An Expert’s Perspective on the Expanded Approval of Venetoclax

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Topics include: Treatment

What new treatment opportunities will the recent approval for the expanded use of venetoclax (Venclexta) provide for people living with chronic lymphocytic leukemia (CLL)?  CLL expert Dr. Susan O’Brien, from UC Irvine Health,shares exciting findings from the Murano trial that propelled the approval, how the label and uses have changed, and the impact it will have on CLL patients. Dr. O’Brien also discusses what kind of response is seen, the ability to achieve MRD negative and average rate of progression on venetoclax. How will patients with 17p deletion be affected? Will the approval make a difference in insurance coverage? Watch now to find out the latest CLL treatment news.

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Transcript

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 and welcome to Patient Power.  I'm Andrew Schorr in Southern California, near San Diego.  And to the north is my dear friend from many years, a world-renowned CLL specialist, Dr. Susan O'Brien, who is at the University of California Irvine. 

Dr. O'Brien, welcome back to Patient Power. 

Dr. O'Brien:

Thank you, Andrew.  It's a pleasure to be here. 

Andrew Schorr:

So, Dr. O'Brien, recently we've had expanded approval for a drug called venetoclax or Venclexta, and for a broader percentage of CLL patients and then also the approval of that in combination with another well-known drug, rituximab or Rituxan.  So, first of all, what does this mean as far as expanded use and combination use?  What opportunity is this for people living with CLL? 

Dr. O'Brien:

This is a very important opportunity, Andrew, and that's because up until now venetoclax was approved as a single agent in patients with relapsed CLL, but importantly the label, what we call the FDA label, was restricted to patients who had a 17p deletion.  What does that mean?  Well, if a drug is FDA approved for CLL, I could prescribe it for anybody I want with CLL.  The issue is, will insurance pay for it?  And we know with these oral drugs that they are not inexpensive. 

So what they often go by is what does the label say?  And so, for example, I have had patients that I tried to prescribe venetoclax for who did not have 17p deletion, and sometimes I was successful and sometimes I wasn't, depending on their insurance.  So it was great to have something for patients with 17p deletion, because we know that they're a group that don't respond well to chemo, so we're really only looking at small molecule oral therapy there. 

But that left sort of everybody else out who didn't have a 17p deletion.  So what this new labeling has done is say that any patient with relapsed CLL now can be prescribed venetoclax whether or not they have a 17p deletion or not.  So that makes it available for many more patients. 

Andrew Schorr:

All right.  Now, what about combining it with Rituxan?  What does that offer patients? 

Dr. O'Brien:

So rituximab, as many of your audience knows, is an antibody that is very commonly given either as a single agent or more likely in combination with chemotherapy.  So we have the FCR regimen, which is FC chemo with rituximab, the BR regimen, and bendamustine (Treanda) and rituximab.  So I think everybody is very familiar with this antibody, which is generally very well tolerated. 

So what they did in the MURANO trial, which is what led to this improved or expanded label, they did a randomized trial, and in this trial venetoclax was combined with rituximab.  So we have the oral agent and the IV antibody, and then patients with relapsed CLL were randomly assigned to either be treated with that combination, venetoclax rituximab, or bendamustine and rituximab, very common chemo regimen that we use across Europe and the United States. 

And what that trial showed is that not only were response rates higher with venetoclax and rituximab, but the time that the patients spent in remission was much longer.  So the progression-free survival, which is more or less how long do people continue in remission before the disease progresses again, was about 18 months with bendamustine and rituximab, which is about what you would expect in this patient population.  And we don't even know what the average is with venetoclax rituximab, because it was nowhere near reached.  So, in other words, most of the patients at the two-year follow-up were still in remission. 

The other interesting finding is that the incidence of MRD negativity, minimal residual disease negativity, which implies a very deep remission, was also much greater with venetoclax and rituximab.  And, in general, we would expect that patients who become MRD-negative are going to have the most durable remissions, because they have the deepest remissions.  So what the label has also done now is allowed physicians to prescribe either venetoclax or the venetoclax-rituximab combination to patients who would be able to take rituximab in addition to venetoclax. 

Andrew Schorr:

Okay.  Now, I know there's no one size fits all, but just generally, how would you decide which way to go?  And we'll talk about ibrutinib (Imbruvica) in this mix in a minute, but among these two choices, how do you decide which way to go? 

