Jennifer R. Brown, MD, PhD, discusses the FDA approval of acalabrutinib plus venetoclax for chronic lymphocytic leukemia and how it improves QOL.
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In an interview with OncLive®, she discussed data from the phase 3 AMPLIFY trial (NCT03836261) that supported the approval, underscoring that the combination improves patient QOL compared with other approved regimens, such as obinutuzumab (Gazyva) plus venetoclax, without sacrificing efficacy.
Data from the trial showed that patients in the acalabrutinib-plus-venetoclax arm (n = 291) achieved a 3-year progression-free survival (PFS) rate of 76.5% (95% CI, 71.0%-81.1%) compared with 66.5% (95% CI, 59.8%-72.3%) for those in the chemoimmunotherapy arm (n = 290).2 Regarding safety, common grade 3 or higher adverse effects (AEs) for patients in the investigational arm were neutropenia (32.3%), infection (12.4%), and cardiac AEs (1.7%).
Brown is the director of the Center for Chronic Lymphocytic Leukemia of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston, Massachusetts.
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Brown: This is our first combination therapy of a BTK inhibitor and a BCL-2 inhibitor to be approved in the US, and those are our 2 most active drug classes. [Additionally,] it’s an all-oral regimen. There has been some reluctance to use venetoclax—a BCL-2 inhibitor—in the [CLL] community because of the difficulties with ramp-up [dosing]. [With this combination], we have the lead-in with acalabrutinib for a couple of months, which makes the ramp-up much easier [because] first there’s a debulking of the tumor. Patients like an all-oral regimen as well; it’s going to be coming into widespread use.
The all-oral aspects will significantly improve patient QOL for a frontline venetoclax-containing regimen. Prior to this approval, we’ve been using venetoclax plus obinutuzumab. Obinutuzumab is an anti-CD20 antibody infusion, and patients have to come to the clinic for [the infusion] weekly for 3 weeks, including 2 days in the first week, and then they go right into their venetoclax ramp-up, which is an additional 5 weeks.
Essentially, [with venetoclax plus obinutuzumab], patients come to the clinic for 8 straight weeks for at least a full day or often part of a second day. This has a big effect on patients’ time. Whereas with [acalabrutinib plus venetoclax], starting the BTK inhibitor is easy, and patients don’t have to come [to the clinic] much at all for the first 2 months. Then, by the time patients get to the venetoclax-containing portion, most of them will have low-risk disease,…making their time commitment for the ramp-up [shorter] as well.
I don’t see that this combination will have a negative effect on QOL. You could consider the possibility of seeing more AEs from 2 drugs at once, but [this combination] was well tolerated in AMPLIFY. Stopping the BTK inhibitor after 14 months is also useful for minimizing AEs, [because] that tends to be before the cardiac AEs come in.
The AMPLIFY trial was an international phase 3 trial that investigated acalabrutinib plus venetoclax with or without obinutuzumab compared with chemoimmunotherapy. In the acalabrutinib-plus-venetoclax arm, we saw a 10% improvement in 3-year PFS rate [compared with the chemoimmunotherapy arm], which was striking, especially given that the regimen was well tolerated and easy [to administer].
Acalabrutinib Plus Venetoclax Improves Patient QOL in CLL: Highlights
[Another] aspect [of AMPLIFY] that was striking to me had to do with the higher-grade infections—those that require admission to the hospital. Almost all our frontline regimens have a high-grade infection rate of approximately 20% to 25%. But in the acalabrutinib-plus-venetoclax arm, [this rate] was only 12%, so severe infection was less frequent.
This trial was conducted during the height of the COVID-19 pandemic, which affected the study regarding the anti-CD20 agent–containing arms, where we saw more infectious toxicity from COVID-19.
