Earlier Studies of Zanubrutinib in Chronic Lymphocytic Leukemia: History
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Contributor:
Stefano Molica
,
Constantine Tam
,
David Allsup
,
Aaron Polliack

Due to improved selectivity and favorable toxicity profiles, the next-generation Bruton’s tyrosine kinase inhibitors (BTKis) are replacing ibrutinib in the treatment of B-cell malignancies including chronic lymphocytic leukemia (CLL). While efficacy between different BTKi agents is probably similar, there are important differences in toxicity profiles (including lower incidences of cardiovascular complications) that favor the choice of second-generation BTKis such as zanubrutinib.

  • CLL
  • zanubrutinib
  • BTK inhibitors

1. Introduction and Background

The inhibition of Bruton’s tyrosine kinase (BTK) has provided an array of therapeutic options for the effective treatment of chronic lymphocytic leukemia (CLL) [1][2]. In 2014 the first-in-class oral BTK inhibitor (BTKi) ibrutinib was licensed and represented a major advance in CLL treatment. Responses to treatment with ibrutinib were favorable in patients with high-risk CLL who had relatively poor response rates to chemo-immunotherapy (CIT) in the past [3][4][5][6][7][8][9]. BTKi treatment, though highly effective, does not generally achieve deep responses in terms of low levels of measurable residual disease (MRD), which results in a therapeutic paradigm where indefinite, continuous treatment is required to maintain clinical responses. Consequentially, patients are exposed to BTKi therapy for prolonged periods and are therefore prone to developing therapy-related toxicities, which include bleeding, infections, diarrhea, arthralgias, arrhythmias, and hypertension [10].
Randomized clinical trials have investigated the efficacy of second-generation BTKis such as acalabrutinib and found reduced toxicity when compared with ibrutinib. These improvements in the safety profile are attributed to the greater selectivity of the second-generation BTKi’s, which as a class have reduced off-target kinase inhibition compared with ibrutinib. In a phase III open-label, randomized, prospective study (ELEVATE-RR trial), acalabrutinib had equivalent efficacy but enhanced safety compared to ibrutinib, with fewer episodes of atrial fibrillation and lower rates of drug discontinuation due to side effects [11]. Accordingly, acalabrutinib was the first covalent, second-generation BTKi to receive Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for CLL treatment [12][13].
Zanubrutinib (zanu) is another next-generation small molecule BTKi that forms a covalent bond with cysteine residues in the BTK active binding site, leading to potent inhibition of kinase activity [14]. Zanu was initially approved for the treatment of patients with relapsed mantle cell lymphoma (MCL) and relapsed/refractory (R/R) marginal zone lymphoma (MZL) based on the results of single-arm studies. Subsequently, it received approval for the treatment of Waldenstrom’s macroglobulinemia (WM) based upon the results of the phase 3 ASPEN study, which compared the efficacy and safety of zanu with ibrutinib, and showed reduced toxicities in favor of zanu [15][16][17][18]. Finally, in January 2023, the FDA and EMA approved zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) based on the results of the pivotal phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials [19][20][21][22]. Due to the increased selectivity, improved efficacy, and superior toxicity profile of zanu, this agent is now listed as the preferred treatment option for patients with CLL in the updated National Comprehensive Cancer Network (NCCN) (v2.2023) guidelines and recently released German algorithm [23][24].

2. Earlier Studies of Zanubrutinib in CLL

The first-in-human, open-label, multicenter, phase I/II study of zanu (AU-003 study) included R/R patients with B-cell malignancies who received the drug at doses of 40, 80, 160, or 320 mg once daily or 160 mg twice daily, and safety, tolerability, and maximum tolerated dose were the primary endpoints [25]. The expansion study enrolled a further 94 treatment-naïve (TN) or R/R CLL/SLL patients who received zanu at the maximum tolerated dose until disease progression, loss of clinical benefit, or dose-limiting toxicity. Patients were given zanu at doses of 160 mg twice daily (81 patients), 320 mg once daily (40 patients), or 160 mg once daily (40 patients). After a median follow-up of 13.7 months, 89 patients with CLL/SLL (94.7%) were still on the study. The overall response rate (ORR) was 96.2% for 78 evaluable patients, while the estimated 12-month PFS was 100%. Most of the toxicities were grade 1/2; neutropenia was the only grade 3–4 toxicity observed in more than two patients, while a grade 3 subcutaneous hemorrhage occurred in only one patient [25]. These relatively favorable safety results were in keeping with the reduced affinity of zanu for off-target kinases (including epidermal growth factor receptor (EGFR), Janus kinase 3 (JAK3), human EGFR2, interleukin-2 (IL2), inducible T-cell kinase (ITK), and TEC) compared to ibrutinib [26].
Cull et al. [27] recently reported updated safety and efficacy data of the AU-003 study involving 123 patients with a median follow-up of 47.2 months. The ORR was 95.9% (TN, 100%; R/R, 95%), with 18.7% achieving a complete response (CR). In 16 patients with del(17p)/TP53 mutation, the ORR was 87.5% (CR 16.7%). The estimated 3-year PFS was 83% (TN, 81%; R/R, 83%, respectively). Discontinuation of the drug due to adverse events (AEs) or disease progression were rare. The efficacy results of this updated analysis are also consistent with those of a single-arm Chinese study (NCT03206918) that reported an ORR of 84.6% (CR 3.3%) in 91 R/R CLL patients, with 87.2% of patients still alive and progression-free at 12.9 months. In relation to long-term safety, the results of the AU-003 study indicate that neutropenia (15.4%), pneumonia (9.8%), hypertension (8.9%), and anemia (6.5%) were the most commonly reported Grade 3 AE, while the annual incidence of atrial fibrillation, major hemorrhage, grade 3 neutropenia, and grade 3 infection decreased over time [27]. The latter study, which included a significant proportion of patients with TN and R/R CLL/SLL treated with single-agent zanu for 4 years, provided significant evidence of its long-lasting efficacy and safety.
Overall, data generated in these phase I/II studies demonstrated that:
  • The twice-daily dosing of zanu achieves 8-fold higher plasma drug exposure than ibrutinib and a longer half-life than acalabrutinib (4 vs. 1 h) [25][28].
  • Zanu shows complete and sustained occupancy of the BTK binding site across lymph nodes and in peripheral blood mononuclear cells [25][28].
  • Consistent with the favorable oral bioavailability evident in preclinical studies, oral administration of zanu achieves therapeutic plasma drug concentrations using the recommended phase II dose of 160 mg twice daily, with maintenance of drug levels above the IC50 required for full occupancy of the BTK binding site [25][28].
  • Zanu is less prone to pharmacological interactions with food, drug–drug interactions with strong or moderate CYP3A inhibitors, and proton pump inhibitors (PPIs) leading to more consistent, sustained therapeutic exposures and improved dosing convenience. In addition, the clinical use of zanu is less sensitive to impairments of liver function than ibrutinib [29].

This entry is adapted from the peer-reviewed paper 10.3390/cancers15143737

References

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