Professional Documents
Culture Documents
Asco CSP Cml-Slides
Asco CSP Cml-Slides
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
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.
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
* 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.
n Nilotinib 300 mg BID 282 Nilotinib 400 mg BID 281 Imatinib 400 mg QD 283 By 12 months 55%, P<.0001
67%, P<.0001
23%-27%
51%, P<.0001
24%-28%
27%
44%
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
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.
70 60 50 40 30 20 10 0
71
67
72 61 44 46
71
67
44
65 years
253
248
36
65 years
28
35
282
Overall
281
283
Imatinib 400 mg QD
Data cutoff: 20Aug2010
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
sensitive measure of leukemic burden available. IS, International Scale Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.
20 15 10 5 0 2
0.7%
17 12
Percentage
3
1.1% 4.2%
5 2
0.7% 1.8% 6.0%
* Defined
PFS on Treatment*
Nilotinib 300 mg BID n = 282 Number of events Estimated 24-month rate of PFS, % P value
* Progression
5 98.0 .0736
Fluid retention Diarrhea Headache Muscle spasm Any grade Nausea Pruritus Rash Vomiting Anemia Grade 3/4 Neutropenia Thrombocytopenia
-0.5
0.1
0.2
0.3
0.4
0.5
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
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
Nilotinib 400 mg BID n = 281 3 Gastric cancer 6 weeks after stopping nilotinib
in survival follow-up
Suicide
on treatment
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 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
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.
All sequence variants were verified to be present in nontranslocated ABL; therefore they are polymorphisms. * T240T and E499E are previously reported polymorphisms.
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
Total
The majority of mutations emerged in patients with high and intermediate Sokal score
*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
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)
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.
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.
Imatinib 400 mg QD
P<.0001
80
72
70 60 50 40 30 20 10 0
Percentage
46
n = 282 203 7 0
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.
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
* 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
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.
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 = 282 n = 281
n = 283
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.