Acalabrutinib Approval Leads Frontline Advances in CLL

Jennifer Woyach, MD

A number of therapeutic options have become available in the frontline setting for patients with chronic lymphocytic leukemia (CLL), most recently the second-generation BTK inhibitor acalabrutinib (Calquence).

The November 2019 approval of acalabrutinib, which is indiciated for adult patients with CLL or small lymphocytic lymphoma, was based on 2 phase III randomized trials: ELEVATE-TN and ASCEND. In ELEVATE-TN, investigators evaluated the safety and efficacy of acalabrutinib alone or in combination with obinutuzumab (Gazyva) versus chlorambucil/obinutuzumab in 535 treatment-naïve patients with CLL.

Results showed that the median progression-free survival (PFS) was 22.6 months (95% CI, 20-28) in the control arm, but was not yet reached in the acalabrutinib/obinutuzumab arm (HR, 0.10; 95% CI, 0.06-0.17; P <.0001) or the single-agent acalabrutinib arm (HR, 0.20; 95% CI, 0.13-0.30 P <.0001).¹

In ASCEND, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or rituximab (Rituxan) in combination with idelalisib (Zydelig) or bendamustine. Data showed that the median PFS with acalabrutinib was not reached compared with 16.5 months in the control arms (HR, 0.31; 95% CI, 0.20-0.49; P <.0001), translating to a 69% reduction in the risk of progression or death with the BTK inhibitor.²

Beyond acalabrutinib, ibrutinib (Imbruvica) is the other BTK inhibitor currently available in the frontline setting. In addition, physicians can use venetoclax (Venclexta) with obinutuzumab. Although chemoimmunotherapy is still available, in the form of fludarabine, cyclophosphamide, and rituximab (FCR), it is more commonly used in the setting of patients with IGHV-mutant CLL.

However, the frontline space of CLL continues to be redefined, Woyach added, with combination strategies of BTK inhibitors, targeted therapies, and chemoimmunotherapy being explored in clinical trials.

In an interview with OncLive during the 24th Annual International Congress on Hematologic Malignancies, Woyach, an associate professor, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center—James, discussed the advances in the frontline setting for patients with CLL, and other strategies that are under investigation in this space.

OncLive: What are the frontline treatment options for patients with CLL?

Woyach: For CLL, we have a number of frontline options. We have ibrutinib, which can be used by itself and it usually is used on its own. We have acalabrutinib that can be used with or without obinutuzumab, and we have venetoclax plus obinutuzumab in terms of our targeted agents. We also still have chemoimmunotherapy options, such as FCR, which is to be considered especially for those young, fit patients who IGVH-mutated disease. We also have bendamustine/rituximab and chlorambucil/obinutuzumab still available, although there are not a lot of scenarios where you would use those.

What are the toxicity concerns with these agents?

With the BTK inhibitors, specifically ibrutinib, we know a lot about long-term safety profiles. The toxicity that are of concern with ibrutinib include atrial arrythmias, which happen in about 10% to 15% of patients. You can see grade 3 or higher hypertension, and that is something that actually happens more commonly with a longer duration of therapy. You can also see other adverse events that are more common, and less dangerous, such as arthralgias, fatigue, and upper-respiratory infections.

With acalabrutinib, it seems like you probably see some atrial arrythmias, although it seems to be much less frequent than with ibrutinib. You tend to see less bruising with acalabrutinib, as well as less arthralgias. You do see headache with acalabrutinib, although that is predominantly low grade and goes away over time.

With venetoclax, you can see neutropenia—especially early on—and you can see risk of tumor lysis syndrome, especially with the first ramp-ups. With chemoimmunotherapy, our primary concerns are cytopenias, both during and prolonged cases after [the treatment]. With FCR, more specifically, patients have almost a 5% risk of myelodysplastic syndrome or acute myeloid leukemia.

Could you discuss the impact of the ELEVATE-TN trial?

This was the study that led to the approval of acalabrutinib in the frontline setting of CLL. In this study, patients who were either over the age of 65 years or who had multiple comorbidities were included. They were randomized 1:1:1 to acalabrutinib alone, acalabrutinib in combination with obinutuzumab, or chlorambucil in combination with obinutuzumab. The primary endpoint was PFS and compared acalabrutinib/obinutuzumab with chlorambucil/obinutuzumab. There was also a secondary comparison of acalabrutinib alone versus chlorambucil/obinutuzumab.

The study read out at the 2019 ASH Annual Meeting, and it showed an improved PFS for both acalabrutinib alone and in combination compared with chlorambucil/obinutuzumab. There is currently no difference in overall survival between the arms.

Could you discuss the safety findings in this trial?

Acalabrutinib does have some mild toxicities. It can cause some bruising. It has a less than 5% risk of atrial fibrillation, although we will have to see what happens when patients are on longer durations of treatment. The risk of hypertension appears less with acalabrutinib than with ibrutinib, and risk of major bleeding is very low with this agent. It is actually very well tolerated. There is a little more neutropenia and risk of infection when obinutuzumab is added to it.

What are the challenges we still need to overcome in patients with CLL?

The biggest challenge right now is trying to decide what is the best frontline therapy for each patient. There are a few randomized studies that will help us with that. One is a head-to-head comparison of ibrutinib and acalabrutinib. It completed enrollment a few years ago, so hopefully it will read out sometime in the next few years. It is actually in relapsed high-risk CLL, but hopefully the efficacy and safety differences, if any, can be extrapolated to any setting.

We also are very interested in whether single agents given sequentially or combination therapy is better. To this point, there are 2 studies. In 1 study, patients under the age of 70 years are under evaluation; whereas, in the second study, patients are older. Both are comparing ibrutinib/obinutuzumab with ibrutinib/obinutuzumab plus venetoclax to see if the addition of venetoclax deepens remission with ibrutinib-based therapy and can allow for successful discontinuation of treatment.

What other novel approaches being evaluated in CLL?

The novel approaches are the BTK inhibitors and BCL-2 inhibitors. There is a lot of interest right now in combining those 2 [classes of agents], so there are studies combining ibrutinib or acalabrutinib with venetoclax with or without obinutuzumab. Right now, those should be done primarily in the context of clinical trials. I do not use those approaches outside of a clinical trial. However, that is something that looks effective that we will continue to follow closely for the future.

How would you define the current treatment landscape in CLL?

In CLL right now, we are in a very good place for frontline treatment. There are a lot of options. For most patients, we can very confidently say that there is not really a wrong option. Most patients will go on to have a long PFS with any agent that we choose.

The biggest challenge now will be to make sure we continue enrolling our patients on clinical trials. We do not want to become complacent with this approach right now, so we need to figure out what is the best approach for each patient.

References

1. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (o) or alone vs o plus chlorambucil (clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl_1):31. doi: 10.1182/blood-2019-128404.
2. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (idr) or bendamustine (br) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL). Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2606.