Independent review committee-assessed progression-free survival of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) was significantly improved in patients receiving acalabrutinib, an orally-administered inhibitor of Bruton’s tyrosine kinase (BTK), compared with investigator’s choice of a combination regimen of rituximab and idelalisib or bendamustine, according to an interim analysis of results of the randomized, open-label, phase 3 ASCEND study (ClinicalTrials.gov Identifier: NCT02970318).

In addition, no new safety signals were identified for acalabrutinib. Although the data from the study have not yet been released, the results were deemed “statistically significant and clinically meaningful,” and the trial will be closed to enrollment early for benefit.¹

“[Acalabrutinib] is the first BTK inhibitor to show benefit in a phase 3 trial as a monotherapy compared to current standard-of-care combinations used in relapsed or refractory chronic lymphocytic leukemia. We look forward to presenting detailed results at a forthcoming meeting,” stated José Baselga, MD, PhD, executive vice president, R&D Oncology, AstraZeneca.¹

Use of BTK inhibitors in the treatment of patients with CLL is under active investigation. Acalabrutinib is a selective, covalent inhibitor of BTK that is currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with previously treated mantle cell lymphoma.² Another orally administered, covalent BTK inhibitor, ibrutinib, is currently FDA-approved for both the first-line and subsequent treatment of patients with CLL with or without a 17p deletion, as well as other hematologic malignancies, including mantle cell lymphoma.³

Both ibrutinib and off-label use of acalabrutinb are included as treatment options in the v.4.2019 version of the National Comprehensive Cancer Network (NCCN) CLL guidelines.⁴ Ibrutinib is designated as a category 1/preferred recommendation for first-line treatment of patients with disease not characterized by the 17p deletion/TP53 mutation, whereas ibrutinib and acalabrutinib are categorized as 1/preferred and 2A, respectively, for subsequent therapy of patients with disease lacking the 17p deletion/TP53 mutation.

For patients with CLL characterized by the 17p deletion/TP53 mutation, ibrutinib has a category 2A/preferred and a category 1/preferred designation for first-line and subsequent treatment, respectively, whereas acalabrutinib is designated as a category 2A recommendation for subsequent treatment only.

Inclusion of ibrutinib in the NCCN CLL guidelines was based on the results of a number of phase 3 clinical trials in these 2 treatment settings, including a comparison of ibrutinib with ofatumumab, an anti-CD20 antibody, in the relapsed/refractory setting.^5-8 In the case of acalabrutinib, a very high response rate was observed in a single-arm, phase 1/2 study of patients with relapsed/refractory CLL.⁷

While the mechanisms of action of ibrutinib and acalabrutinib are believed to be similar in that both agents covalently bind to a cysteine residue in the active site of BTK, resulting in interference in B-cell antigen receptor and cytokine receptor pathway signaling, there is evidence that acalabrutinib is a more selective BTK inhibitor.^2,3,10 And, while ibrutinib is administered once daily, the dosing schedule for acalabrutinib involves twice-daily administration.^2,3

Clinical studies involving head-to-head comparisons of acalabrutinib and ibrutinib are ongoing in the setting of CLL (eg, ClinicalTrials.gov Identifier: NCT02477696). Other BTK inhibitors also currently being investigating in CLL include zanubrutinib and LOXO-305, including a head-to-head trial of zanubrutinib versus ibrutinib in relapsed/refractory disease. (ClinicalTrials.gov Identifiers: NCT03740529; NCT03734016).

References

1. AstraZeneca. Calquence phase III ASCEND trial met primary endpoint at interim analysis in relapsed or refractory chronic lymphocytic leukaemia and will stop early. Accessed May 9, 2019.
2. Acalabrutinib (Calquence^®) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2017.
3. Ibrutinib (Imbruvica^®) [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2019.
4. National Comprehensive Cancer Network (NCCN) chronic lymphocytic leukemia/small lymphocytic leukemia clinical practice guidelines. www.nccn.org. Accessed May 9, 2019.
5. Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE™ phase 3 trial of ibrutinib versus ofatumumab [published online March 6, 2019]. Blood.  doi: 10.1182/blood-2018-08-870238
6. Brown JR, Hillmen P, O’Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83-91.
7. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437
8. No authors. First-line ibrutinib confirmed for CLL. Cancer Discov. 2019 Feb;9(2):OF4.
9. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323-332.
10. Patel V, Balakrishnan K, Bibikova E, et al. Comparison of acalabrutinib, a selective Bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic leukemia cells. Clin Cancer Res. 2017;23:3734-3743.