ASH 2025 CLL Research Highlights | Dr. William Wierda

Transcript:

 

Jamie Forward:

So, Dr. Wierda, just this last December, cancer experts gathered from around the world to share their research at the American Society of Hematology annual meeting, also known as ASH. Can you share some of the highlights from ASH with our viewers as well as any other CLL research updates?

Dr. William Wierda:

I would be happy to do that. I have some slides because most of us are most comfortable talking with slides. As you indicated, every year we have a large meeting, and I think most of the participants probably are familiar with that, that we are reviewing both benign and malignant hematology advances and research. And the most important findings are being presented at this meeting, and that’s the American Society of Hematology meeting.

So, I have two slides that summarize the highlight presentations that were made at the December meeting, and I’m just going to walk through each of those to give you an idea of what was presented and what we’re talking about this year, what we talked about last year, I should say, December 2025 at ASH.

And I’ve divided these into two slides, one for previously untreated patients and one for previously treated patients, and I’ll just walk again through each of those. So, the first item there is a trial that the German CLL study group has done called CLL-17. The first time it was presented was at this last ASH meeting. That was a randomized trial of different treatments for patients with CLL, no chemotherapy and patients would receive either ibrutinib (Imbruvica), ibrutinib plus venetoclax (Venclexta) or venetoclax plus obinutuzumab (Gazyva).

This was actually a plenary presentation, meaning it was the top of the top presentations. There’s a plenary session where the top of the top data is presented, and this particular abstract was presented as a plenary session, and it demonstrated the outcomes were similar in terms of progression-free survival between all three of those treatments for patients who received them in the frontline setting.

And I think it does support an approach of fixed duration treatment, meaning treatment to get patients in a remission and get them off treatment, so they can enjoy their remission with a reasonable expectation of a long progression-free survival or long remission duration. And that you could achieve similar outcomes at least with a follow-up that we have from this study if patients receive venetoclax-obinutuzumab compared to if they receive ibrutinib continuous treatment, for example. And so that was an important trial.

I think for me it will also be important to see what the follow-up is from that trial because it’s a frontline trial. In order for us to get a full understanding of the impact of a treatment and the value of a treatment in the frontline setting, we need a long follow-up to see how long those remissions last and how patients do long-term.

Moving to the next trial, this was two Phase III trials actually that looked at pirtobrutinib (Jaypirca) in previously untreated patients, and those were CLL-313 and CLL-314, both randomized Phase III trials that were done by Eli Lilly. In 313, patients were randomized to receive treatment in the frontline setting with either pirtobrutinib, which is a non-covalent BTK inhibitor that we associate with better tolerability, less side effects and toxicities, a low risk for atrial fibrillation compared to ibrutinib and the other second-generation BTK inhibitors that are covalent BTK inhibitors.

And so that was one trial that was presented with pirtobrutinib. Frontline, it demonstrated improved progression-free survival for patients who received pirtobrutinib compared to chemotherapy or bendamustine (Treanda) plus rituximab (Rituxan).

The BRUIN CLL-314 trial was a trial that randomized patients between pirtobrutinib versus ibrutinib. And it was a mixed population, 30 percent of them had been previously untreated, 70 percent of them were previously treated, and that was a noninferiority trial that was intended to show that the outcomes were no worse with pirtobrutinib compared to ibrutinib in the frontline setting. And, in fact, there were trends of improvement in outcomes for patients who received pirtobrutinib over ibrutinib in that analysis. Again, we need longer follow-up.

The follow-up was relatively short, but these two trials are encouraging data looking at more selective BTK inhibitor, pirtobrutinib being used in the frontline setting and the impressive tolerability with that agent and efficacy. Moving down to the next trial is a Phase III trial called FLAIR.

There were several abstracts that were presented, three of them, in fact, related to the FLAIR data. The FLAIR data highlights the regimen of ibrutinib plus venetoclax where that combination is given from two to six years. It’s based on MRD response, and the data continued to be impressive and confirmed the improved outcomes for patients who received the combination of ibrutinib and venetoclax. Not currently approved in the FDA, but it is on the NCCN guidelines.

I think the main concern with that regimen has been the use of ibrutinib and the toxicities we see with ibrutinib. Nevertheless, it’s a very effective combination. We’ve done work with ibrutinib and venetoclax, and we will continue to see updates from that data that has been very positive. There’s a Phase II trial with sonrotoclax, which is a newer BCL2 inhibitor that work similar to venetoclax where a combination was being tested of sonrotoclax plus obinutuzumab.

This appeared to be a well-tolerated combination. The follow-up is very short in the presentation of this Phase II data, but it is encouraging and the responses were encouraging. We’ll see what the longer follow-up with that combination looks like in the frontline setting. Dr. Jain from MD Anderson presented an updated presentation on our Phase II trial with pirtobrutinib, venetoclax, and obinutuzumab, which has been evaluated in the frontline setting. He reported on the responses among 80 patients who received it as their first treatment.

