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How Are Combination Therapies Improving Outcomes in CLL?

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Published on September 14, 2021

Combination Therapies Are Improving Patient Outcomes

With so many new treatments for CLL, both approved and in late-stage trials, studies have turned to improving outcomes by combining drugs with different targets. In this segment, Patient Power co-founder and CLL patient advocate, Andrew Schorr, is joined by CLL expert, Nitin Jain, MD, of MD Anderson Cancer Center, to discuss the lessening role of chemotherapy in CLL treatment and how combination therapies have dramatically changed how doctors are treating CLL. They also discuss the promising results achieved through the use of innovative drug combinations.

Support for this series has been provided by AstraZeneca Oncology. Patient Power maintains complete editorial control and is solely responsible for program content.

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Transcript | How Are Combination Therapies Improving Outcomes in CLL?

Andrew Schorr: Hello, and welcome to Patient Power. I'm Andrew Schorr, now a CLL patient for 25 years. And joining us from MD Anderson Cancer Center in Houston, Texas is a regular on Patient Power, and a noted CLL specialist, Dr. Nitin Jain. Thank you so much for being with us again.

Dr. Jain: Sure, absolutely. Great to be here.

Andrew Schorr: Okay. So, the name of the game, and we've talked about it many times, is combination therapy for successful treatment for CLL. I had it at your institution 21 years ago, and that was then adding rituximab (Rituxan) to fludarabine (Fludara) and cyclophosphamide (Cytoxan), FCR. And then many people got it. And I had a 17-year remission, which I'm very grateful for. But now, in recent years, we have many new agents, both approved, and promising and late-stage trials. So, you have with your colleagues, studies, some you've been involved in personally, combining different agents.

So, let's talk about combination therapy, where we are today. And first, let's start with, for somebody like I was 21 years ago, having had no treatment, but needing treatment, what's your thinking now? And, what's the data related to combination therapy for a patient being treated for the first time?

What Are Combination Therapies?

Dr. Jain: So, the field obviously has changed dramatically in the last 20-25 years, more so in the last five years. So, I think when we talk about combination therapy these days, we are really, in some sense, not talking about chemotherapy anymore. The role for chemotherapy has really, really declined. And I can tell you that our center, we are not really using chemotherapy at all for patients with CLL. So, the combination therapy really means combining drugs with different targets together. So, I think there are three main classes of therapy we are using these days for CLL.

So, one is the BTK inhibitors. So, here we have ibrutinib (Imbruvica), we have acalabrutinib (Calquence), we have zanubrutinib (Brukinsa), giving some nice data. And then we have LOXO-305, which is pirtobrutinib, which is also coming along. So that's the BTK inhibitor. Then we have Bcl-2 inhibitor, which there is only one drug right now, venetoclax (Venclexta). So that's one drug for that class. And then we have CD20 antibody, for which really the two main ones are rituximab or obinutuzumab (Gazyva). So, these are the three main classes of drugs.

Now there is also a PI3 kinase inhibitors, which are more relevant in the lab setting, not that in the front, at least at this time. But if you look at these three classes of drugs, BTK, Bcl-2, and CD20 antibody… So basically, you can mix and match them together, to form different combinations and all sorts of formulations have been done, are being done right now. So, you can take ibrutinib, you can combine it with the CD20 antibody, you can take ibrutinib, you can combine it with obinutuzumab.

You can take ibrutinib and venetoclax and also do a triplet, add with the CD20 antibody altogether. So, a lot of these trials are happening right now, in what is called Phase 2. Some are also being tested in Phase 3 clinical trials. But what is approved right now, FDA approved right now, in the frontline setting in terms of combination, is really the combination of venetoclax plus obinutuzumab, which is two drugs together, one IV, one pill, which is approved in the frontline setting. We also have ibrutinib approved in the frontline setting, but that just stand-alone. And we also have acalabrutinib approved, which actually can be used alone or in combination with obinutuzumab as well. So, there is some data to that effect.

Those are the three kinds of regimens available. Then there is a combination of ibrutinib plus venetoclax. So, two pills together, no antibody at all. That's something which we saw some data at the EHA meeting, European Hematology Association meeting a couple of months ago, positive data. So, it is expected that it may get an approval by the FDA, these two oral drugs together for patients with CLL as well. That's something which is expected, maybe in the next six months. We'll see.

