Dr. Jeff Sharman: My Perspective on ASH 2015 News

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On location at ASH (American Society of Hematology) 2015, Dr. Jeff Sharman, Medical Director of Hematology Research at The US Oncology Network, shares the latest in CLL news.  Listen as Dr. Sharman explains in detail the expected outcomes of the RESONATE Phase III trial, as well as the ongoing research on ABT-199.  When asked if he is hopeful, Dr. Sharman responds with an enthusiastic, “Oh, gosh, yeah!...The statistics aren’t real anymore….CLL patients are living much more normal lives…” 

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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.          

Andrew Schorr:

Hello.  Andrew Schorr on location at the ASH meeting, American Society of Hematology, in Orlando.  I'm with Dr. Jeff Sharman, a noted CLL expert and with US Oncology Network and also based in Oregon.  Thank you so much for being with us, Jeff.  Let's talk about CLL news, okay?  So we've had really some novel agents, and one of them, ibrutinib (Imbruvica), has been followed.  It's been a big deal for people, but we're trying to decide and study whether it has application earlier, so there was some news about that, right? 

Dr. Sharman:

Yes.  So reporting today will be the randomized RESONATE 2 study, which compares the efficacy of ibrutinib versus chlorambucil (Leukeran).  Now, chlorambucil is hopefully never going to be studied again as a control arm in a study.  This should…

Andrew Schorr:

…it's an old medicine. 

Dr. Sharman:

It's an old medicine, and I think that now with the results of this study and a prior study with the addition of obinutuzumab, or Gazyva, we've now shown two studies with not only superiority in terms of progression-free survival, but both of these now report overall survival benefits compared to chlorambucil monotherapy.  So as of today chlorambucil, done, no more. 

Andrew Schorr:

Dead. 

Dr. Sharman:

Yeah.  And it has been fading in North America for quite some time.  But in terms of the results of this study, this was a randomized Phase III study, half patients of chlorambucil, half patients with ibrutinib, primarily in patients who would be considered appropriate for chlorambucil.  Now, there was crossover allowed in this study, and this study started before ibrutinib was approved, and so I think that there were a number of patients who said, I'll take chlorambucil, just so that they had a 50/50 chance knowing that if things didn't go well they could then go on ibrutinib.  

Ideally this is unique to those patients who are older with co-morbidities or other medical issues that prevent them from getting aggressive chemoimmunotherapy-type strategies, but regardless I think the most useful interpretation of this data isn't so much the expected outcome that ibrutinib did better than chlorambucil but how well patients do on ibrutinib monotherapy. 

This should lead to FDA approval of this drug in frontline.  What we don't know is how narrow or how broadly the FDA will construct that approval.  That's important, because what the FDA writes in their guidelines and guidance is oftentimes what insurance will pay for. So—and if they make it a challenge for insurance—it really gets in all sorts of games, if you will.  This study is in older patients who are considered inappropriate for chemotherapy, and that's actually been a patient population for which idelalisib was approved with similar language. 

So I think the devil will be in the details of the wording here, but it will introduce ibrutinib broadly or more broadly into the frontline treatment rather than restricted to those patients with 17p, as the label currently is formulated. 

Andrew Schorr:

Okay.  Now, other news here, a couple of others I wanted to talk about, one is about what had been ABT-199, the letters of venetoclax, and its utility, and that seems to be coming along, and it seems to be a powerful drug. 

Dr. Sharman:

Venetoclax is a very powerful drug in contrast to the B?cell receptor signal inhibitors, so there—the B-cell receptor signaling pathway is a sequence of enzymes that help transmit biochemical signals within a CLL cell, and there are a sequence of these.  And they include BTK, SIK, PI3 kinase and a variety of others, and there are probably two to five drugs for each of those targets. 

