SUMMARY: The American Cancer Society estimates that for 2022, about 20,160 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4410 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.
Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® demonstrated survival benefits when compared to chemoimmunotherapy both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to IMBRUVICA® discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.
Zanubrutinib (BRUKINSA®) is an irreversible, potent, next-generation, small molecule inhibitor of Bruton’s Tyrosine Kinase, designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity, while minimizing off-target inhibition of TEC- and EGFR-family kinases. It has been hypothesized that the increased selectivity of BRUKINSA® may minimize toxicities, (such as those often associated with IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.
ALPINE study is a randomized, global, Phase III trial in which BRUKINSA® was compared with IMBRUVICA® in previously treated patients with relapsed or refractory CLL or SLL. In this trial, a total of 652 patients were randomly assigned 1:1 to receive either BRUKINSA® 160 mg orally twice daily or IMBRUVICA® 420 mg orally once daily, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior systemic therapy and were required to have measurable lymphadenopathy by CT scan or MRI. Exclusion criteria included current or past Richter’s transformation and prior treatment with BTK inhibitors. Approximately 20% of patients had a del(17p) and/or TP53 mutation and fewer than 15% of patients were on anticoagulants. The Primary end point of the trial was Overall Response Rate (ORR) assessed by investigator and Independent Review Committee (IRC), and Secondary end points included Progression Free Survival (PFS), event rate of Atrial Fibrillation or Flutter, Duration of Response, Time to Treatment Failure, Overall Survival (OS), Patient-Reported Outcomes, and Safety.
BeiGene recently announced that BRUKINSA® achieved superior Progression Free Survival (PFS) when compared to IMBRUVICA® in the final analysis of this Phase III ALPINE trial, as assessed by an Independent Review Committee (IRC) and investigator. This data will be presented at future scientific meetings. The interim analysis conducted at a median follow-up was 15 months showed significantly higher Overall Response Rate with BRUKINSA®, compared with IMBRUVICA® (78.3% versus 62.5%; P =0.0006). The Overall Response Rate was higher in patients with del11q (83.6% versus 69.1%) and del17p (83.3% versus 53.8%) with BRUKINSA®, as well as the overall 12-month Progression Free Survival (94.9% versus 84.0%) and Overall Survival rates (97.0% versus 92.7%). Major bleeding rates as well as adverse events leading to treatment discontinuation, was lower with BRUKINSA®, compared to IMBRUVICA®. The rate of Atrial Fibrillation/Flutter, a pre-specified safety endpoint, was significantly lower with BRUKINSA®, compared to IMBRUVICA® (2.5% versus 10.1%; P=0.0014).
It was concluded from this randomized, Phase III study that, among patients with relapsed/refractory CLL/SLL, BRUKINSA® was superior to IMBRUVICA®, with a lower rate of Atrial Fibrillation/Flutter. The researchers added that BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes.
First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Brown JR, Hillmen P, Eichhorst B, et al. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-115.