BTK- and Venetoclax-Based Approaches Move the Needle Forward in CLL Management

Inhye Ahn, MD

Covalent BTK inhibitors, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), have become the standard of care for most patients with chronic lymphocytic leukemia (CLL), and further efforts are focused on finding optimal combinations and settings for these agents, according to Inhye Ahn, MD. However, venetoclax (Venclexta)-based regimens also play a key role in this disease, and several factors must be considered to choose the optimal approach for each patient.

“The question in the field is how we choose between 2 largely different approaches: continuous treatment with a BTK inhibitor or fixed-duration therapy with a venetoclax-based regimen,” Ahn, a physician at Dana-Farber Cancer Institute and member of the Faculty of Medicine at Harvard Medical School, said.

Data from the phase 3 Alliance (NCT01886872) and CLL14 (NCT02242942) trials demonstrated similar 4-year progression-free survival (PFS) rates. In the former trial, patients who received ibrutinib monotherapy or an ibrutinib/rituximab (Rituxan) combination experienced a 4-year PFS rate of 76%.¹ In the latter trial, those who were given venetoclax in combination with obinutuzumab (Gazyva) achieved a 4-year PFS rate of 74%.² “To [date], these regimens are considered equally effective, at least in patients without high-risk genetic markers,” Ahn said.

To determine which approach is best for each patient, prior treatment status, preference, and safety profiles, all needed to be considered. For example, if a patient experienced atrial fibrillation or cardiovascular diseases in the past, then a fixed-duration approach that does not include a BTK inhibitor may be the optimal approach for that patient.

In an interview with OncLive^®, Ahn discussed the evolving treatment landscape of CLL, the advances made with BTK inhibitors and venetoclax-based regimens, novel combination regimens under exploration, and other research efforts that are underway.

OncLive^®: What are the greatest recent advances made in the management of patients with CLL?

Ahn: The current management of [patients with] CLL largely [leverages] targeted agents, but chemoimmunotherapy regimens have limited roles in young, fit patients who can tolerate [that approach]. Targeted agents have been standard of care for most patients, and this includes multiple BTK inhibitors—especially covalent BTK inhibitors. We now have 3 agents commercially available in the United States, and a fixed-duration regimen [comprised of] venetoclax in combination with a monoclonal antibody.

The recent update from the Alliance trial, which compared ibrutinib [Imbruvica]-based regimens with chemoimmunotherapy, showed that the 4-year PFS [rate] was 76% [in both the ibrutinib monotherapy and ibrutinib/rituximab (Rituxan) arms]. Similarly, the frontline regimen of venetoclax plus obinutuzumab reported a 4-year PFS [rate] of 74%, [according to data from the CLL14 trial]. As such, these PFS rates [were very] comparable.

Could you expand on how BTK inhibitors are being leveraged in this disease?

Within the [realm of continuous] BTK [treatment, we] now [have] 3 covalent BTK inhibitors. Ibrutinib is the first-in-class drug that is less selective compared with other drugs. Acalabrutinib and zanubrutinib are more selective BTK inhibitors that have less off-target activity. Zanubrutinib has more inhibition of TEC, but it is still more selective than ibrutinib.

In recent years, [it has been reported] that [acalabrutinib and zanubrutinib] are safe, especially from a cardiovascular standpoint. The rates of atrial fibrillation and hypertension were lower in patients treated with acalabrutinib compared with ibrutinib. Also, zanubrutinib seems to have a safer [toxicity] profile compared with ibrutinib; the rate of atrial fibrillation appeared to be only 3%, [which was] comparable to patients treated with chemoimmunotherapy. As such, there seems to be a benefit of using more selective BTK inhibitors in terms of safety.

Intriguingly, in 2021, the phase 3 ALPINE study [NCT03734016] reported interim results that showed PFS benefit at 1 year of follow-up [in zanubrutinib vs ibrutinib]. A longer follow-up is needed to better understand the efficacy of these more selective BTK inhibitors and their safety profiles. However, so far, there are favorable results. It is great to have multiple options available in the clinic for our patients.

What efforts have been made to further explore novel venetoclax-based combinations?

[Efforts have been made to determine] how to combine venetoclax with a monoclonal antibody. Studies have shown, especially in the laboratory, that when you use venetoclax with a CD20 antibody, they are synergistic; they work very well [and can] induce deep responses.

Now, we have multiple monoclonal antibodies. The 2 leading [agents] are rituximab and obinutuzumab. The difference [between] these 2 antibodies is that rituximab is a type-1 antibody, and obinutuzumab is a type-2 antibody with better direct-cell killing. [As such, it has been] hypothesized that obinutuzumab may a better antibody to combine with venetoclax.

[Data from the] recent German phase 3 CLL13 study [NCT02950051] were reported during the 2021 ASH Annual Meeting & Exposition and showed that the obinutuzumab/venetoclax combination was better at inducing deep responses, much better than [what was seen with chemoimmunotherapy]. The [undetectable minimal residual disease (MRD)] rate was [52%] with [chemoimmunotherapy] vs [rates ranging from 86% to 92%] when obinutuzumab was added to venetoclax-based regimens. Clearly, deeper responses [were produced] with the addition of obinutuzumab to venetoclax.

Those data are based on [what has been seen with this approach in the] frontline [setting]. We do not have much data [regarding its use in patients with] relapsed/refractory [disease], and whether obinutuzumab is still better in the relapsed setting. That is still a question [that we face] in clinic.

What has been found with regard to combining BTK inhibitors with BCL-2 inhibitors?

