ENESTnd trial comparing nilotinib and imatinib as first line CML therapy

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Published: 18 Feb 2011
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Prof Timothy Hughes - Institute of Medical and Veterinary Science, Adelaide, Australia
Prof Timothy Hughes speaks to ecancer.tv about the ENESTnd trial which is evaluating the efficacy and safety of the second generation tyrosine kinase inhibitor nilotinib in newly diagnosed chronic myeloid leukaemia (CML) patients. This study compared standard imatinib treatment with nilotinib 300mg twice daily or nilotinib 400mg twice daily and found that both nilotinib regimens had superior efficacy over imatinib with significantly higher rates of major molecular response, complete cytogenetic response and significantly lower rates of progression to accelerated phase / blast phase. Prof Hughes discusses the differences in toxicity between the two agents and between the two nilotinib regimens, considers the benefits of putting patient straight onto nilotinib as first line treatment and talks about CML becoming a truly chronic manageable disease.

2010 American Society of Hematology Annual Meeting 3rd - 7th December

Interview with Prof Timothy Hughes - Institute of Medical and Veterinary Science, Adelaide, Australia 

ENESTnd trial comparing nilotinib and imatinib as first line CML therapy

 

 

IV         Interviewer

TH        Tim Hughes

 

 

TH        Nilotinib has been shown to be a very effective drug for patients who fail the first line drug Imatinib, and so it was logical to see if it would be a better drug as a first line therapy, and there have been some promising phase two trials using it as first line therapy that led to this randomised trial.  So there are three arms to the trial – there is what is regarded as the standard dose of nilotinib has been used in imatinib failure, of 400 milligrams twice daily.  But there is also an arm using a somewhat modified dose of 300 milligrams twice daily, and that’s been compared to the standard imatinib dose of 400 milligrams daily – so three arms of the study powered to look for a difference in major molecular response at 12 months.

 

IV         And you’ve got more than 800 patients?  That’s a good sample.

 

TH        Yes, it’s a big study.

 

IV         What did you do with the patients and what did you find?

 

TH        Well, the patients received their therapy as scheduled, and the key endpoint was found last year, and presented last year at the society meeting where the achievement of major molecular response was significantly higher in the patients receiving nilotinib compared to imatinib, in the order of 44% versus 24% - so very clear cut differences in the achievement of major molecular response.

 

We’ve now got the 24 month data and there was some speculation those differences might disappear over time, which sometimes you see with a more potent drug, but the differences are just as dramatic at 24 months.  So we’re seeing around about 60% of patients achieving major molecular response on the two nilotinib arms versus around 37% on imatinib.

 

IV         Now interestingly, what was the difference between the two doses of nilotinib, because I think a lower dose did slightly better, didn’t it?

 

TH        Well, yes, the trial was not powered to compare the two nilotinib doses – they really wanted to use the conventional dose and they wanted to see whether a slightly modified dose might give a better toxicity profile with a similar efficacy, and I think that’s actually what they’ve seen.  Because the efficacy you could argue may be 300, it’s better on some scores and not on others; I think you really can’t say too much about that.  The difference really is between the nilotinib arms and the imatinib arm.  But in terms of the tolerability certainly patients are able to adhere to the dose more closely at 300 twice a day, than 400 twice a day.

 

IV         I’d like to ask you about toxicity and tolerability in a minute, but could you clear something up for me first, because you are looking at major molecular response, you’re looking at complete cytogenetic response, and you’re also looking at something called complete molecular response.  Now obviously the molecular responses are very interesting, but what did you find in terms of the cytogenetic responses and more standard approaches?

 

TH        Well, all of them were dramatically different but CCYR, complete cytogenetic response really represents about a 2 log reduction in the leukaemia load, whereas major molecular response represents a 3 log reduction and what we talk about as the CMR represents a 4 or a 4.5 log reduction.  So we’re really talking about just depth of response, whether it be measured by a conventional cytogenetic test or whether it be measured by a molecular test, and on all counts the differences are quite stark, probably more stark as you get to a deeper level.  So that the complete molecular response rates at 24 months look substantially higher, in the order of almost 40% for the patients... sorry, in the order of 24% for the patients on nilotinib versus about 10% for patients on imatinib - so it’s consistent with the idea that we’re depleting more rapidly and in more patients.

