ASH 2022 | Key highlights in CLL: clinical trial updates & the role of combination therapies and novel BTKis

Matthew Davids:

Hi, I’m Matt Davids from Dana Farber. I’m here with my good friend and colleague, Lindsey Roeker from Memorial Sloan Kettering. We’re here to discuss some of the highlights from the 2022 ASH meeting in CLL. So Lindsey, this morning you co-moderated a session that was focused on doublet therapies with ibrutinib plus venetoclax, two very important drugs in CLL. There were actually six abstracts presented with this doublet. Clearly an important regimen. So what were some of the takeaways from this session for you?

Lindsey Roeker:

This morning we really saw a lot of longer term follow up on studies that we’ve seen before. So, we saw further follow up on both CAPTIVATE and GLOW. So CAPTIVATE being a Phase II study. Today’s focus was really on that population who had achieved undetectable MRD, looking at those who had received either placebo or ibrutinib. We see that both sets of patients are doing extraordinarily well. We saw longer term follow-up data from I+V in a study from MD Anderson. Dr Jain presented that this morning and saw that there’s really long-term efficacy with this regimen.

Then we also learned more about unmutated versus mutated IGHV and how that plays into responses for patients treated with this combination.

Then finally, we saw an add-on approach. So patients who had received ibrutinib in clinical practice and then had venetoclax added to the regimen. Really proving that you can consolidate responses and then have treatment-free observation periods with durable response after discontinuing therapy.

So, a lot of data coming out of this. I think really seeing that I+V is going to be a future very important player in CLL and still really figuring out exactly how it fits in and for whom we should be using it.

Matthew Davids:

I think just to highlight that last abstract in particular, with Dr Thompson’s data now, we have a lot of patients out there who are on ibrutinib as a monotherapy continuous treatment. A lot of them would like to come off drug. So I guess based on these data, do you feel more comfortable with the strategy of adding in venetoclax to get patients off ibrutinib?

Lindsey Roeker:

Yeah. I mean, these data look great. I think we’re seeing that there is the possibility of taking patients on BTK inhibitors, who are not achieving deep responses just by mechanism of BTK inhibitors. But by adding venetoclax, we’re able to achieve deeper responses and patients are able to come off of these drugs. So, obviously not a standard of care yet, but I think it’s going to be a future option for our patients who are on these monotherapies. A lot do experience some form of toxicity or some side effect, that there is a goal to get off treatment.

Then beyond I+V, we’re also going to see data presented at this meeting on triplet therapy. So, can you tell us a bit about that?

Matthew Davids:

Triplets are building on the I+V type of experience with a BTK inhibitor, Bcl-2 inhibitor and adding an antibody. Typically obinutuzumab is the antibody. So, there’s a session with actually two different studies. One is looking at the IVO triplet with ibrutinib, venetoclax and obinutuzumab. This is a study that focused exclusively on patients with high-risk disease, Deletion 17p or TP53 mutation. Even despite the fact that these were high-risk patients, they saw high rates of undetectable MRD, high rate of complete remission. The durability seems good so far. I think one of the challenges though as we think about rolling that out to a larger patient population is there are some of the typical ibrutinib side effects, atrial fibrillation, hypertension, some infectious complications.

So in the same session we’re actually presenting data from our AVO triplet study, with acalabrutinib, venetoclax and obinutuzumab. Similarly, we’re seeing high rates of undetectable MRD and complete remission, but I do think the tolerability seems better, as we’ve seen from head-to-head studies comparing ibrutinib with acalabrutinib. So, hopefully that’s the type of regimen we could potentially in the future roll out to larger numbers of patients, even those who are older and with comorbidities. So, not practice-changing yet. There’s a Phase III study with AVO that we’d need to read out first and show that that’s superior to the current standards of care. But we’re certainly optimistic about the data, based on our Phase II experience.

Lindsey Roeker:

Fabulous. Do you see, is the combination of acalabrutinib and venetoclax also being explored? Because we obviously saw a ton of data on I+V.

Matthew Davids:

Yeah, exactly. There are a number of studies underway, looking at acalabrutinib and venetoclax as a doublet. We haven’t really seen much in the way of data presented yet. The study I just referred to of AVO versus chemoimmunotherapy also has an AV doublet arm. So, that’s the amplified study. Hopefully we’ll read out relatively soon. That’s going to be an important dataset.

The other study that we’re very excited about, that I know you have open at Memorial as well is called the MAGIC study. That’s looking at an all-comer population in the frontline setting, comparing acalabrutinib and venetoclax to venetoclax plus obinutuzumab, with both arms being guided by MRD in terms of therapy duration. So I think, eventually we’ll have a lot more AV data, and I think that’s also a promising doublet.

Lindsey Roeker:

Exciting upcoming data for sure.

Matthew Davids:

Yeah.

Lindsey Roeker:

The other abstract that I think we’re all really excited to see is the ALPINE study. So could you tell us a little bit about that and how that you see that informing your practice?

Matthew Davids:

Yeah. ALPINE is a study in the relapsed setting, comparing patients treated with continuous zanubrutinib, a newer, more selective BTK inhibitor, compared to ibrutinib, traditionally within the standard of care over the last few years. We had seen some early data from the ALPINE study readout last year, which did look promising, but it was very immature at that time. So, I think we’re very excited at the late-breaking abstract session here at ASH, to see the updated data with longer followup from ALPINE. In addition to seeing improvements in the safety profile of zanubrutinib compared to ibrutinib, we also see now a PFS benefit that seems to be maintained with, I think close to 30 months of follow up based on the abstract. That’s pretty intriguing to see a PFS benefit in this setting. I don’t know. What do you make of that? Do you think that that’s going to be practice changing?

Lindsey Roeker:

I think it’s going to be a really exciting change because it’s the first time we’ve actually seen a covalent BTK inhibitor outperform another covalent BTK inhibitor. In the study of acalabrutinib versus ibrutinib, the hazard ratio for progression-free survival is 1.00. So, efficacy is completely similar for those two agents. So, I think it is going to be interesting to see those data. I think that zanubrutinib, obviously not yet FDA-approved for CLL, but probably is going to have an increasing role in the treatment of CLL.

Matthew Davids:

Yeah, I agree. I mean I think for me, the ALPINE study’s pretty convincing, if I was considering ibrutinib versus zanubrutinib, that I’d want to choose zanubrutinib. But I think the tougher challenge is zanubrutinib versus acalabrutinib because we don’t have a head-to-head comparison there. We’re looking across different studies that were done at different times, with different methodologies. So, I think that’s going to be an ongoing thing.

Lindsey Roeker:

And different follow up.

Matthew Davids:

Exactly.

Lindsey Roeker:

So, I think we’re also going to see with more time, what happens with ALPINE and how the toxicity profile evolves over time as well.

Matthew Davids:

Yeah, great point. I think those are some of our key takeaways from CLL at ASH 2022. We hope you enjoyed watching this video. Thank you very much.