Abstract
The Bruton’s tyrosine kinase (BTK) is an essential in the B-cell receptor (BCR) signaling pathway which was identified as crucial in the pathogenesis of B-cell malignancies. Ibrutinib, a first-in-class BTK inhibitor, has been approved for the treatment of distinct B-cell malignancies. To overcome off-target side effects of and emerging resistances to ibrutinib, more selective second-generation BTK inhibitors were developed. Acalabrutinib is a novel second-generation BTK inhibitor and has shown promising safety and efficacy profiles in phase 1/2 clinical trials in patients with relapsed CLL and pretreated MCL. Recently, acalabrutinib was approved by the FDA for treatment of adult patients with MCL who received at least one prior therapy. However, clinical trials on a direct comparison between ibrutinib and acalabrutinib and on combination treatment options with other agents as CD20 antibodies are warranted.
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1 Introduction
B-cell receptor (BCR) signaling pathway has been identified to play an important role in the pathogenesis and progression of B-cell malignancies (Bojarczuk et al. 2015). As Bruton’s tyrosine kinase (BTK) is an essential kinase in the BCR signaling pathway, ibrutinib, a first-in-class BTK inhibitor, has been approved for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma and Waldenstrom’s macroglobulinemia (WM) (Thompson and Burger 2017; Agency EM 2017; Martin et al. 2016; Kapoor et al. 2017; Noy et al. 2017). More specific second-generation BTK inhibitors were developed to overcome off-target side effects of and emerging resistances to ibrutinib (Wu et al. 2016). Herein, the mechanism of action, preclinical and clinical data, including toxicity profile and drug interactions of the novel second-generation BTK inhibitor, acalabrutinib (also known as ACP-196), are summarized.
2 Structure and Mechanism of Action
The molecular formula of acalabrutinib is C26H23N7O2, the chemical name 4-{8-Amino-3-[(2S)-1-(2-butynoyl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide, and the molar mass 465.507 g/mol (AstraZeneca 2017). The chemical structure is shown in Fig. 1.
Acalabrutinib and its active metabolite, ACP-5862, bind covalently to a cysteine residue (Cys481) in the adenosine triphosphate- (ATP-) binding pocket of BTK via a reactive butynamide group thereby acting as an irreversible small-molecule inhibitor of BTK (Barf et al. 2017; Wu et al. 2016). Acalabrutinib was demonstrated to inhibit BTK with a half maximal inhibitory concentration (IC50) of 5.1 ± 1.0 nM in the immobilized metal ion affinity-based fluorescence polarization (IMAP) assay (Barf et al. 2017; Byrd et al. 2016). In vitro, increasing concentrations of acalabrutinib led to a dose-dependent inhibition of the BCR signaling pathway in primary human CLL cells (Byrd et al. 2016).
In order to determine the selectivity of acalabrutinib, inhibitory assays on kinases with a cysteine residue in the same position as BTK were performed. Herein, acalabrutinib showed almost no inhibitory activity on epidermal growth factor receptor (EGFR), IL2-inducible T-cell kinase (ITK) and tyrosine-protein kinase Tec (TEC) (Barf et al. 2017; Byrd et al. 2016; Patel et al. 2017). These findings indicated a higher selectivity of acalabrutinib over ibrutinib with reduced off-target side effects. In this regard, ibrutinib but not acalabrutinib treatment resulted in a reduced platelet–vessel wall interaction compared to healthy controls in a humanized mouse model of thrombosis. These results demonstrated that acalabrutinib did not inhibit platelet activity, probably due to its improved selectively (Byrd et al. 2016).
3 Preclinical Data
Preclinical in vivo data on single-agent activity of acalabrutinib were obtained from mouse and canine animal models.
Herman et al. demonstrated acalabrutinib to be a potent inhibitor of BTK in two murine models of human CLL: the human NSG (NOD-Scid-IL2Rgcnull) primary CLL xenograft model and the Eµ-TCL-1 adoptive transfer model. In both mouse models, acalabrutinib treatment had on-target effects including decreased activation of key signaling molecules such as BTK, phospholipase C-γ2 (PLCγ2), ribosomal protein S6, and extracellular signal regulated kinase (ERK). Moreover, a significant inhibition of CLL cell proliferation, reduced tumor burden, and increased survival were observed (Herman et al. 2017).
In a model of spontaneously occurring canine lymphoma, a B-cell malignancy similar to human diffuse large B-cell lymphoma, Harrington et al. proved activity of acalabrutinib. In particular, upon treatment at dosages of 2.5–20 mg/kg every 12 or 24 h an overall response rate (ORR) of 25% and a median progression-free survival (PFS) of 22.5 days have been observed (Harrington et al. 2016).
These preclinical studies provided detailed insights into the mechanism of action of acalabrutinib and paved the way for subsequent clinical trials.
4 Clinical Data
The safety and efficacy of single-agent acalabrutinib was evaluated in phase 1/2 clinical trials in relapsed CLL and previously pretreated MCL.
