ALPINE Trial Highlights Zanubrutinib's Advantage in CLL

Habte Yimer, MD

The development of Bruton tyrosine kinase (BTK) inhibitors has transformed the treatment landscape for patients with chronic lymphocytic leukemia (CLL). However, oncologists often question which is best to use for their patients.

The phase 3 ALPINE trial (NCT03734016) has played a pivotal role as it compares the efficacy and safety of different generations of BTK inhibitors. Specifically, the trial aims to determine the efficacy of zanubrutinib (Brukinsa), a newer BTK inhibitor, compared with the established ibrutinib (Imbruvica).

Follow-up data from the ALPINE trial showed superior PFS and safety signals with zanubrutinib vs ibrutinib in this patient population. After a median follow-up of 39.0 months, a sustained PFS benefit was seen with zanubrutinib vs ibrutinib, reducing the risk for disease progression by 32% (HR, 0.68; 95% CI, 0.53-0.86; P =.0011). This benefit was seen across all subgroups, including age, sex, prior lines of therapy, baseline 17p deletion and/or TP53 mutation status, bulky disease, baseline IGHV mutation status, disease stage, and complex karyotype.

In an interview with Targeted Oncology^TM, Habte Yimer, MD, hematologist/oncologist with Texas Oncology and investigator of the study, discussed the trial's findings and explored how these results are shaping clinical decisions in CLL treatment.

Chronic lymphocytic leukemia cells: © Mari-stocker - stock.adobe.com

Targeted Oncology: Can you discuss what we already know about the phase 3 ALPINE trial?

Yimer: This is a trial that was designed to answer a very important question and to see which BTK inhibitor we have on the market—we have 3 now—is [best]? It was designed to see if the latest generation BTK inhibitor, which is acalabrutinib [Calquence], is better than the first-generation BTK inhibitor, ibrutinib.

How significant is the sustained PFS benefit with zanubrutinib over ibrutinib in this patient population?

I think it is very significant. They show early benefits, which might not carry over into the 3-year or 5-year mark. What we have shown is that the actual progression-free survival benefits that were seen at the 2-year mark actually persisted at the 3-year mark, showing that zanubrutinib still [has] a better progression-free survival than ibrutinib.

What extended follow-up data from the trial can you share?

We presented the safety, whether they [are] still carrying over. And even though, for example, if we look at hypertension—hypertension rate is equal between both ibrutinib and zanubrutinib arms—tThe degree of rise in systolic blood pressure is less with zanubrutinIb. And over time, [there are] cardiac safety issues also. You see less atrial fibrillation, much less atrial fibrillation and flutter with zanubrutinib. There were 6 deaths, cardiac-related deaths on ibrutinib compared with 0 on zanubrutinib.

Were there any other efficacy findings that community oncologists should take away from this research?

Zanubrutinib is still showing over time that it seems like the depth of response continues to go higher, even at the 4-year mark, the overall response rate is higher still and it is going up with a [complete response] rate crossing that 10% mark, as compared with ibrutinib at around the 7% mark.

Are there any specific patient populations where zanubrutinib might be more beneficial first?

It has shown to be effective in the whole overall general population, but all subgroups benefited on zanubrutinib compared with ibrutinib. But specifically, if you look at the high-risk patient with 17p deletion or TP53 mutations, those patients have a higher benefit when they are on zanubrutinib as compared with ibrutinib. The progression-free survival with zanubrutinib in those patients was around 57% or 56% as compared with 41% on ibrutinib, so the benefit is significant.

How do these findings fit into the broader landscape of treatment options for this patient population?

BTK inhibitors as a class have changed how we manage our patients [with CLL] in the frontline setting and the second-line setting. The question is, which one to choose from? ALPINE did show that zanubrutinib is more effective and is also safer than ibrutinib. It has become a first-line treatment and also a second-line choice for our patients with CLL.

Are there any key considerations that one should know about when trying to decide which BTK inhibitor to use?

The first thing is efficacy. Does it work for my patient? This study shows that zanubrutinib had a better progression-free survival. After that, you want to make sure, since [patients] are going to be on this treatment for many years, is it safe to be on the medication? We are seeing at the 3-year mark that zanubrutinib still is keeping its safety profile.

Are there any next steps for research with zanubrutinib?

The next step in the frontline setting is to combine it with either venetoclax or other agents and to see if we can stop the drug in time-limited fashion for first-line patients. Can you treat a patient for 1 year and stop it or for 2 years and stop it? Using [minimal residual disease (MRD)] status will be the next step for this drug.

REFERENCE:

Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Blood. 2023;142(1):202. doi:10.1182/blood-2023-174289.