Andrew Schorr: Okay. Now how do you extrapolate from some of this? So, for instance, ibrutinib plus venetoclax, does that mean that the acalabrutinib would work as well?

What Is the Benefit of Combining Treatment Drugs?

Dr. Jain: Yeah, so that's a tricky question. That's a good question. And I think... There is this recent, some medical data reported in relapsed patients with CLL, where they gave half of the patients ibrutinib and half of the patients acalabrutinib. And these are patients whose disease had relapsed after chemotherapy. And what they found was that after a few years, about three years later, both the groups, it was equally effective. So acalabrutinib was equally effective as ibrutinib, but acalabrutinib had less side effects, less risk of heart issue, atrial fibrillation, less hypertension and less diarrhea and other side effects as well. So, it appeared that acalabrutinib was safer, and equally effective, compared to ibrutinib for patients whose disease had relapsed. Now you could extrapolate that to a newly diagnosed patient as well, because you would say that if it works for the relapsed patients, it should work for newly diagnosed as well in the same way.

So, right now, I think when the drug... The trial, which will lead to approval of the ibrutinib plus venetoclax, I think the FDA approval will be for ibrutinib plus venetoclax. I guess a question in the field, and for the CLL investigators and others, will be can you swap the BTK inhibitor to acalabrutinib, or maybe zanubrutinib. So, I think that’s… Things are being done now in clinical trials. We have a trial right now with acalabrutinib plus venetoclax at our center. Other groups are doing zanubrutinib-based trials as well. I think unless we know more about those trials, that is very likely, I think eventually that we will be able to use potentially different BTK inhibitors in the frontline setting, in combination with venetoclax. But the first one to go into that space will be ibrutinib plus venetoclax.

Andrew Schorr: So doctor, you mentioned the CD20 monoclonal antibodies. Let's talk about rituximab first, then obinutuzumab, which I've received as well. I've received both. So, it's an infused therapy where the others you're talking about are pills. So that means coming into the clinic. There's also the question of whether these drugs depress the immune system during COVID, anything about immunity we worry about. So how essential is a CD20 in the combination, do you feel?

Dr. Jain: Right now we truly don't know because the clinical trials… So ideally to know that, you have to do a clinical trial where you are giving a patient ibrutinib plus venetoclax and another group of patients you give ibrutinib plus venetoclax, plus the CD20 antibody. So, you do a randomized trial. Some of those trials are happening right now, but they’re not expected to be reported anytime soon.

But if you look at other Phase 2 data, where single centers have done these combinations, there doesn't appear to be, so far, a really incremental benefit over the two drugs alone. So, if you have a BTK inhibitor, again ibrutinib, acalabrutinib, or zanubrutinib, you can pick, you add venetoclax to it. Whether you need the third component, whether you need a CD20 in the body, it's not clear at this time. And those are being tested in clinical trials.

So I don't think you will be able to access those as a standard therapy, outside of the clinical trial setting. But they are being given an opportunity to trial, with a goal to see if that will lead to deeper remission, more MRD negative remission. And whether eventually, what is most important is two, three, four years down the line, more patients will be alive, in remission and doing well. So those data will take some time to come about. We don't have those right now, but again, certainly in the next two or three years, we'll know more. But at least for now, I don't think, outside of a clinical trial, we should be looking at combining three drugs together.

Andrew Schorr: Right. Well, let me just say though, in fairness to the CD20s, I've had both and they've led to significant remissions added to other therapies, not the BTKs, but I'm grateful. So, they've certainly had their place, but you're right. You need the data in the trials. You mentioned earlier about people who've relapsed, and we're talking about side effects. People who've been previously treated, they may not have quite the strength of somebody who's being treated at the very beginning. So, are there studies related to combinations there? You mentioned about one with zanubrutinib, maybe fewer side effects. Other studies you want to call upon here for combination options for relapsed patients?

