Acalabrutinib

Acalabrutinib, also known as ACP-196, is an orally available, selective inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity (BTK is a cytoplasmic non-receptor tyrosine kinase that transduces signals from a variety of cell surface molecules).

Upon administration, acalabrutinib inhibits BTK activity and prevents activation of the B-cell antigen receptor (BCR) pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This results in inhibition of the growth of malignant B cells overexpressing Bruton tyrosine kinase (BTK). BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in malignant B cells; it plays an important role in B lymphocyte development, activation, signal transduction, proliferation, and survival.

Acalabrutinib (Calquence®) demonstrated strong efficacy in the 4-year follow-up of ELEVATE TN(2). In addition, the ELEVATE RR(3) study showed significantly lower rates of atrial fibrillation and hypertension compared directly with ibrutinib. The data were presented at ASCO 2021. Acalabrutinib already showed an advantage in selectivity in preclinical studies: the BTKi binds the target molecule even more selectively compared to ibrutinib and thus hardly affects signaling pathways of related kinases. Presumably, this is the reason for the different side effect profile, which was shown in registration studies as well as in direct comparison.

The ELEVATE RR trial compared the two approved BTKi in patients with pretreated CLL and high-risk factors. The primary endpoint of non-inferiority in PFS (progression free survival) was met. The median PFS was 38.4 months in both treatment arms after a median follow-up of 40.9 months. In the first head-to-head study comparison with ibrutinib, the ELEVATE RR3 study, acalabrutinib demonstrated a differentiated cardiovascular safety profile. In particular, the rate of atrial fibrillation was significantly reduced. Significantly fewer events of other adverse events such as hypertension or bleeding were also observed with acalabrutinib. With acalabrutinib, 14.7% of adverse events led to study discontinuation, compared to 21.3% with ibrutinib.

Treatments are administered in 28-day cycles. To reduce infusion-related reactions, acalabrutinib is administered for one cycle before obinutuzumab.

Approval of the drug was based on several studies.

In a larger study of 535 patients (Sharman JP et al. 2020).

• 179 patients received acalabrutinib-obinutuzumab
• 179 patients received acalabrutinib monotherapy
• 177 patients received obinutuzumab-chlorambucil.

At a median follow-up of 28-3 months (IQR 25-6-33-1), median progression-free survival was longer with acalabrutinib-obinutuzumab and acalabrutuzumab monotherapy than with obinutuzumab-chlorambucil (median not reached with acalabrutinib and obinutuzumab versus 22-6 months with obinutuzumab, hazard ratio [HR] 0-1; 95% CI 0-06-0-17, p<0-0001; and not reached with acalabrutinib monotherapy vs. 22-6 months with obinutuzumab, 0-20; 0-13-0-3, p<0-0001). Estimated progression-free survival at 24 months was 93% with acalabrutinib-obinutuzumab (95% CI 87-96%), 87% with acalabrutinib monotherapy (81-92%) and 47% with obinutuzumab-chlorambucil (39-55%).

In the ASCEND trial, after a median follow-up of 16.1 months, median progression-free survival (PFS) was significantly longer with acalabrutinib monotherapy than with investigator's choice therapy (16.5 months). Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients treated with acalabrutinib monotherapy, I-R, and B-R, respectively. Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL (Ghia Pet al. 2020).

In summary, acalabrutinib with or without obinutuzumab significantly improved progression-free survival compared with obinutuzumab-chlorambucil chemoimmunotherapy and provided a chemotherapy-free treatment option with an acceptable side effect profile consistent with previous studies. These data support the use of acalabrutinib in combination with obinutuzumab or alone as a new treatment option for patients with therapy-naïve symptomatic chronic lymphocytic leukemia (Sharman JP et al 2020).

Acalabrutinib (Calquence®) is approved: as monotherapy or in combination with obinutuzumab for the treatment of adult patients with non-pretreated chronic lymphocytic leukemia (CLL)

as monotherapy for the treatment of adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy

Acalabrutinib is approved for use as first-line therapy and is recommended in the new Onkopedia guideline for all therapeutic segments, regardless of age or genetic risk factors.

The most common grade 3 or higher ADR in all groups was neutropenia 30% of 178 patients in the acalabrutinib-obinutuzumab group, 9% of 179 patients in the acalabrutinib group, and 41% of 169 patients in the obinutuzumab-chlorambucil group. Infusion reactions of all severities occurred less frequently in the acalabrutinib-obinutuzumab group (13%) than in the obinutuzumab-chlorambucil group (40%). Grade 3 or higher infections occurred in 21% of patients receiving acalabrutinib-obinutuzumab, 14% of patients receiving acalabrutinib monotherapy, and 8% of patients receiving obinutuzumab-chlorambucil.

Deaths occurred in 4% patients receiving acalabrutinib-obinutuzumab, 7% patients receiving acalabrutinib, and 9% patients receiving obinutuzumab-chlorambucil.

In the ELEVATE TN2 trial, acalabrutinib also demonstrated a consistent safety profile at 4-year follow-up, with cardiovascular events such as atrial fibrillation/flutter or hypertension occurring in the single digits (Baker P et al 2019). Due to adverse events, 13% of patients discontinued acalabrutinib + obinutuzumab and 12% discontinued acalabrutinib (vs. 15% obinutuzumab + chlorambucil (G+Clb) (Sharman JP et al 2020).

Calquence®

1. Baker P et al (2019) Exercise-induced cardiac troponin elevation: An update on the evidence, mechanism and implications. Int J Cardiol Heart Vasc 22:181-186.
2. Davids MS (2020) Acalabrutinib for the initial treatment of chronic lymphocytic leukaemia. Lancet 395:1234-1236.
3. Ghia Pet al (2020) ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol 38:2849-2861.
4. Sharman JP et al (2020) Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet 395:1278-1291.