Abstract 207

Background:

Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months.

Methods:

846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS).

Results:

With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented.

Conclusions:

With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML.

Table 1
Overall Efficacy with Median 18-Month Follow-upNilotinib 300 mg bid (n=282)Nilotinib 400 mg bid (n=281)Imatinib 400 mg qd (n=283)
MMR, % 66 62 40 
 P < .0001* P < .0001*  
by Sokal, %    
Low (n=103, n=103, n=104) 70 69 51 
Intermediate (n=101, n=100, n=101) 67 63 39 
High (n=78, n=78, n=78) 59 51 28 
BCR-ABLIS≤ 0.0032%, % 21 17 6 
 P < .0001* P < .0001*  
CCyR, % 85 82 74 
 P < .001* P=.017*  
Suboptimal response†(at 12 months), % 2 2 11 
Treatment failure†(at 12 months), % 3 2 8 
Progression to AP/BC 2 (0.7) 1 (0.4) 12 (4.2) 
Excluding clonal evolution, n (%) P=.006** P=.003**  
Including clonal evolution, n (%) 2 (0.7) 3 (1.2) 17 (6.9) 
 P <.001** P=.002**  
Total deaths, patients (n) 5 2 9 
CML-related deaths, patients (n) 2 1 8 
Estimated OS (at 18 months), % 98.5 99.3 96.9 
 P=.28** P=.03**  
Overall Efficacy with Median 18-Month Follow-upNilotinib 300 mg bid (n=282)Nilotinib 400 mg bid (n=281)Imatinib 400 mg qd (n=283)
MMR, % 66 62 40 
 P < .0001* P < .0001*  
by Sokal, %    
Low (n=103, n=103, n=104) 70 69 51 
Intermediate (n=101, n=100, n=101) 67 63 39 
High (n=78, n=78, n=78) 59 51 28 
BCR-ABLIS≤ 0.0032%, % 21 17 6 
 P < .0001* P < .0001*  
CCyR, % 85 82 74 
 P < .001* P=.017*  
Suboptimal response†(at 12 months), % 2 2 11 
Treatment failure†(at 12 months), % 3 2 8 
Progression to AP/BC 2 (0.7) 1 (0.4) 12 (4.2) 
Excluding clonal evolution, n (%) P=.006** P=.003**  
Including clonal evolution, n (%) 2 (0.7) 3 (1.2) 17 (6.9) 
 P <.001** P=.002**  
Total deaths, patients (n) 5 2 9 
CML-related deaths, patients (n) 2 1 8 
Estimated OS (at 18 months), % 98.5 99.3 96.9 
 P=.28** P=.03**  
*

CMH test stratified by Sokal vs imatinib

**

Log-rank test stratified by Sokal vs imatinib for time to AP/BC and OS

†

According to 2009 ELN criteria at 12 months for suboptimal response (PCyR) and treatment failure (less than PCyR, loss of CHR, loss of CCyR, progression to AP/BC, or clonal evolution)

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Disclosures:

Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Topics:
imatinib mesylate, leukemia, myelocytic, chronic, nilotinib, follow-up, measles-mumps-rubella vaccine, bcr-abl tyrosine kinase, cardiac mri, adverse event, surrogate endpoints, treatment failure

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Author notes

*

Asterisk with author names denotes non-ASH members.

© 2010 by The American Society of Hematology
2010
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