[That is a] big question we have now. [Can we] use BTK inhibitors and BCL-2 inhibitors together, and can [that] improve outcomes—especially [in terms of] depth of response and duration of response. Multiple studies have been published in the past couple of years. The most important one [examined] ibrutinib plus venetoclax, [and this showed] showed that these strategies are feasible—especially in the relapsed/refractory population. Then, this regimen moved to the up-front setting, and the CAPTIVATE study [NCT02910583] and the phase 3 GLOW study [NCT03462719] presented those results.

[At the 2021 ASH Annual Meeting & Exposition], we saw updated results from the GLOW study, and the rate of undetectable MRD [with this] regimen was 50% in the bone marrow, which was still very good.

You mentioned that several options are now available in the frontline setting. What factors do you consider when selecting the optimal treatment approach for each of your patients?

I spend a lot of time in clinic, explaining to my patients what approaches are available to them. In most cases, patients are eligible for all approaches. The way to choose [among these options is to consider] their prior treatment status, their preference, and the safety profiles [of the drugs involved].

[For example, the] key [adverse effect with] BTK inhibitors is cardiovascular toxicity—especially with ibrutinib, somewhat with acalabrutinib, and maybe even with zanubrutinib. [It is also important to look at] past medical history. If [the patient] had atrial fibrillation or cardiovascular diseases [in the past], then we may lean more toward a fixed-duration approach that does not include a BTK inhibitor.

When patients are traveling a lot and do not want to take medications every day, they [may] want to invest in a [treatment that has a] fixed duration of time and [then] be off therapy. [In this case], they may choose a venetoclax-based regimen over a continuous BTK inhibitor. This is a discussion with a patient, rather than a one-way direction from physician to patient.

What is some of the work that is being done with triplet regimens?

Moving forward, several studies are using this backbone of a BTK inhibitor and venetoclax, and using the third drug, obinutuzumab, as a monoclonal antibody. Those triplet combinations, such as acalabrutinib, venetoclax, and obinutuzumab, have led to high rates of MRD negativity in blood and bone marrow, reaching up to [86%], as reported by Matthew S. Davids, MD, MMSc, of Dana-Farber Cancer Institute, [and colleagues].

These [triplet] combinations seem to be very effective. Now, randomized are studies comparing a single-agent vs doublet approach, and a single-agent vs triplet approach. We are waiting to see which regimen might be the way to go, and how durable these responses could be when patients achieve deep remissions, such as MRD negativity.

You mentioned an ongoing study of a triplet comprised of acalabrutinib, venetoclax, and obinutuzumab. Are there specific subsets of patients who may derive more benefit from this approach?

The data I alluded to previously, which had been published in Lancet Oncology in 2021, was [from] a single-arm study [that evaluated] acalabrutinib [plus] venetoclax and obinutuzumab. [The triplet generated] high rates of undetectable MRD—even in patients with TP53 [mutations or deletions], which is 1 of the high-risk groups in CLL. These were promising data. However, using 3 drugs in combination does [come with added] toxicity.

Patients experience a higher rate of thrombocytopenia, neutropenia, fever, and infection. As such, there is a cost related to this up-front, intensified approach. If you ask whether all patients would benefit from this triplet approach, I will have to cautiously guess that not all of them would. My best guess is that the patients with higher-risk markers, such as TP53 aberration, may benefit from this more intensified approach with the hope of eradicating the disease as much as possible, as opposed to those with indolent diseases. Their disease may be controlled well with a single-agent BTK inhibitor, for instance. [Efficacy] may depend on the biology of the disease.

Investigational therapeutics, such as CAR T-cell therapies, are emerging in the relapsed/refractory setting. Do you foresee that approach taking on a larger role in the treatment paradigm?

In terms of CAR T cells, we now have data published in Nature [that detail a] decade-long remission in patients [with CLL] treated with CAR T-cell therapy. It seems that immune-directed treatment approaches can [potentially] cure [this disease]. Would that [approach] replace other targeted agents? It is an interesting question.

One of the pitfalls of the CAR T-cell data that we have is that these cellular products have been used in the relapsed/refractory setting when patients were heavily pretreated with chemotherapy. Their T cells were not as healthy, and engineering these T cells can work, but they are not as durable; they are still exhausted.

The big question in the field is [whether] we can move those cell therapies into the frontline setting, when patients have a healthier immune system and healthier T-cell material to begin with. Would that translate to a better outcome? That is an exciting question [to explore further], but we do not have any data to answer whether CAR T-cell [therapies] will replace other therapies.

Is there any ongoing research being done at Dana-Farber Cancer Institute that you would like to spotlight?

I would like to promote a couple of trials. A new randomized phase 3 trial [NCT05057494], for example, is comparing acalabrutinib plus venetoclax with venetoclax plus obinutuzumab. This is an exciting trial that is open for all comers in the frontline setting.

For [those with] relapsed/refractory CLL, we [are exploring the] combination of zanubrutinib and venetoclax. [Since] zanubrutinib is a more selective BTK inhibitor, with a better safety profile, this is an exciting trial [NCT05168930] examining a combination regimen [that may be] more selective and safer [than existing approaches].

References

1. Woyach JA, Ruppert AS, Heerema NA, et al. Long-term results of Alliance A041202 show continued advantage of ibrutinib-based regimens compared with bendamustine plus rituximab (BR) chemoimmunotherapy. Blood. 2021;138(suppl 1):639. doi:10.1182/blood-2021-153146
2. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807-3814. doi:10.1200/JCO.2017.73.2289