Weighing the Impact of Long-term Safety and Efficacy Data for Ibrutinib in the Treatment of CLL

In recent years, the treatment landscape for chronic lymphocytic leukemia (CLL) has been marked by a significant increase in agents that target various mechanisms of B-cell differentiation and growth. Among the most prominent of these mechanisms is Bruton tyrosine kinase (BTK), an essential component of the B-cell receptor (BCR) signaling pathway required for proliferation, differentiation, development, trafficking, chemotaxis, adhesion, and cell survival.¹ Autophosphorylation of BTK on the BCR activates its kinase activity, which subsequently sets in motion a cascade of downstream effects.² The absence or inhibition of BTK has been correlated with a high rate of apoptosis in various B-cell lineages. Malignant B cells, as in the setting of CLL, upregulate BTK expression, making BTK an actionable therapeutic target to initiate malignant B-cell death.^2,3

Ibrutinib, which covalently binds to the cysteine-481 moiety within the active site of the ATP-binding domain of BTK, is an oral, first-generation BTK inhibitor that was approved in 2014 for the treatment of CLL in patients who have received one prior therapy. Having since been evaluated for a variety of other applications in patients with CLL, ibrutinib is the first BTK inhibitors with FDA approvals for the first-line treatment of CLL as well as for patients with CLL who carry the deletion in chromosome 17 (del(17p)), a high-risk prognostic category.^4-7

The approval of ibrutinib in the first-line setting was based on findings of the phase 3 RESONATE-2 trial, an international, open-label, randomized study in which investigators compared ibrutinib to chlorambucil in patients with treatment-naive CLL or small lymphocytic lymphoma who were aged 65 years or older. Patients (N=269) were randomly assigned 1:1 to either ibrutinib (420 mg/d taken orally) or chlorambucil (administered on days 1 and 15 of a 28-day cycle for up to 12 cycles). The primary efficacy end point, as assessed by an independent review committee, was progression-free survival (PFS). Those in the ibrutinib arm experienced a significantly prolonged median PFS compared with those in the chlorambucil arm (not reached vs 18.9 months, respectively; HR for progression or death, 0.16; 95% CI, 0.09-0.28), with an estimated PFS rate at 24 months of 98% vs 85%, respectively.⁸

In recent years, as second-generation BTK inhibitors have been developed and investigated for the treatment of CLL, emerging data for ibrutinib have demonstrated its efficacy in different patient populations, in addition to offering clinicians additional insights on its long-term safety and efficacy.

Results published in a 5-year follow-up analysis of RESONATE-2 demonstrated that the significant treatment benefit of ibrutinib was sustainable through at least 60 months. Median PFS remained not reached in the ibrutinib arm and was 15 months in the chlorambucil arm (HR, 0.146; 95% CI, 0.098-0.218), with an estimated PFS rate at 60 months of 70% vs 12%, respectively.⁹ In addition, ibrutinib was associated with significantly improved PFS in a subgroup analysis of those with a high prognostic risk (defined as a TP53 mutation, 11q mutation, and/or unmutated IGHV. These patients were nearly 92% less likely to experience disease progression or death compared with those who received chlorambucil (HR, 0.083; 95% CI, 0.047-0.145).⁹ This finding was particularly promising because of the treatment-induced mutations, which have been previously reported in the literature with shorter-term use of ibrutinib.10 Of note, new long-term safety and efficacy data from the RESONATE-2 are expected to be presented at an upcoming medical meeting.

More recently, data from patients with CLL bearing TP53 aberrations or del(17p) who had received ibrutinib-based therapy in the first-line setting (n=89) were pooled from 4 different studies, and the findings were reported at the 62nd American Society of Hematology Annual Meeting and Exposition. The analysis revealed that PFS and overall survival at 4 years were 79% and 88%, respectively, which the investigators noted was highly promising for a population with historically poor outcomes.¹¹ Median duration of ibrutinib-based treatment was 46 months, with 46% of patients remaining on ibrutinib therapy at the time of the analysis. Adverse events of grade 3 or higher noted over the 8-year time span across the 4 studies were infection (22%), hypertension (13%), atrial fibrillation (12%), and major hemorrhage (7%)—all of which are consistent with the safety profile observed in other clinical trials of ibrutinib.¹² These results are indicative of sustained efficacy in those with del(17p) or TP53 or mutations among patients treated with ibrutinib.¹¹

In consideration of the broader profile of ibrutinib since its initial United States Food and Drug Administration approval in 2014, the long-term safety and efficacy data coupled with study results showing its potential in specific patient populations suggest that the role of this agent is both flexible and evolving in the overall spectrum of CLL treatment.

References

1. Ibrutinib. Prescribing information. Pharmacyclics; 2020. Accessed April 1, 2021. https://www.imbruvica.com/files/prescribing-information.pdf
2. Li CJ, Jiang C, Liu Y, et al. Pleiotropic action of novel Bruton's tyrosine kinase inhibitor BGB-3111 in mantle cell lymphoma. Mol Cancer Ther. 2019;18(2):267-277. doi:10.1158/1535-7163.MCT-18-0478
3. Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240. doi:10.3747/co.26.4345
4. Lymphoma Research Foundation. Chronic lymphocytic leukemia/small lymphocytic lymphoma: FDA updates. Accessed April 2, 2021. https://lymphoma.org/aboutlymphoma/cll/cllfdaupdates/
5. Seiler T, Dreyling M.Bruton’s tyrosine kinase inhibitors in B-cell lymphoma: current experience and future perspectives. Expert Opin Investig Drugs. 2017;26(8):909-915. doi:10.1080/13543784.2017.1349097
6. Kim HO. Development of BTK inhibitors for the treatment of B-cell malignancies. Arch Pharm Res. 2019;42(2):171-181.doi:10.1007/s12272-019-01124-1
7. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2021. Accessed April 2, 2021. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
8. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388
9. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x
10. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi:10.1200/JCO.2016.70.2282
11. Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukemia (CLL) with 4 years of follow-up in patients with TP53 aberrations (del(17p) or TP53 mutation): a pooled analysis from 4 clinical trials. Blood. 2020;136 (suppl 1):23–24. doi:10.1182/blood-2020-134431.
12. Strati P, O’Brien SM. BTK inhibitors for the treatment of chronic lymphocytic leukemia. Oncol Times. 2019;41(17):1,6-8,29. doi:10.1097/01.COT.0000581600.17621.64