Zanubrutinib, Liso-Cel Data Highlight the Evolving Treatment Landscape in CLL

Luke J. Mountjoy, DO

Data for the selective BTK inhibitor zanubrutinib (Brukinsa), included findings from the phase 3 ALPINE study (NCT03734016) that compared the agent against ibrutinib (Imbruvica), have had key implications for the treatment landscape for patients with chronic lymphocytic leukemia (CLL), according to Luke J. Mountjoy, DO.

Zanubrutinib was approved by the FDA for the treatment of patients with CLL or small lymphocytic lymphoma (SLL), based on data from the phase 3 SEQUOIA trial (NCT03336333), in January 2023.¹ Data from ALPINE then showed that zanubrutinib led to an improvement in progression-free survival (PFS) vs ibrutinib, and zanubrutinib was associated with fewer cardiac adverse effects (AEs).²

“Ibrutinib is still a very good drug, but zanubrutinib is probably the way to go in the relapsed/refractory setting based upon the ALPINE study,” Mountjoy explained.

In an interview with OncLive®, Mountjoy, an assistant member physician at the Colorado Blood Cancer Institute, in Denver, Colorado, discussed the implications of the SEQUOIA and the ALPINE trial, the importance of coming up with feasible and effective treatment options for patients with 17p deletions and TP53 mutations, and the investigation of lisocabtagene maraleucel (liso-cel; Breyanzi) in patients with relapsed/refractory CLL.

OncLive: How does zanubrutinib differ from other BTK inhibitors, and what may make it a more effective option?

Mountjoy: Zanubrutinib [and ibrutinib were] compared [in the ALPINE trial]. Zanubrutinib, specifically compared to ibrutinib, has a more selective BTK inhibition.

Another thing that's unique about zanubrutinib is that while it is similar to ibrutinib and acalabrutinib [Calquenca] in the sense that it binds to BTK, if you look at some of the pharmacokinetic data with zanubrutinib, it looks like it persists in the bloodstream longer than ibrutinib. Therefore, you get better, more consistent BTK inhibition. It raises the question: if a patient is on ibrutinib, do they lose BTK inhibition over time? When there are new clones of the underlying disease replicating, are we not inhibiting that? Our best guess is that there is better BTK inhibition that is sustained and persistent [with zanubrutinib], inhibiting new CLL formation.

What key data from SEQUOIA supported the FDA approval of zanubrutinib? How does this approval underscore the importance of next-generation BTK inhibitors?

SEQUOIA looked at zanubrutinib vs traditional bendamustine plus rituximab [Rituxan]. [Notably,] in the process of [designing] the trial, it was still reasonable to give bendamustine and rituximab. As we know now, we generally avoid traditional chemoimmunotherapy in place of these newer drugs, such as BTK inhibitors and BCL-2 inhibitors. SEQUOIA followed a standard [design] we see in CLL, where you take a newer therapy [and compare it to] traditional chemoimmunotherapy.

I appreciate any time a clinical trial looks at AEs and quality-of-life measures, which they subsequently did. In SEQUOIA, patients were [randomly assigned] to zanubrutinib vs bendamustine plus rituximab, and they found that there was a superior PFS in patients receiving zanubrutinib.

Something that's extremely important [to note] is that zanubrutinib had good activity in patients with 17p deletions or disruptions in TP53, which is a high-risk finding in CLL. We have data showing that utilizing traditional chemoimmunotherapy in patients with this disruption of TP53 or 17p can lead to inferior outcomes because you could select out the more aggressive clone, and the disease could get more aggressive. Credit to the trial design, because any patient with disruptions in 17p and TP53 received zanubrutinib. A nice PFS benefit was seen from those patients, as well. When you look at the AEs, grade 3 [or higher] AEs were, across the board, lower in the patients in the zanubrutinib arm.

In update [presented at the 2022] EHA Congress, they looked at quality-of-life measures using the European Organization for Research and Treatment of Cancer QLQ-C30, and they found that patients on zanubrutinib compared with traditional chemoimmunotherapy tended to have better physical functioning, less diarrhea, less fatigue, and less AEs. Across the board, using BTK inhibitors as opposed to traditional chemoimmunotherapy is the way to go.

What impact did key data from ALPINE have on treatment decisions in this space?

The ALPINE trial is another nice design where they [evaluated] patients with relapsed/refractory CLL/SLL who had at least 1 line of prior therapy. [These patients were randomly assigned] to zanubrutinib or ibrutinib. There were other stratifications for those patients with 17p [deletions] or TP53 [mutations]. They looked at non-inferiority and [potentially] superiority of an investigator-assessed overall response rate [ORR]. [Patient] characteristics for this randomized trial were similar [for both arms].