Dr. O'Brien:

I think the data, and there's no head-to-head comparison of venetoclax with venetoclax-rituximab, but if you look at the published venetoclax data and you look at the published venetoclax-rituximab data, the latter looked better.  Better, what do I mean by better?  In terms of higher response rates and suggesting more durable remissions.  So really my choice would be the combination, but there are occasionally patients, and they're not that common, that have had bad reactions to rituximab and perhaps would be unable to take rituximab in combination with venetoclax.  But barring that problem, I would clearly go with the combination. 

Andrew Schorr:

Okay.  That's very clear.  All right.  So we have lots of patients who lately have been on ibrutinib, and it doesn't last for everybody, or there may be some side effects they may have or heart issues that you and I have talked about before.  So what about switching?  Does this offer a chance to switch, and is that desirable, and how do you know when? 

Dr. O'Brien:

So the difficult group are the group that actually become, as you alluded to, resistant to ibrutinib.  In other words, it stops working.  There are also people, as you suggested, who stop ibrutinib, because they can't tolerate it.  For that patient population, depending on what they've already had, we could give them chemotherapy.  We could give them idelalisib (Zydelig), which is a PI3K oral inhibitor, or we could give them venetoclax. 

The tricky population who are more difficult to treat are the ones who have actually become resistant to ibrutinib.  So while they're taking the drug, the disease, which initially responded is now starting to come back.  And we just had data published in the past couple of months looking at the outcomes for patients who receive venetoclax after becoming resistant to ibrutinib.  And that's very important because, as you just alluded to, many patients are getting ibrutinib nowadays, and so many of the patients that would actually go on to get venetoclax would be these patients who are resistant. 

This data that was collected on a clinical trial was using single-agent venetoclax, so not the venetoclax-rituximab combination.  But what that data showed is that these patients who were becoming resistant to ibrutinib—and, by the way, all these patients have had multiple lines of chemotherapy.  These are not patients we might see nowadays who have started with ibrutinib and have never been treated with chemo. 

So this was a very refractory group, because their disease had progressed through chemo and through ibrutinib.  And what we saw in this publication is that the response rate was about 65 percent, so that was encouraging.  About two?thirds of patients with very refractory disease were able to go on and respond to venetoclax, and the median progression-free survival, again how long they stay in remission, if you will, appeared to be an average of two years.  And, again, there was a subset of patients with very deep remissions who became MRD negative, and they—we don't know what the average remission length in those patients is going to be, because we haven't reached the 50 percent mark. 

But the fact that these patients could respond to venetoclax and even though they had very difficult disease that had come back after many treatments still respond for on average about two years I think was extremely encouraging

Andrew Schorr:

Wow.  You and I have been discussing therapies for CLL for so many years, and it just sounds so much more encouraging.  So we have some questions that have come in from CLL patients.  So Julia wants to know, what kind of response are we seeing with patients who relapsed on ibrutinib and go to venetoclax, and you just discussed that.  And what is the average time of progression on venetoclax?  And it sounds like in some cases we don't know yet, right? 

Dr. O'Brien:

Right.  If you took all comers on that trial it was, as I mentioned, about two years, but—of course that's an average, and we all have to remember that there are patients who are going to be less than the average or longer than the average—but what that trial also showed, as I mentioned, is that if patients were able to achieve MRD negativity, those remissions are even more durable, and, as you just said, we're not even quite sure how long their remissions last in that population, because the majority of those people were still in remission at the time of the publication. 

Andrew Schorr:

One of the things that's come up with venetoclax is, is there the idea that if you can get to an MRD-negative status, you might be able at some point to stop or at least take a vacation from therapy, and then given the cost of drugs that would be desirable.  Do we have any thought about that at this point? 

Dr. O'Brien:

I think it's a little bit early to know.  Certainly it provides that possibility.  In general, the reason that we give the oral agents that we use continuously rather than stopping after a fixed period of time like with chemo, is that most patients were not achieving a complete remission or had some amount of disease that was still persisting, usually very, very low level.  But the idea was, well, we don't really want to stop a patient who has some amount of disease, because then the disease might progress once we take them off the drug.  So that's why with all of the oral agents that we have up until now the idea was you just keep treating with them. 

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Page last updated on May 15, 2019