 

IV         Okay.  What about safety of this new agent, this second generation agent?

 

TH        In terms of overall toxicity the general impression from clinicians is that the new agent, nilotinib is better tolerated than imatinib.  In terms of the day to day toxicity that we see in oedema, GI upsets, diarrhoea, vomiting, nausea, they’re all substantially lower in the nilotinib arms.  We do see some other things that are not seen in the imatinib arms, so we do see some abnormalities of the enzyme suggesting pancreatic inflammation in some patients, around 5% on nilotinib; sometimes you see liver abnormalities but low numbers of patients are getting significant findings.  So overall, the discontinuation rate from the trial, which is a pretty good measure of the level of tolerance, is actually highest in the imatinib arm and lower in the nilotinib arms, and lowest in the 300 milligram twice daily arm.

 

IV         So as things stand at the moment are you able to say whether it’s better to go in first with the second generation agent, or should you start you patient on nilotinib... on imatinib, and then transfer to the second generation agent when that eventually fails?

 

TH        Well, I think you need to look at the total amount of evidence.  This study is a strong piece of evidence, that going in up front with the more potent drug does achieve a deeper, earlier molecular response.  And what we haven’t talked about is the transformation to acute phase, and the number of patients who transform to acute phase is substantially higher in the imatinib arm.  So there are patients that go to what we call the accelerated or blast phase of the disease, and that’s a somewhat difficult stage to treat. The fact that you’ve got in the order of 4% of patients going to the accelerated phase or blast crisis on the imatinib arm versus just 1%, is probably one of the strongest arguments for going up front with a more potent agent right from the beginning of therapy.

 

IV         If you use a second generation agent like nilotinib what would happen then?  What’s your feeling about the way things are going with CML?

 

TH        Well, I think we look at the US market where now all three drugs are licensed for front line therapy – nilotinib, dasatinib and imatinib – and it will be interesting to see, over time, how that plays out in terms of the preference for the drugs.  I think we still have a lot to learn about how optimally to use these drugs because ultimately our aim is to minimise transformation to blast crisis but also, if we can, achieve complete molecular response and get people off the drugs eventually – so I think we have a lot more still to learn about how to use these drugs most effectively.

 

IV         However, imatinib miraculous as it is, is now familiar territory?

 

TH        Yes.

 

IV         A lot of physicians are going to want to stay with what they know – what would you say to them?

 

TH        Well, I think they need to look at the evidence very carefully, and I think the strongest evidence in favour of using nilotinib up front would be the prevention of transformation to acute phase.  If you’re preventing that in 3% of patients, well, that’s a very substantial gain.

 

IV         Do you think you are progressing eventually towards having this disease controlled in a maintenance manner, rather like Diabetes as a chronic disease?  Do you think that could happen?

 

TH        I think it’s happening at the moment.  I think the vast majority of patients that we see, that can tolerate the drug and are still taking it two or three years down the track, have achieved major molecular response and have extremely low risk of progressing.  So I think we’ve already achieved the status of a chronic disease managed by drug.  The challenge now is take it from there and possibly get them to the stage where they can come off drug altogether, and there are some hints that that may be possible in some patients.

 

IV         And what about famous T315i mutation?

 

TH        It’s still a concern because it’s not covered by any of these three drugs; we’re looking to a third generation of drugs that might be able to cover that mutation.  Putting that in perspective only about 1% or 2% of patients will develop that mutation if they start their therapy up front with either of the current drugs available.

 

IV         Finally, what would you say to busy cancer doctors at the moment?  What should they be thinking of?

 

TH        Well, I think they’ve got great choices now.  I think they could think very seriously about whether they want to adopt these second generation drugs as first line therapy straightaway, which I think is a very reasonable approach, but I think that there is still an argument for the use of imatinib with the early adoption of a second generation drug if there are any signs of failure to achieve a very good response.  So I think there are still questions to be asked but this data is certainly very exciting.

 

IV         Tim, thank you very much for joining us here on ecancerTV.

 

TH        Thanks very much.