Nicole Lamanna, MD, discusses the implications of the FDA approval of frontline acalabrutinib plus venetoclax in CLL.
With Bruton tyrosine kinase (BTK) inhibitors and venetoclax (Venclexta) already ingrained in the chronic lymphocytic leukemia (CLL) treatment paradigm, the
The approval was based on data from the phase 3 AMPLIFY trial (NCT03836261), which evaluated acalabrutinib plus venetoclax with or without obinutuzumab (Gazyva) vs investigator’s choice of chemoimmunotherapy with fludarabine plus cyclophosphamide and rituximab (Rituxan) or bendamustine plus rituximab in patients with CLL without 17p deletions or TP53 mutations.1,2
Results supporting the approval showed that patients treated in the acalabrutinib and venetoclax arm (n = 291) achieved a 3-year progression-free survival (PFS) rate of 76.5% (95% CI, 71.0%-81.1%) vs 66.5% (95% CI, 59.8%-72.3%) for patients in the chemoimmunotherapy arm (n = 290). The median PFS was not estimable (NE; 95% CI, 51.1-NE) in the experimental arm vs 47.6 months in the control arm (HR, 0.65; 95% CI, 0.49-0.87; P = .0038).
“This [approval] is going to change the landscape for patients [with CLL] who may not want an intravenous infusion of obinutuzumab [in combination with venetoclax]. They can now do an all-oral combination,” Lamanna said in an interview with OncLive®.
In the interview, Lamanna expanded on the significance of the approval, the data supporting it, and specific shifts that she anticipates in clinical practice for CLL.
Lamanna is an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Irving Medical Center in New York, New York.
Lamanna: What’s great about CLL is that there have been so many excellent agents approved over the last decade. We have covalent and noncovalent BTK inhibitors, [along with] venetoclax and venetoclax-based, time-limited therapy. In the frontline setting, [patients] are either treated with what we call a chronic, continuous BTK inhibitor or a time-limited option. Venetoclax plus obinutuzumab has been the standard for time-limited approaches for a long time.
Fast forward to December at the [2024] ASH [American Society of Hematology Annual Meeting and Exposition, where we saw] an important study called AMPLIFY, which looked at a time-limited approach of acalabrutinib and venetoclax with or without obinutuzumab vs chemoimmunotherapy for patients in the frontline setting. The caveat to the study is that it didn’t include high-risk individuals, [such as] patients with TP53 mutations or 17p deletions, [as] there was a chemoimmunotherapy arm.
[Data from this study] led to the approval of an all-oral, time-limited approach [with acalabrutinib plus venetoclax]. Our European colleagues already had an approval with ibrutinib [Imbruvica] plus venetoclax from the phase 3 GLOW study [NCT03462719], although the FDA and others were looking for a second-generation BTK inhibitor with less cardiac toxicity than ibrutinib. Hence, we had our first all-oral combination approved in February with acalabrutinib and venetoclax.
[AMPLIFY data] showed that for acalabrutinib plus venetoclax with or without obinutuzumab, the PFS was far better than chemoimmunotherapy, [which was] not a shock. We’ve had multiple studies showing that chemoimmunotherapy really shouldn’t be used anymore [in the frontline setting], unless there [are] some rare, extreme circumstances. Targeted therapies have supplanted chemoimmunotherapy, and the PFS for patients was [better with acalabrutinib/venetoclax-based therapy].
What’s interesting to note about this study is the triplet combination of acalabrutinib, venetoclax, and obinutuzumab, [which demonstrated] an improvement compared to acalabrutinib plus venetoclax [alone], but mostly for patients with unmutated IGHV. This is something we have to think about: How do we do better for patients with higher-risk disease, such as those with unmutated IGHV? Otherwise, our patients [with mutated IGHV who were treated] with acalabrutinib and venetoclax without obinutuzumab did just as well as those given the triplet.
When we think about the design of trials, hopefully, we’ll start seeing breakdowns of patients based on the type of genomic features they have. We need to ask questions like: [Which patients] are the best for a triplet? That question still remains to be answered. It might be [only] our higher-risk patients, and not everybody needs a triplet, but we need to figure this out.
What [AMPLIFY data] did show is that patients who [received] an all-oral combination are doing well. You can achieve high levels of minimal residual disease (MRD) undetectability with these types of regimens.
With these combinations, it’s always important to think about toxicity issues. When [the study] compared acalabrutinib and venetoclax with or without obinutuzumab with chemoimmunotherapy, there were certainly infectious complications among all groups; in fact, [infectious complications were] higher with [acalabrutinib-based combination than] chemoimmunotherapy. People always think that oral regimens don’t [lead to] complications, but you still need to monitor your patients and have them report about infectious complications. There was certainly more neutropenia related to the arms that had monoclonal antibodies, which were the triplet and chemoimmunotherapy arms.
Patients in the frontline setting can receive a chronic, continuous BTK inhibitor vs a time-limited [approach] either with venetoclax and obinutuzumab or acalabrutinib and venetoclax. This is going to change the [CLL treatment] landscape for patients who may not want an intravenous infusion of obinutuzumab. They can now do an all-oral combination. It is a little logistically easier to use an all-oral combination than venetoclax and obinutuzumab, [as patients] can frontload the BTK inhibitor for 2 to 3 cycles and then add venetoclax and monitor tumor lysis [status] in an outpatient [setting]. [Acalabrutinib and venetoclax is] an easier regimen on the patient’s part but also on the physician’s part, compared with venetoclax plus obinutuzumab.
Now, having an all-oral combination approved, it will be a discussion with patients about whether they will move from venetoclax and obinutuzumab to an all-oral [regimen], just for ease of administration. That will be more of a topic that comes into play. We’re going to see some patients who are on chronic, continuous BTK inhibitors ask, “Can I add venetoclax now and get off therapy finally?” We’re going to see this as an emerging pattern in clinical practice. It’ll be very interesting because some of those patients have been on a BTK for much longer, and that will be important data. It would be great to capture those data. We’ll probably [capture them] in some of these real-world studies. Theoretically, if venetoclax [is added] later, these individuals will have a more prolonged time-limited duration because some might have been on BTK inhibitors for several years already with a longer PFS.
It’ll be interesting to see this shift in how patients do over time. It may be that you’ll see [some] patients coming off chronic, continuous BTK inhibitors, and then you might see some [patients on obinutuzumab and venetoclax] choose the all-oral combination. There are multiple regimens now for patients to choose [from], and hopefully, the physicians will guide them if there are issues.
[For] high-risk patients, we [still] have to figure out if chronic, continuous BTK inhibitors are still the best approach or [if] a time-limited approach is OK, [possibly with a] longer duration because [these patients] don’t do as well with shorter durations. [Another possibility for these patients could be] a triplet if they can tolerate the enhanced adverse effects and toxicities. [Ultimately], finessing duration times for some of our higher-risk patients or [finding the] optimal regimen for them, whether that’s a doublet or a triplet, [will be important].
We still have more things to figure out in CLL, which is always a good problem to have. When we have all these great drugs and sequencing, as patients eventually develop resistant disease, [figuring out] the right subsequent lines of therapy [will be important, as well]. When patients are on time-limited approaches, hopefully, they are not developing any resistant mutations, and that should be evaluated. [If they do not have resistance mutations], then they could potentially recycle some of the older drugs that they've had or receive newer combinations of older drugs, and that’s exciting for those patients as well.