It’s 13 cycles of combined treatment. The outcomes have been exceptionally good where almost 90 percent of the patients consistently achieved undetectable MRD remission by the end of treatment.

And so, we’re excited about this combination. It’s probably the most effective combination that we’ve tested, and we’re excited to see what the follow-up will be for those patients, but a very high undetectable MRD rate by clonoSEQ, which is the most sensitive measure of minimal residual disease, and again I mentioned that that’s 90 percent MRD-undetectable by clonoSEQ. Dr. Ferrojoli, in fact, has a trial with that same combination for previously treated patients, and so far, I’m encouraged by the patients that I’ve treated on that combination, and we’re seeing good outcomes for those patients.

The last item on that list is our Phase II trial with acalabrutinib-venetoclax (Calquence-Venclexta) with or without early obinutuzumab, and the update from that presentation that Dr. Swaminathan made on our study was that obinutuzumab could be delayed.

Administration in that combination could be delayed till later, the first six months of the second year on treatment, and if that was the case, it was equally effective and perhaps had less associated side effects and toxicities associated with it. And so, we haven’t published that data yet, but we’re in the process of summarizing it. Moving into relapsed and refractory disease, I mentioned the Phase III BRUIN CLL-314 trial pirtobrutinib versus ibrutinib demonstrating noninferiority of pirtobrutinib over ibrutinib, and, in fact, response and progression-free survival perhaps better for patients who received pirtobrutinib over ibrutinib.

Lisaftoclax is another BCL2 inhibitor that’s been developed by a company by the name of Ascentage. There were data presented on a Phase II trial with lisaftoclax as monotherapy. We see activity with that compound in previously treated patients with CLL.

And that development continues including in combination trials, combination with acalabrutinib, for example, is being evaluated with lisaftoclax. The next item is a Phase I trial. I spelled it incorrectly. It should be rocbrutinib, R-O-C, not R-O-X. Rocbrutinib has been known previously as LP-168. That’s a BTK inhibitor that works both covalently and non-covalently that’s in development and Jen Woyach presented an update on that compound.

It appears to have activity including in patients who have resistance to covalent BTK inhibitors like acalabrutinib, ibrutinib, zanubrutinib (Brukinsa) and including patients who have various mutations in BTK that have been associated with resistance to covalent BTK inhibitor. So, you’ll hear more about rocbrutinib in further development. It has activity particularly in patients who are failing covalent BTK inhibitors.

There are two degraders. Actually, there are three BTK degraders in development. We heard presentations on two of those, BGB-16673, which is being developed by BeOne, and bexobrutideg, which is NX-5948 being developed by Nurix. The data that were presented were expanded Phase I, cohorts of patients who received in the relapsed setting either of these two BTK degraders.

And we’re seeing activity in patients who are treated with both of these agents either the BGB-16673 or the bexobrutideg particularly in patients who have failed a covalent and noncovalent BTK inhibitors and patients who have various mutations in BTK associated with resistance to the inhibitors.

The degraders work differently than the inhibitors. The inhibitors will bind to the BTK protein and block the enzymatic function of BTK. The degraders bind to the BTK and cause the cells to degrade the protein so they eliminate the protein, which is different than inhibiting the function. And I think these drugs will be very important as treatment options for patients who have had our inhibitors and have developed resistance to inhibitors.

There was an abstract presented as a real-world experience with the liso-cel (lisocaptagene maraleucel [Breyanzi]) or CD19 CAR T-cell therapy where in the real-world experience in patients who have received that treatment, the response rates have been higher than what was reported on the liso-cel TRANSCEND CLL 004 trial, and so that was encouraging data because it looks like the use is better in the hands of the community or the centers that are using it than what we have reported for the clinical trial.

Then, there were two trials that were presented for patients with Richter transformation. The first one was one that Dr. Jain presented from our group. It was a cohort of 15 patients with Richter transformation who received combined pirtobrutinib, venetoclax, and obinutuzumab. And so far, we haven’t been impressed with the response rate with that combination and the durability of the responses. The follow-up is reasonably short, and the number of patients who’ve been treated are limited, but we’re seeing activity with the combination.

It’s very well-tolerated and so our work with that combination continues, and then the CLL study group presented an update on the checkpoint inhibitor with zanubrutinib-tislelizumab (Brukinsa-Tevimbra) with zanubrutinib for patients with Richter transformation.

And that’s a nonchemotherapy option, has activity in treating patients with Richter transformation, and we’ve done work with nivolumab (Opdivo), and there are others that have worked with other various checkpoint inhibitors which appear to have activity in treating Richter transformation, not such great activity treating the CLL. There are a number of meetings coming up where we’ll hear more data. Again, the big meeting for us is the ASH meeting, but we do oftentimes hear updates at these other meetings such as the European Hematology Association, meeting ASCO, the German CLL study group meeting, etcetera.