In an uncontrolled multicenter study (NCT02029443) acalabrutinib was administered orally at a dose of 100–400 mg once daily (phase 1 dose escalation) and 100 mg twice daily (phase 2) to 61 patients with relapsed CLL (median of three previous therapies). Among the recruited patients, 75% had an unmutated immunoglobulin variable-region heavy-chain gene, 31% a chromosome 17p13.1 deletion, and 29% a chromosome 11q22.3 deletion. The median age was 62 (range 44–84) years. Compared to once-daily dosing, the twice-daily application improved the kinase occupancy allowing continues BTK inhibition without increasing toxic effects. The ORR was 95%, including 10% of patients with partial response (PR) with lymphocytosis and 85% with a PR, after a median follow-up of 14.3 months. Stable disease (SD) was observed in the remaining 5% of patients. In patients with a chromosome 17p13.1 deletion, the ORR was 100%. Only one patient, with a chromosome 17p13.1 deletion, experienced disease progression during therapy. Interestingly, at progression a C481S mutation in BTK (major clone) and a L845F mutation in PLCγ2 (minor clone) was found in this patient. Overall, acalabrutinib showed promising efficacy in relapsed CLL (Byrd et al. 2016). Based on these data, a subsequent phase 3 clinical trial comparing acalabrutinib versus ibrutinib in pretreated patients with high-risk CLL has been initiated (NCT02477696). Further clinical trials evaluating acalabrutinib in combination with other agents in CLL are ongoing (Table 1).
In another phase 2 open-label, single-arm clinical trial (ACE-LY-004, NCT02213926) acalabrutinib was administered at a dosage of 100 mg twice daily until progression. 124 patients with relapsed/refractory MCL (median of two previous treatments, including 18% of patients with prior stem cell transplant) were included. Previous BTK treatment was defined as an exclusion criterion. The median age was 68 (range 42–90) years. 44 and 17% of patients had intermediate or high risk with regard to MCL International Prognostic Index (MIPI), respectively. At a median follow-up of 15.2 months, the ORR was 80%, with a 40% complete response (CR) and 40% PR rate (AstraZeneca 2017b). These data demonstrated the potential impact of acalabrutinib in treatment of relapsed/refractory MCL and led to an accelerated Food and Drug Administration (FDA) approval of Calquence® (acalabrutinib) for treatment of adult patients with MCL who received at least one prior therapy (FDA 2017).
5 Toxicity
Side effects of acalabrutinib were reported in the two previously described phase 1/2 clinical trials.
The most common non-hematological side effects described in the acalabrutinib/relapsed CLL trial (NCT02029443) were headache (43%), diarrhea (39%), weight gain (26%), pyrexia (23%), upper respiratory tract infection (23%), hypertension (20%) and nausea (20%). Severe (grade ≥ 3) diarrhea, weight gain, pyrexia, fatigue, hypertension, and arthralgia were rare (2–7%). Grade 1–2 petechiae were reported in 16% of patients, grade ≥ 3 anemia and neutropenia in 2% of patients, respectively. Overall, no dose-limiting toxicities in the phase 1 part of the trial and no cases of atrial fibrillation (common during ibrutinib treatment) were observed (Byrd et al. 2016).
In the acalabrutinib/pretreated MCL study (ACE-LY-004, NCT02213926) anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (36%), diarrhea (31%), fatigue (28%), myalgia (21%), bruising (21%), nausea (19%), and rash (18%) were common side effects. Grade ≥ 3 non-hematological events included diarrhea, headache, abdominal pain as well as vomiting and were also rare (2–3%). Grade ≥ 3 anemia, thrombocytopenia and neutropenia were observed in 10, 12, and 15% of patients, respectively. Dose-adjustment and treatment discontinuation was reported in 2 and 7% of patients (AstraZeneca 2017a, b).
6 Drug Interactions
Acalabrutinib is predominantly metabolized by CYP3A enzymes in the liver. Therefore, plasma concentrations and side effects were elevated when administered in combination with moderate and strong CYP3A inhibitors such as itraconazole, erythromycin, fluconazole, or diltiazem. On the other hand, co-administration of CYP3A inducers, like rifampicin, resulted in reduced plasma concentration. Furthermore, solubility of acalabrutinib was affected by the pH. Thus, co-administration with antacida and proton pump inhibitors decreased absorption. In combination with CYP3A inhibitors, CYP3A inducers or gastric acid-reducing agents dose adjustments and/or separate dosing are recommended (AstraZeneca 2017).
7 Biomarkers
So far, no predictive or prognostic biomarkers were reported for acalabrutinib.
8 Summary and Perspective
Acalabrutinib is a novel second-generation BTK inhibitor with improved selectivity compared to the first-in-class BTK inhibitor ibrutinib. Acalabrutinib showed promising safety and efficacy profiles in phase 1/2 clinical trials in patients with relapsed CLL and pretreated MCL. In contrast to ibrutinib, so far no cases of atrial fibrillation have been reported during treatment with acalabrutinib. Recently, acalabrutinib was approved by the FDA for treatment of adult patients with MCL who received at least one prior therapy. However, clinical trials and a direct comparison between ibrutinib and acalabrutinib are warranted to reveal the superiority and possible resistance mechanisms of acalabrutinib. Currently, several phase 1, 2, and 3 clinical trials on acalabrutinib single-agent activity and combinations with other agents in hematologic malignancies (Table 1) and solid tumors (Table 2) are ongoing. As indicated in preclinical studies, combinations of acalabrutinib with other agents as CD20 antibodies, phosphoinositide 3 (PI3) kinase and BCL-2 inhibitors will likely increase rates and duration of response (Patel et al. 2017; Niemann et al. 2017; Golay et al. 2017; Deng et al. 2017) Finally, additional selective BTK inhibitors, as ONO/GS-4059, CC-292, BGB-3111, are currently tested in B-cell malignancy models and early phase clinical trials (Thompson and Burger 2017; Robak and Robak 2017; Vidal-Crespo et al. 2017; Wu et al. 2017; Walter et al. 2016).
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Kriegsmann, K., Kriegsmann, M., Witzens-Harig, M. (2018). Acalabrutinib, A Second-Generation Bruton’s Tyrosine Kinase Inhibitor. In: Martens, U. (eds) Small Molecules in Hematology. Recent Results in Cancer Research, vol 212. Springer, Cham. https://doi.org/10.1007/978-3-319-91439-8_14
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