluding E255K/V, Y253H, F359C/V)

treated with nilotinib achieved rapid and durable cytogenetic responses

• Rapid reduction of BCR-ABL ratio is important for optimal response and

long-term outcome

• Nilotinib induced comparable clinical responses in CML-CP patients

regardless of age

Conclusions

Rescue

Baccarani M, et al. Haematologica. 2010;95(s2):53 [abstract 0132].

• The majority (57%) of patients with assessments at 3 months had a response better

than ELN suboptimal response at 3 months on nilotinib and achieved a PFS of 93% at 12 months and 79% at 24 months Study 2101 ELN PFS Analysis

PFS by ELN 2009 Response Recommendations at 3 Months (ITT Population)

Months Since Start of Treatment

100 80 60 40 20 9 24 33

Patients Without Progression, %

3 6 12 15 21 27 30 36 39 Better than suboptimal 90 70 50 30 10 18 Suboptimal Treatment failure P = .018 P < .001

Baccarani M, et al. Haematologica. 2010;95(s2):53 [abstract 0132].

• At 6 months, few patients (14%) were considered ELN suboptimal responders and had a PFS rate of

89% at 12 months, while those who failed treatment had a PFS rate of 82%. At 24 months, the rate for these groups decreased to 71% and 51%, respectively

• Patients who were considered better-than-suboptimal responders had PFS rates of 100% and 86% at

12 and 24 months, respectively

Study 2101 ELN PFS Analysis

PFS by ELN 2009 Response Recommendations at 6 Months (ITT Population)

100 80 60 40 20 9 24 33

Patients Without Progression, % Months Since Start of Treatment

3 6 12 15 21 27 30 36 39 Better than suboptimal 90 70 50 30 10 18 Suboptimal Treatment failure P < .001 P = .038

le Coutre PD, et al. Blood. 2009;114(22):457. .Abstract # 1115.

• 1. Treatment duration was calculated as days from the first dose date until 28 days after the final dose date.
• 2. An AE was considered to have occurred in the second period if: (a) it was a “new” AE and started in the second period or (b) it was

a “carryover” AE and started in the first period and continued into the second period.

• The percentage of patients treated for at least 180 days (n=970) with at least one AE decreased over time from

35.6% in the first 90 days of treatment to 18.7% in the second 90 days of treatment

• Of the 18.7% of patients with an AE that occurred in the second 90 days:
• 12.8% had a new occurrence of an AE
• 8.4% had “carryovers” of AEs that began in the first period
• 2.5% had both new and carryover AEs
• Similar trends were observed when looking at all treated patients (N=1422), regardless of treatment duration

ENACT AEs

Percentage of Patients With at Least One AE Suspected of Being Study-Drug Related and Grade 3/4

T

• tal: 1 8.7%

Both: 2.5%

S econd 90 D ays n = 970

T

• tal: 38.5%

F irst 90 D ays N = 1 422

T

• tal: 21 .1 %

S econd 90 D ays n = 1 230

T

• tal: 35.6%

A llC M L

• C

Ppatients treated ≥ 1 80 days

F irst 90 D ays n = 970

1 0 30 20 40 50

Percentage of Patients

N ew 1 2.8% C arryover 8.4% A lltreated C M L

• C

Ppati