Progress in Resistant CLL and Richter Transformation

Transcript:

Prof Constantine Tam: Hi, my name is Con Tam. I am a hematologist in Melbourne, Australia, and a CLL researcher. And it gives me really great pleasure to speak to you today about some of the progress, especially at the more difficult end of CLL for patients with resistant disease, and for patients with a rare complication of CLL called Richter’s transformation.

 

Within Australia, in Melbourne, we’ve been very lucky recipients of the funding from CLL Global, which was started by Professor Michael Keating, my mentor, and continued by Professor William, Bill Wierda. CLL Global Research Foundation has funded us in Australia, my group in particular, for research, for six years now. And shown here are the papers that we have published, based on the funding that were very generously granted to us by you, the patient, to allow us to fund the CLL research.

 

As you can see, there are a number of papers here. I struggled to fit the titles on the screen. But essentially, we have come a very long way in understanding how our drugs work in CLL, how to better use our drugs and new technology to monitor CLL. And I want to say that much of the huge leaps and progress that we’ve made in the last 10 years in CLL were thanks to the funding from the research foundation. So, a real tribute to all of you for helping to fund this work.

 

I want to start by telling you a story about some of the work that we’ve done so far, especially in patients with resistant CLL. You will be aware, as a patient, that there have been some real successes in targeted therapy for CLL. One class of drug on the left are the BTK inhibitors, of which the first member was ibrutinib. And some of you may have experienced ibrutinib before. But now, we’re moved on to zanubrutinib (Brukinsa), acalabrutinib (Calquence), pirtobrutinib (Jaypirca), and newer generations. But really, these have been a real pillar in CLL therapy.

 

And on the right, there is a second group of drugs, a drug called venetoclax (Venclexta), which inhibits a second protein called BCL2. And once again, this had been a very important pillar in CLL therapy. And these days, as a patient with CLL, patients would typically get both classes of drugs at some time in their lifetime. Either one after the other sequentially, or in some cases, receiving both at the same time.

 

But really, these are the two main pillars of CLL therapy these days, and probably the largest group of patients. The very few patients who have disease that became resistant to both this type of treatment, other type of patients where we are having the most trouble with these days, and that’s where we’re focusing our research to develop new therapies. But these two groups of drugs have completely changed the way CLL has been managed. We do not give chemotherapy anymore because both these groups of drugs perform better than chemotherapy.

 

Our group’s very interested in finding what causes venetoclax resistance. And we’re very lucky, in 2018, to have discovered the mechanism for venetoclax resistance. And this is a change in the protein where venetoclax binds, and a change in the spelling sequence of the protein, which stops the drug from binding. These are some of the results that we have shown.

 

But we’ve actually done a lot more work on understanding why patients become resistant to venetoclax. Because if we take a typical patient who has this mutation that stops venetoclax from binding, that mutation is only in a small percentage of cells in the CLL. And the rest of the CLL cells actually do not carry that mutation, and should, in principle, still be sensitive to the drug.

 

Our group has done some really interesting work on something called single-cell sequencing, which is when we look at the individual cells within a CLL patient to understand, not whether the patient has a mutation or not. But at the individual cell level, we look at each individual cancer cell, whether they actually carry the resistant mutation or not.

 

And very interestingly, we’re discovering that not only, some of the cells do carry the resistant mutation, but other cells within that same patient will carry other mechanisms of resistance which will still describe it. And, of course, this is a really important piece of work. Because if we now understand that a patient has developed resistance to a drug because of a mutation, but the mutation is only in a minority of the cells, and we target that mutation, then we’re ignoring why the rest of the cells are becoming resistant.

 

So, we’re now working on understanding the entire landscape of venetoclax resistance, so that we can develop new treatment that will cover both the cells that have the resistant mutations and the cells that do not. This is a work in progress, but we’ve made huge leaps in progress so far.

 

Exciting developments spurred on by the venetoclax story is a drug called BGB-11417, or sonrotoclax (Beqalzi). This is a drug that is 10 times more potent than venetoclax, and recently has received FDA approval, starting from a, first, in human phase at our group. And this is a drug that may be coming to you soon, as a patient.

 

And what this drug does is, it is so potent that it’s able to overcome some of the venetoclax-associated mutations. Although, as I pointed out before, that there are other mechanisms of resistance that we still need to address. So, this is one step towards understanding and overcoming venetoclax resistance.

 

On the other hand, on the ibrutinib, on the BTK side, we have made very large leaps in progress. And we now understand, in most patients, what causes a resistance to a BTK inhibitor. And we now have at least two new generations of drugs to overcome that resistance.

 

This is not our work; this is work from the U.S. group that showed initially that for patients on ibrutinib long term, the first-generation drug, then most patients who become resistant have a mutation at exactly the place where ibrutinib binds, and this is in a place called cysteine 481.

 

Now, this is a really important mutation, because for subsequent drugs like acalabrutinib and zanubrutinib, they all bind to the same place. So, if you have this mutation, you are resistant not only to ibrutinib, but also to zanubrutinib and acalabrutinib.

