Therapeutic Revolution in Frontline CLL

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Transcript: 

Dr. Nitin Jain: Good afternoon, everyone. So, I’m Nitin Jain from the Department of Leukemia at MD Anderson. I’m a clinician, I treat patients with CLL and run clinical trials with new drugs and new accommodations with patients with CLL.

So, in the next 15 minutes or so, I’m going to talk to you today about some of the major advances which have happened in the field of CLL. And also, show you some of the clinical trial data we have generated in patients. And tying to the support of CLL Global in several of these trials, which were funded in part through CLL Global.

So, as this was the first talk of this session, I thought I would put a little schema in the way of figures to kind of impress upon you how the field of CLL has moved remarkably over the course of last decades. And up until 10 years ago, we were doing chemo-immunotherapy as our frontline therapy options. But since 2014, when ibrutinib (Imbruvica) was approved as a first oral target therapy, and subsequently, we have had many other target therapies approved, including venetoclax (Venclexta), a BCL-2 inhibitor. We have a novel BTK inhibitor, such as pirtobrutinib (Jaypirca), approved. We have CAR T-cell therapies approved in the lab for fracture CLL. And if you look at the bottom part of the slides, 2026 and beyond, just thinking ahead, we have some exciting new drugs coming, and I will briefly talk about them towards the end of the slide deck.

Namely, BTK degraders, they are also researching CD20 bispecifics; there are some novel BCL-2 inhibitors beyond venetoclax, which are in Phase III studies. And also, some novel BTK inhibitors which are kind of coming along. So, all these have really, in the last decade or so, we have made tremendous progress in the context of CLL in improving patient outcomes. And if you look at these drugs, which I just kind of named, you this is a review article we published last year, where it kind of shows you some of the major classes of drugs in the context of CLL. So, we have BTK inhibitors; you will hear much more about these drugs. We have BCL-2 inhibitors, such as venetoclax. We have anti-CD20 antibodies such as rituximab (Rituxan). And these three drug classes play a crucial role in newly diagnosed patients with CLL.

And as I mentioned, we also have CD19 CAR T, which was approved last year and is really an important tool for us for patients whose disease has relapsed. I also thought I would take this moment to emphasize the point that it has been just about one decade when ibrutinib was first approved for patients with CLL. Ibrutinib was approved in February 2014. And that was the first really revolution which brought about in the context of CLL, and now, we’re just over 10 years out, and now you can see how much the field has evolved with new drugs. But I think an important point for us in the field is how we can design better, safer regimens for our patients, which can potentially, as was mentioned in the initial presentation, could cure patients and give them a normal life span and a healthy life span without any side effects.

Again, in the field of CLL as we have moved away from chemotherapy, the three classes of drugs, namely BTK inhibitor, BCL-2 inhibitor, and the CD20 antibody, which you see listed on the right side of the slides are really the tools which we have and a lot of work which we and others are doing are how best to combine these drugs together. The ones which are highlighted, or grayed out, are the ones such as nemtabrutinib, sonrotoclax (BGB-11417), lisaftoclax (APG-2575), are drugs which are not yet FDA-approved, but they are in clinical trials. But we have multiple BTK inhibitors, covalent and non-covalent, approved. And again, we work with really all of them for patients, but in clinical trials, we have focused on ibrutinib, acalabrutinib (Calquence), and  pirtobrutinib in combination strategies.

So, I’m going to mention to you two different trials which we have worked and have been really helped and funded by the CLL Global. The first one is a trial which we designed almost – more than 10 years ago, back in 2014, combining ibrutinib with sonrotoclax as two oral target therapies in patients with CLL. We have five-year follow-up data, and soon, we will hopefully publish seven-year follow-up data for these patients.

So, ibrutinib and venetoclax are both oral drugs. And what we argued, and there was a pre-conclude work done by Dr. Varsha Ghandi, here in our lab, that the combination is synergistic. So, based on that, we designed this trial combining Ibrutinib plus venetoclax, given for two-year duration. And the study was published in The New England Journal several years ago, and now it was updated also in a German oncology paper.

So, with this regimen, we treated 120 patients with newly diagnosed CLL who needed treatment. So, two pills, no infusions, given for a total of two years. Now, this is a slide, but the point I’m trying to emphasize here, whatever you see green is patients whose bone marrow was negative bi-flow cytometry for CLL. And that’s a very good level, deep level of remission, by MRD. Bi-flow cytometry, as you can see, upwards of 70 percent of patients were in this deep level of remission in the bone marrow, making the point that this kind of regimen of Ibrutinib plus venetoclax can be quite effective for patients.