We have a lot of experience with venetoclax now, and we understand that the associated AEs primarily include GI [gastrointestinal] toxicity. Venetoclax can cause nausea if patients don’t take it with food, and even if they do take it with food, sometimes it can still cause nausea. We have strategies to manage [these toxicities], where we can give patients antiemetics as premedication; taking [those] at night once patients are done with venetoclax ramp-up seems to help a lot with nausea. Venetoclax can also give some patients diarrhea, but generally that tends to get better over time, if patients have it to begin with.
Most patients do well with venetoclax. The other AEs include low blood cytopenia levels and low blood counts, which tend to be manageable, if they occur at all. Some patients will get the odd occasion of neutropenia, but if you give them growth factor, that tends to go away, and you can continue [to administer venetoclax] at the full dose. These experiences all apply in this case [of the AMPLIFY regimen]. Tumor lysis syndrome risk is also reduced [with this regimen], probably because of the 2-month lead-in with the acalabrutinib.
AMPLIFY did include the 3-drug arm of acalabrutinib, venetoclax, and obinutuzumab. In this arm, we saw that [this regimen] resulted in an even better 3-year PFS rate of 83.1% [95 CI, 78.1%-87.1%]. This difference was particularly striking in the patients with higher-risk, unmutated disease. The addition of the obinutuzumab substantially improved the PFS rate [vs chemoimmunotherapy] in these patients by 16.6% at 3 years. Now, the cost of this [improvement] was that there was a higher rate of infection, including some COVID-19–associated deaths.
Where would I use [acalabrutinib plus venetoclax and obinutuzumab]? Particularly in young, fit patients who have higher-risk, unmutated disease and want a time-limited regimen, [this triplet] results in high rates of undetectable minimal residual disease [MRD] and seems to overcome the relatively adverse effect of the unmutated IGHV. You just have to be careful about the infection risk when selecting patients for this triplet option.
The approval of acalabrutinib plus venetoclax adds a third category of frontline regimen [for CLL]. We’ve had continuous BTK inhibitors, which are [administered for an] indefinite duration. We’ve had venetoclax plus obinutuzumab, which is just [given for] 1 year, but involves that 8-week period where the patients have to come into the infusion center extensively. Now, we have this all-oral BTK/BCL-2 inhibitor combination, an additional time-limited treatment option for patients.
I’m hesitant right now to use it in very high-risk patients because we only have 3 years of follow-up; it’s becoming more the case that 5 or 6 years of follow-up is what we need to see how well remissions are sustained. I may hesitate [to administer acalabrutinib plus venetoclax] if patients are younger [and have high-risk disease]. But for the patients who are older or have low-risk disease, it’s well tolerated and an effective regimen.
An interesting study that has completed enrollment but hasn’t read out yet is [the phase 3 MAJIC trial (NCT05057494), which is] investigating this acalabrutinib plus venetoclax combination slightly differently.3 It has one MRD-guided time point; after 12 cycles, patients are evaluated for undetectable MRD, and if they have undetectable MRD, they can stop [treatment]. If patients don’t [have undetectable MRD], they receive 12 more cycles [of treatment]. After 24 cycles, all patients stop treatment. In this randomized trial, acalabrutinib plus venetoclax is being compared with venetoclax plus obinutuzumab, which also has a 1-year MRD decision point. [MAJIC] is going to add information regarding the likelihood of undetectable MRD at the 1-year time point with the 2 different regimens, and whether adding an additional year of treatment affects PFS. [MAJIC] is going to give us insight relative to how we would use these 2 different regimens.
There’s also a registrational trial that is evaluating another BTK/BCL-2 inhibitor combination that has completed accrual. This is evaluating zanubrutinib (Brukinsa)—a different BTK inhibitor—plus sonrotoclax (BGB-11417), which is a not-yet-approved novel BCL-2 inhibitor. This combination has shown high rates of undetectable MRD in early-phase studies, and it will be interesting to see how it looks in these registrational trials regarding rates of undetectable MRD and PFS compared with acalabrutinib plus venetoclax.