 

Our specific group have contributed to development of the second-generation drugs. So, we worked very hard, and, in fact, I was very lucky to be the principal investigator of zanubrutinib. And as you know, zanubrutinib is a drug that is more potent than ibrutinib. It worked better, and it has less side effect. And similarly, for acalabrutinib, these are all second-generation drugs, which have less side effect. But they all bind to the same place.

 

Now, one discovery that we made some years ago, founded by the CLL Global Research Foundation, was that patients on zanubrutinib actually carry a second mutation in a place called L5 A28W. And for acalabrutinib, there’s a second mutation called the T474I. Now, these mutations were not just of academic interest. We love CLL, and we’re geeks, but these mutations are really important. Because what they do is they actually confirm resistance to pirtobrutinib.

 

So, now, our eyes have been opened. When we’re talking about BTK mutation, we do not need to consider just the 1681 mutation, but, in fact, a whole list of other mutations, in order to best choose the drug that’s likely to work for our patients. Especially if you are going to use one drug after another.

 

But the latest chapter in that story is that we have now been working with a BeOne company to work on this drug called BGB-16673, which is actually a fourth-generation BTK inhibitor. And what this drug does is, it doesn’t just block BTK; it destroys the protein. So, all the previous generations of drugs block BTK function, but this is a protein degrader. It destroys the protein. And the advantage of that mechanism is that if you destroy the protein, then it overcomes most of the resistant problems with the resistant mutations.

 

And indeed, I want to highlight here, in a early report, that, down at the bottom, that a patient that we treated on this study, even the people who carry a resistant mutation in BTK, there’s a three and four chance that that patient will have a really good response to BGB-16673, which is a next-generation degraded drug.

 

So, once again, just a flavor that we are understanding what causes resistance to drugs, and we’re finding ways to overcome them by understanding, in detail, the science behind the mutations. This is to show that patients who carry mutation have just as long as a response, and as durable as response, as patients without.

 

Now, I want to move quickly onto Richter’s transformation, because this is the new frontier where we really need to devote our funding and our research efforts towards. What is Richter transformation? In about five to 10 percent of patients with CLL, the disease no longer uses CLL. After a while, it becomes an aggressive, fast-growing lymphoma, something called diffuse large B-cell lymphoma. And when that happens, it’s very bad. Because usually, Richter’s transformation is resistant to all the drugs that we use, including BTK and BCL2 inhibitors.

 

This is just to show that if you have – we typically try and treat these patients with Richter’s transformation with old-fashioned chemotherapy, and the various regimens are listed there. But what I want to point out on the right is the average survival of the people who are treated with chemotherapy for Richter’s transformation in different studies. And you can see that, really, the outcome is pretty terrible.

 

For someone, if you’ve got Richter’s transformation, and you get typical chemotherapy and nothing else, you’re looking at an average lifespan of about six to 12 months, which is why it is such an urgent problem.

 

A progress in Richter’s transformation is that we have now developed what we call bispecific antibodies. And, in fact, this is a group of drugs that was identified by Dr. Keating as being promising in CLL over 20 years ago. And what these drugs do is, they bring the immune system to the cancer.

 

The one that we’re looking at here is acalabrutinib, and what this drug does is, it handcuffs the patient’s immune system to the cancer, and it forces the immune system to attack the cancer. And in early studies of patients with Richter’s transformation, which is a very aggressive disease, we see that there’s about a 50 percent chance of the patient going into a complete remission, meaning that the cancer is completely destroyed by this therapy.

 

In Australia, what we’ve done, the other thing that we’ve done in Australia is that we have now introduced CAR-T cells for Richter’s transformation. And a lot of you may have heard of CAR-T cells because this is something that we use for aggressive lymphomas. And in Australia, we’re very lucky to have actually got access to CAR-T cells for Richter transformation. And this is survival curve of the latest generation of CAR-T cells in the red line, which is with axis cell.

 

And what this survival curve tells us is that probably around half the patients with Richter’s transformation, even when they don’t respond to chemotherapy, can be saved by CAR-T cells, and potentially have a chance to cure. So, this is, once again, a proof of principle that Richter’s transformation do not respond to the typical CLL drugs, do not respond well to chemotherapy, but can be effectively destroyed by drugs which target the immune system. Including the bispecific antibodies, as well as CAR-T cells, which harnesses the power of the immune system.

 

And obviously, this is only the first chapter in a big bulk of our work that we’re still developing. But showing you, there is a glimmer of hope. And we now understand, have good ideas about how we need to target this difficult disease.

 

I hope I’ve given you flavor to show that, although most patients who have CLL these days do really well with first and second-line treatment options that we have developed with the help of the foundation, we understand that, to move beyond that, we need to understand the mechanisms of resistance to our drugs, which we have made a lot of progress towards, and we have developed third and fourth-generation drug, and that Richter’s transformation remains a bugbear. But we’re getting close. We’re getting close to solving this problem.

 

And I want to thank you for your interest, and I want to point out that we’re only here because of the support for research. And I want to thank the CLL Global Research Foundation for their very generous funding of our work here in Australia. We hope to work together hand in hand to finally cure this disease for all of you. Thank you.