But ibrutinib, idelalisib, duvelisib, entospletinib, you know, a variety of these targeted enzymes, those are B-cell receptor signal inhibitors.  In contrast, venetoclax is a Bcl-2 inhibitor.  Bcl=2 is important for keeping one substructure within a cell arrive, what we call the mitochondria.  Mitochondria is like the power generator of a cell, and what Bcl-2 does is it keeps that power generator functioning.  If you administer a Bcl-2 inhibitor, that power generator goes into self-destruct mode and takes the CLL cell out with it, and so we see instead of these kind of slow responses that transpire over many months and even years with the B-cell receptor signal inhibitors, we see dramatic changes sometimes even after a single pill with the Bcl?2 inhibitors. 

Andrew Schorr:

Which is why for people in the trials they have to be monitored very carefully at the beginning.  

Dr. Sharman:

Yeah.  So many of the studies that have looked at Bcl?2 inhibitors have included mandatory hospitalizations for the administration of the drug.  And so that's how that going to translate into a drug that we would generally give as an outpatient I think remains to be seen and are some of the hurdles for that drug. 

Andrew Schorr:

But a powerful drug.  

Dr. Sharman:

Very powerful drug. 

Andrew Schorr:

Okay.  And so that gets us to clinical studies, and you discuss them all the time here.  As you're looking at combining drugs now, and that can be expensive.  If these drugs get approved or are approved—this is another insurance question maybe too—but can that lower the likelihood that if you were taking let's say ibrutinib by itself your cancer becomes resistant to it because you're trying to hit the cancer cell multiple ways, down and out, right?  And that maybe is the new horizon for CLL, right?  Combinations? 

Dr. Sharman:

Yeah.  In oncology, the history of oncology has always been dominated by combination therapy.  With rare exception the addition of other drugs leads to more cures than just one drug alone.  Now, there are exceptions to that, but that is the nature of most—the last 50, 60 years of oncology. 

I think what patients want is the opportunity to have a very effective therapy that gets their disease into remission and not stay on therapy, and that's where we wish to take the field.  We're not there yet.  Currently, ibrutinib is once you start it you stay on it indefinitely, and there's no end point. 

Now, that's okay in many regards because ibrutinib for most patients is a very well tolerated drug with acceptable side effects, but not for everybody.  Joint pains, bruising, bleeding, atrial fibrillation, there are a variety of reasons why some patients might be intolerant of ibrutinib.  And in that regard if we can move the field towards shorter duration of therapy, maybe that overcomes some of the cost limitations because if you start doing a Bcl?2 inhibitor and a BTK inhibitor and maybe a CD20 antibody you could be talking very quickly about a half million dollars of therapy in aggregate cost, and that's obviously unsustainable if that's going to be done in perpetuity. 

Andrew Schorr:

Okay.  So we have economic questions.  We have questions on how to outsmart the smart CLL cell.  So just to wrap up, Jeff, you hear the news, you're part of the news, and you're seeing patients all the time.  For people coming to you now and people out here and watching our video, are you hopeful? 

Dr. Sharman:

Oh, gosh, yeah.  I mean, I think one of the sort of magical moments, if you will, of being a doctor is meeting that patient who's been told they have some cancer. And they don't know much about it and walking them through those first hours of talking to an oncologist perhaps over several visits and watching this transformation from somebody who is very often understandably very alarmed to giving some hope for what's out there that—I think in a prior discussion we talked about average survival eight-and-a-half years, you know, some of these statistics that are old, those statistics aren't real anymore. 

Our patients with CLL with rare exceptions are going to be living much more normal lives than their counterparts even just a few years ago.  

Andrew Schorr:

Great.  Wow.  You know, that's very exciting.  I want to thank you for all you do. 

Dr. Sharman:

Sure. 

Andrew Schorr:

Thank you for the hopeful news, and just remind all of you that, you know, it's said all the time, it almost sounds trite, but it's so true.  Knowledge is power.  Be a full partner in your care, consult with someone, a team that's really knowledgeable in CLL, have an active dialogue.  It will give you confidence, it will give you hope, and now you're hearing that there are more and more tools to help you whatever your CLL situation is.  We'll keep you informed on Patient Power.  Thank you for joining us. 

From Orlando, Florida and the ASH meeting, I'm Andrew Schorr.  Remember, knowledge can be the best medicine of all.  

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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Page last updated on April 21, 2016