Combination Therapy Options for Relapsed Patients

Dr. Jain: In the relapse setting, I think one of the treatment decisions, one of the important factors we have to figure out, when you're deciding what treatment is, what the patient received previously. If a patient received chemotherapy previously, and they have never had any ibrutinib or venetoclax, then the options are slightly different than a patient, let's suppose, that was started on ibrutinib three, four, years ago as the first therapy. And now they're free of ibrutinib when they're coming to you. So, their previous therapy really matters for what you decide on the next therapy. So that's one requirement. But in terms of the coming to the combination aspects, I think one of the most important regimens is the combination of venetoclax plus rituximab, which is based on a trial called MURANO Study; a trial where patients were given chemotherapy in the relapsed CLL, or they were given this doublet. Venetoclax for two years and rituximab for six months.

And what the investigation showed is, not even that more patients were in remission long-term with venetoclax, more patients are alive. So, the survival was also improved. It's very difficult in CLL studies these days to show survival benefit. And when something shows survival benefit, obviously we really should be pursuing that approach and, in the relapse CLL, the combination, venetoclax plus rituximab showed survival benefit over chemotherapy. So, I think that's a very important combination regimen to consider, especially if you have not yet received venetoclax as your first line of therapy. And there are other combination strategies we are seeing. Venetoclax plus ibrutinib is also being studied in the relapsed patient population. We have a trial where we are studying acalabrutinib plus venetoclax, with and without the antibody, in the relapsed population.

So, there are different sorts of combinations, including some new novel targets, which are being pursued. So PI3 kinase inhibitor, not really a novel target, but there is a drug called umbralisib (Ukoniq), which is being tested now both in the frontline and lab setting. And then there are some really new, totally new targets, which are being pursued as part of clinical trials, for patients who have had multiple lines of therapy and their disease is not responding. So, trying to see if there are other targets we could explore. So those are right now main times in Phase 1 studies, but eventually are moving to combining them with other ibrutinib or venetoclax as well, as part of clinical trials.

Andrew Schorr: So it sounds like first combination therapies are the name of the game now, non-chemo, combination therapies. Talking about your own situation, side effect profile in the relapse setting, whether you've had certain previous therapies. But they're choices, and you as an investigator must be excited. But I guess in the end, it's all about the data and what proves out, right?

Are These New Options Improving Patient Outcomes?

Dr. Jain: No, that's true. I think one other important aspect on the same line, now that reminds me, is that one of the things which is also happening in combination therapies are that combination therapies tend to be a time-limited approach.

For example, you're going to give venetoclax plus obinutuzumab for one year in the frontline, two years in the relapsed setting with rituximab. If you're combining ibrutinib plus venetoclax, again, the trial, which will lead to approval at the frontline, is for one year. So, the goal of the combination is you do double or triple therapy, but you finish it in one or two years. As opposed to maybe ibrutinib or acalabrutinib just by itself, which is obviously a very, very effective strategy have been… But you need to take those therapies, forever, or as long as they are working or as they're not giving you side effects.

So it's not just moving from combination therapies or just adding those together. We're also shortening the duration of the therapy to a timely new approach. And then the patient is in remission and they're not in a new therapy for maybe several years, maybe longer. And if the disease comes back, then you can either go back to the same combination therapy or see what's the best available approach at that time.

Andrew Schorr: Right. I vote for that. After I had FCR in 2000, I went 17 years before I needed a treatment again. So, anything that can let you just go on with your life, have just regular check-ups, but not getting a lot of intervention, that's a great thing. It sounds like we're in a new era for CLL and that's very encouraging.

Dr. Jain: No, absolutely. I think these days patients coming to me for new patient appointments, I think one of the things I tell them is that, in many cases patients have looked at online and looking at outcomes and survival and life expectancy, and all those questions. I think in today's world of CLL therapies we have right now, and the ones that are coming along, I really believe that for majority of the patients with CLL, hopefully all, I think with the therapies we have, they can live a normal life expectancy. Because we have really, really effective therapy and the things coming down the line, LOXO-305, some other drugs along are safe, effective. And I think hopefully we can find a nice combination of these drugs so that the patients can live on with their normal lives. And this disease will be there, but maybe not bother them for the rest of their life, normal life.

Andrew Schorr: Well, what an encouraging message for our viewers. Dr. Nitin Jain, thank you so much for being with us from MD Anderson, once again.

Dr. Jain: Thank you, Andrew.

Andrew Schorr: I'm Andrew Schorr. Remember knowledge can be the best medicine of all.

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