ENESTnd 5-year Update: Long-term Outcomes of CML Patients in Chronic Phase Treated with Frontline Nilotinib (NIL) versus Imatinib

Clinical Expert Commentaries published on June 13, 2014
Download Transcript Download Audio
ENESTnd 5-year Update: Long-term Outcomes of CML Patients in Chronic Phase Treated with Frontline Nilotinib (NIL) versus Imatinib

Hi, I am Dr. Stuart Goldberg from the John Theurer Cancer Center, and I am here with ManagingCML.com. I am at the 2014 American Society of Clinical Oncology meetings where we are now presenting the 5-year data on the ENESTnd trial. This was a randomized trial of imatinib versus nilotinib at two different doses, 400 mg and 300 mg. Well, similar to other meetings and other presentations, nilotinib is beating our old friend imatinib. We have seen more patients on the nilotinib arms going into complete cytogenic remission, more patients have entered a major molecular response that is a three-log reduction, and now, we are also seeing more patients on the nilotinib arms entering a 4.5-log reduction, the so-called MMR 4.5. Why this is important? Because 4.5 is the degree of suppression that we think might permit some of our patients to be discontinued from therapy. It appears that nilotinib may place more patients in a position where they can come off drug. But we also have some downside, and that is at the 5-year meetings, we are also now seeing that there is a slight increase in cardiovascular events for the nilotinib arms with the 400 arm being slightly worse than the 300 arm and that being slightly worse than imatinib. These are small numbers, but they are a cause for a minor concern. On your patients on nilotinib, we want to follow especially as they get out several years’ cardiovascular risk factors and make sure that we are managing the cardiac issues very well to prevent these complications. Even so, the nilotinib arms are performing extremely well as far as controlling disease, and the majority of the patients on all three arms are still alive 5 years later, a big change from only 10 years ago when the interferon was used. So for our patients with CML, we can have good reason to have hope. A brand new patient can expect to have a normal life span with these agents, and we may have indication that nilotinib may permit some patients to potentially be discontinued. For more information about CML, check out ManagingCML.com. Thanks.

 

NIL 300 mg BID
n = 282

NIL 400 mg BID
n = 281

IM 400 mg QD
n = 283

MR4.5 by 5 y, % (P vs IM)

54 (< .0001)

52 (< .0001)

31

Low Sokal risk

53 (.0148)

62 (.0002)

37

Intermediate Sokal risk

60 (< .0001)

50 (.0126)

33

High Sokal risk

45 (.0041)

42 (.0105)

23

MMR by 5 y, % (P vs IM)

77 (< .0001)

77 (< .0001)

60

5-y freedom from progression to AP/BC,
% (P vs IM)a

96 (.0403)

98 (.0028)

92

5-y OS, % (P vs IM)a

94 (.4881)

96 (.0266)

92

Deaths from advanced CML,
n (P vs IM)b

6 (.0292)

4 (.0057)

16

Safety population

n = 279

n = 277

n = 280

5-y CVE rates, n (%)

 

 

 

Ischemic heart disease

11 (4)

24 (9)

5 (2)

Ischemic cerebrovascular events

4 (1)

9 (3)

1 (< 1)

Peripheral artery disease

7 (3)

7 (3)

0

aKaplan-Meier estimate, including events after discontinuation. bPatients for whom the principal cause of death (during treatment or follow-up) was “study indication” or “unknown” or not reported but subsequent to a documented progression to AP/BC.

Take-home Pearls:

  • Nilotinib continues to result in superior efficacy vs IM in patient with CML-CP with more patients in the nilotinib arms entering a 4.5-log reduction (major molecular response 4.5, MMR 4.5). 
    • Why is this important? Those patients achieving this level of suppression (MMR 4.5) may qualify for discontinuation trials after a period of time (~2-3 years)
  • 5-year freedom from progression to AP/BC, % (P vs IM) is significantly better with both 300 mg BID and 400 mg BID nilotinib vs 400 mg QD imatinib, with fewer deaths from advanced CML
  • 5-year overall survival is also superior with 400 mg BID nilotinib vs 400 mg QD imatinib
    • The difference between the 300 mg BID nilotinib arm and that of the imatinib arm is not significantly different at this time
  • NIL was generally well tolerated; however, a safety signal has been observed with CVEs of interest being more common on nilotinib than patients on imatinib.

Safety Consideration Reminders:

  • Nilotinib is associated with increased risk of ischemic heart disease (IHD), ischemic cerebrovascular events (ICE) and peripheral artery disease (PAD) in both dose arms compared to imatinib
    • The risk of IHD and ICE is greater with 400 mg BID than with 300 mg nilotinib and the risk with both nilotinib arms are greater than that of 400 mg QD imatinib
    • Patient risk factors for CVE should be monitored and practitioners should be guided by patient clinical features and experience when selecting dose adjustments appropriate for their patient
      • The recommended dose of nilotinib is 400 mg BID (12 hours apart and should not be taken with food)
      • You should be aware of the risk warnings for nilotinib including that of QT prolongation and sudden deaths
  • Warnings include: Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to nilotinib administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. Use with caution in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

Reference:

  1. Larson RA, Kim D-W, Jootar S, et al. ENESTnd 5-year (y) update: Long-term outcomes of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib (NIL) versus imatinib (IM). J Clin Oncol. 2014;32:5s (suppl; abstr 7073). [Link to Abstract]
Last modified: June 13, 2014