Thursday, June 4, 2015

Frontline Survival Benefit for Ibrutinib


Resonate-2, the randomized phase III study comparing frontline ibrutinib against chlorambucil met its primary endpoint of progression free survival (how long you are both alive AND without progression) and ended early.  More importantly, the secondary endpoint of overall survival was improved as well

Meeting the primary endpoint was a virtual certainty.  Everybody knew this study would be positive - but the study had to be done in order to get FDA approval for frontline ibrutinib.  Single agent chlorambucil is a dead dog.  It has served as the control arm that has been beaten up by just about every new drug in CLL in the last ten years (including campath, bendamustine, fludarabine, obinutuzumab, and now ibrutinib).  

Meeting the secondary endpoint is a little more provocative.  This study was built with a crossover design - meaning if you were randomized to chlorambucil and experienced disease progression, they gave you ibrutinib at that point.  If there is an overall survival benefit, it means that early ibrutinib saves lives compared to ibrutinib after progression.  This was also true in the Resonate study comparing ibrutinib to ofatumumab and the Gilead study that led to approval of idelalisib in combination with rituximab.  That is three studies that show that patients die faster when they get ineffective therapy compared to novel agents.  It remains to be seen if that is true with standard  regimens that actually work like bendamustine-rituximab or FCR where the bar will be much higher than chlorambucil.

Presumably this will be presented at ASH if it isn't already published by then.  It will also lead to FDA approval of frontline ibrutinib but that is probably still a ways off and the exact prescribing "label" will determine who can get it in the frontline.  I have no particular insight, but suspect that is still 4-8 months away.

There will be several key details I want to see in the presentation:

1) In this "elderly" subset of patients - how well was ibrutinib tolerated?  In most clinical trials it appears that about 5-10% of patients discontinue drug for poor tolerance.  Age has also been shown to be biggest variable leading to drug discontinuation - and the median age in this study is likely to be a fair bit higher than other studies due to the nature of the control arm

2) How good is good?  Our group helped contribute to the "frontline ibrutinib" data published in the Lancet.  In that cohort of about 40 patients, only one patient experienced disease progression and several others discontinued for intolerance.  In this larger - multicenter study, it will be the largest to date of previously untreated patients to go on ibrutinib.  Is the progression rate still that good?  Are there more progressions or is it still in the low single digits?

3) What happens to patients who discontinue ibrutinib?  In the relapsed / refractory setting, patients who discontinue ibrutinib have been extremely sick and many have died very quickly.  There has been a fair bit of discussion about "ibrutinib discontinuation syndrome."  Some have argued that these patients had already failed every other therapy which is why they died so quickly.  In this treatment na├»ve cohort - that excuse cannot hold.  If the overall survival curve looks like the progression free survival curve - I will be worried.

4) Dose intensity.  Do patients start 3 pills per day and stay on three pills per day without dose reduction or interruption?  The ASCO data just presented really gives me considerable apprehension about big dose interruptions.  As a patient, I would be trying to keep skipped doses to a minimum.  Obviously you may need to do that for surgery etc. but if I had the choice, I would not want to do that early in a treatment course when there are a lot more CLL cells running around.

5) Cytogenetics and high risk markers:  While chlorambucil is such a dog it really isn't worthy of a comparison arm, it will be interesting to look at the subgroups treated on ibrutinib.  While comparing across trials is always dangerous, we have expectations for the outcomes of patients with markers like TP53, 11Q, and IgHV mutated/unmutated.  This will serve as some interesting food for thought with those higher risk populations.

This news release follows two positive randomized phase III trials presented at ASCO for ibrutinib in combination with bendamustine/rituximab and idelalisib in combination with ofatumumab.  These latter two studies are important but may not have as much practice impact as the study discussed above.

With a frontline indication for ibrutinib likely available within a year, it begs the question who to treat with chemotherapy and who to treat with targeted agents.  I've attached some slides from a talk I recently gave on this topic but please note that these reflect my approach and guidelines are rapidly changing in this disease.

Thanks for reading.  To leave a comment, click on the title of this post and it will open up the post in a new window with a comment section at the bottom.


  1. Do you think the standard of care for untreated low risk patients will move away from FCR and B+R anytime soon? Secondary cancers, even in a fit younger population, are still are out there, with no predictors as to who is most vulnerable to Richter's or MDS.

    Would using Novel Inhibitors initially in low risk patients needing treatment be a higher standard of do no harm compared to FCR? More directly, if one is "failing" one of this or a combination of these drugs would it not be possible to get FCR at that stage?

    Thanks for all you post here and giving folks access to your presentations. And congrats on your early work on Novel Inhibitors.

    Super Fit 58 year old with low risk but growing CLL

    1. This data set does not answer your question directly and there are prospective trials comparing Ibrutinib to Ibr-Rituxan to FCR and another compared to BR. Until those data sets emerge, I think it will be hard to extrapolate although if the PFS curve on this is outstanding, we will be tempted to try.

      My bias toward aggressive chemo in most favorable patients stems from both the long term follow up at MDA and the German CLL8 study. Although the MDA dataset heavily skewed in favor of the most physicially fit, there are some patients out 14 years remaining MRD negative. If you look at the German CLL8 study and select only the most genomically favorable group, they are close to 70-80% progression free at 8 years and if likely to continue to do well. Some have asked if these patients are possibly curable. Hate to pass that up if available.

      If you are going to try to identify the super low risk though, would also look for TP53, SF3B1, and NOTCH1 mutations not detected by FISH

  2. Excellent piece, thank you. Points all well taken and stated. Regarding chlorambucil as a control therapy in upfront CLL, do you feel that the crossover provision mitigates the "dead dog" ethical issue you describe? Is Chlorambucil still listed as appropriate for first line therapy on NCCN guidelines? Should it not be? Is it fair to say it's the least-toxic or easiest to tolerate cytotoxic protocol for CLL? (Karl, Patients Against Lymphoma)

    1. While the crossover mitigates the trial design, there is still a survival benefit according to the press release - so the mitigation is incomplete.

      I don't want to say that chlorambucil is Never appropriate. There may be some extremely elderly individuals age 90+ who are intolerant of ibrutinib. In that case, I would be trying to give it in combo with obinutuzumab where another survival benefit has been shown.

  3. I am 67, was diagnosed with CLL this summer after a bout with septic shock.
    I am enrolled in a study, and was chosen to go Ibrutnib.

    Wow! No side effects, and if I watch my diet with care I do not have the slightest discomforts. Hope this continues!

    bob hertz
    St Paul MN

  4. Doc I miss your blog. Please come back.


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