Now this was our own trial. This regimen has been pursued by many other groups, including larger studies like the CAPTIVATE study, the FLAIR study, and the GLOW study, and this regimen is actually approved outside of the United States for patients with CLL. And, as I mentioned before, this work was in part funded by CLL Global Foundation to help us manage these patients.

This just shows, again, the progression for survival, which is the number of patients who are alive and well five years out. And while survival, which again, looks very excellent for this regimen with two oral drugs for these patients. Now, other regimen, which is the most recent one I want to talk to you about, is a combination of pirtobrutinib and obinutuzumab (Gazyva). Now, just as a background, ibrutinib is a covalent BTK inhibitor. It was the first generation. Pirtobrutinib is a non-covalent BTK inhibitor which is approved for patients who have failed drugs such as ibrutinib. So, it is a more effective BTK inhibitor, we think. It is also a very safe BTK inhibitor.

And we argued, and this trial was – we started designing it about five years ago, that combining the best available drugs we have, namely pirtobrutinib, namely venetoclax an infusion of obinutuzumab can provide the patients a very, very high rates of remission. And that’s what our hypothesis was going into this clinical trial. Now, this is just a schema, but the point here is that we give this regimen for a one-year duration, with a possibility of a second year for a selected group of patients. What I’m showing you is the data which actually we will be presenting in our oral presentation at ASH in a couple of weeks.

But, what you see here is the green here, for example if you just focus on the green, what I’m highlighting with my pointer, 86 percent is in the blood at one year mark, 86 percent of the patients were MRD undetectable by an essay called Next Generation Sequencing assay at 8:08. So, this is a much deeper level of assay which can detect one cancer cell in one million. And 86 percent of patients were negative by that assay in blood, and 74 percent were negative by that assay in bone marrow. In fact, if you look a more traditional way, what is the flow cytometric cut-off to corresponding numbers would be 196 persons.

Just making a point that we achieving with these regimens very high rates of remission and I think one of the things with this regimen, we are continuing to enroll more patients and we are working with our group here to assess the quality of studies to see which patients are responding and if there are some patients who are not responding, what is the reason for non-response? And this is the regimen, as I said, we’ll be officially presenting in an oral presentation at ASH in a couple of weeks.

Now, just last maybe few more slides. What are the new stuff we and others, I guess, involved in in the context of CLL? I just want to mention a few drugs three kind of agents, but just focus briefly on BTK degraders. So BTK degraders is a new class of drugs which have come along in the last couple of years. These are oral drugs; they degrade the BTK protein, and they are actually working very well for patients whose disease has relapsed. There also CD20 and some emerging CD19 by specific data in the context of CLL. And also, as I mentioned, CD19 CAR T is approved for relapse or fracture in CLL.

As I wanted to focus my talk on the front-line strategy, I just wanted to maybe highlight this BTK degrader; there are several BTK degraders in clinical development. Nurix has one,  BeiGene has one, AbbVie has one. We are working with BeiGene, or no, it’s called BGB-16673, and the reason I’m highlighting this is that we have an upcoming study investigating a new trial coming up with a BGB degrader plus sonrotoclax in first-line CLL. This is a trial which we are about to finalize the protocol, and hopefully we’ll open in about three months.

So, this will be for patients who are newly diagnosed with CLL who need treatment, and they will be given two oral drugs, namely BGB-16673, which is a degrader of BTK, and sonrotoclax, which is a BCL-2 inhibitor. We are very excited about this combination, and as far as I can tell, this will be the first time a degrader will be investigated in first-line CLL, ever in any study. So, we are excited to open this, and again, hopefully, your help can support this study as well.

And as I mentioned, in terms of our front-line portfolio at MD Anderson, we have the perk of an open trial, which we just expanded to 160 patients. I just mentioned to you about the degrader plus sonrotoclax trial, which will have the potential of two oral drugs and bringing degrader in the first-line setting. And then we’ll also have a trial of zanubrutinib (Brukinsa) and sonrotoclax  and obinutuzumab. Another triplet, but we’ll kind of introduce obinutuzumab a bit late in the mix here. And that is another trial we are working on, and hopefully will open in the next three to four months as well. So, hopefully, I gave you a flavor of the frontline strategies and some of the trials we are doing, and thank you.