They found that there was a PFS benefit for zanubrutinib over ibrutinib. At 24 months, the PFS with zanubrutinib was [78.4% vs 65.9%] with ibrutinib. It was a modest but meaningful PFS [benefit]. That seemed to translate across the board. Patients with disruptions in 17p or p53 appeared to have a benefit with zanubrutinib over Ibrutinib. This goes back to the pharmacokinetics and the more selective BTK binding of zanubrutinib over ibrutinib.

That [PFS] benefit has not translated into an overall survival [(OS) benefit] yet. These are still early data, and over time, [we will have to see] if these curves start to separate and translate into OS. We don’t have an OS benefit from using one over the other, but we see a modest benefit using zanubrutinib over ibrutinib.

One of the things they saw on the study was a little more neutropenia with zanubrutinib [over ibrutinib], but AE profiles were very similar, with the exception of cardiac events. Most of us have had issues in the past with ibrutinib causing atrial fibrillation, and in this trial, we saw substantially less serious cardiac AEs from zanubrutinib. There were no fatal cardiac events in the zanubrutinib arm, but there were [6] in the ibrutinib arm.

What has been seen with the use of liso-cel in the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198)?³

Patients with CLL, when moving through the lines of therapy, specifically those with 17p deletions, we are not sure any of those drugs are curative. There are data on combination BCL-2 inhibitors with BTK inhibitors and rates of minimal residual disease [MRD]. Could that be curative with combinations? We need longer data.

In the other disease spaces, the other non-Hodgkin lymphomas, we see these CAR T-cell therapies have curative-intent potential. This is something we as a medical community need to [work] on for patients with CLL.

[TRANSCEND CLL 004] was a nice phase 1 study where patients with relapsed/refractory CLL who have had previous lines of therapy were treated with liso-cel, a standard CAR T-cell therapy, with standard lymphodepleting chemotherapy with fludarabine and cyclophosphamide. It had the same AE profile that is expected using CAR T-cell therapy in other hematologic malignancies.

One of the important things is that day-30 ORR [was 68%], and it looks like those response rates get better over time. We have short follow-up here, so we’re looking forward to longer-term follow-up there, but when patients get rendered MRD negative—[65%] were MRD negative [in the bone marrow]—that's really meaningful. We must come up with better curative-intent therapies for CLL outside of an allogeneic stem cell transplant, which is an effective but morbid procedure.

When you see these response rates, it's very encouraging. I'm hopeful that we'll be getting some updated data from this phase 2 trial that they've opened, and what's going to be interesting is that they have a combination [arm] using liso-cel and ibrutinib together, which will be interesting to see.

How do you approach treatment for patients with CLL who have progressed on covalent BTK inhibitors, given the unmet need for these patients?

The answer is always clinical trials. However, in the absence of a clinical trial, if a patient has had a BTK inhibitor, I generally flip them to a BCL-2 inhibitor if they haven't been exposed to a BCL-2 inhibitor, so something like a venetoclax [Venclexta]-based regimen. If we started on one of the earlier-generation BTK inhibitors like ibrutinib, should we flip to something like zanubrutinib? This is a very reasonable thing to do. I see that done routinely, and you can see response rates.

I tend to change therapy to BCL-2 inhibitor to take that pressure off BTK so that in the future, at next progression, flipping back to a BTK inhibitor like zanubrutinib or acalabrutinib [in an option]. In the absence of robust data on how we think about clonal tides and clonal evolution, this makes more sense right now when you think about it mechanistically.

How do you see the treatment paradigm for CLL shifting as future studies are conducted?

Thankfully, we're getting some brisk movement in the CLL space. We all want to watch closely for these CAR T therapies. We’re also seeing promising data in non-Hodgkin lymphoma using bispecific T-cell engager therapy. Moving those drugs into the CLL space is going to be critical.

Right now, most of us tend to reach for a BTK inhibitor as our frontline treatment. Whether it's a BTK inhibitor or a BCL-2 inhibitor for frontline, we don't know yet. It's one of the age-old questions in oncology: How do I sequence my therapies in the absence of randomized trials? We have all these effective drugs, and now we're doing studies using these effective drugs in combination, combining BCL-2 inhibition with BTK inhibition. Maybe that will be the way to go, and maybe we are going to render patients MRD negative and potentially curative. We need more robust, longer follow-up data to know for sure. It is an exciting time for CLL right now.

References

1. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed June 7, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582
3. Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2022;139(12):1794-1806. doi:10.1182/blood.2021011895