Discussing Zanubrutinib's Recently Approved Indication for Chronic Lymphocytic Leukemia

Gary Owens, MD, president, Gary Owens Associates, discusses the ALPINE study and predicts how zanubrutinib's recently approved indication for chronic lymphocytic leukemia will transform the standard of care.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

In this episode, Dr Gary Owens predicts how zanubrutinib's approval for CLL will change the treatment paradigm.

I'm Gary Owens. I'm the president of Gary Owens Associates, which is a market access and health economics consulting organization based out of Delaware with a second location in Pennsylvania. Happy to chat with you today.

Can you discuss the unmet need that still exists for patients with CLL?

Maybe a little background first, just to be certain everybody's grounded. I think everybody knows that CLL is somewhat of an indolent blood cancer. Lots of immature lymphocytes populate the bone marrow. But at the same time, it's also the most common leukemia in adults in Western countries, comprising about 25% to 35% of all leukemias. Roughly 20,000 new cases were diagnosed last year in 2022. 

There's not a really high death rate. Deaths last year were a little bit over 4500. Far more people were diagnosed, contributing to far more prevalent cases. The 5-year survival rate is pretty good at almost 90%, and the death rate from CLL has been decreasing almost continuously since 1992, thanks to better diagnoses and therapies. 

You asked what are the unmet needs. Certainly, the biggest unmet need is there's really no cure for most patients. It's a chronic disease. CLL does tend to be progressive in many people. There are subgroups of patients that have a bigger need. Those with deletion 17p or aberrant TP53 mutations have a bigger unmet need, mainly because they tend to relapse sooner despite what therapy is given. 

Richter's transformation, which is disseminated small cell lymphoma—another group that has an unmet need. As you know, the IGVH-mutated patients tend to do better, but the unmutated patients tend to be younger and have a worse prognosis. They also have an unmet need. 

Despite the low death rate and very high 5-year survival, there are subgroups of patients with big needs. I think the other unmet need is we're still looking for therapies with fewer side effects and toxicities.

Thank you, Gary. To jump into the ALPINE study, can you discuss the study's design and go through some of the key findings?

I certainly can. The ALPINE study caught a lot of attention because it was a direct head-to-head comparison of two of the Bruton's tyrosine kinase (BTK) inhibitors: ibrutinib, which was the first to market, and zanubrutinib, which was the most recent one to market. ALPINE was presented at the 65th ASH Annual Meeting & Exposition in 2022 and published in The New England Journal of Medicine simultaneously. 

ALPINE was a randomized, phase 3 trial comparing zanubrutinib to the first generation ibrutinib in patients with relapsed/refractory CLL. It was an all-comers population, and the patients had a median of 1 prior therapy before being randomized into this trial. About 23% of patients had 17p deletion or a TP53 mutation, and they received treatment until disease progression or intolerance. 

Some of the major findings showed that zanubrutinib had a significant progression-free survival benefit compared to ibrutinib, and that was measured by an independent review committee and the investigators. The hazard ratio was 0.65, which was pretty progressive. At 2 years, progression-free survival was 79% for zanubrutinib and 67% for ibrutinib. Even in the high-risk groups, those with the 17p and TP53 mutations, zanubrutinib improved PFS by about 22%. Again, pretty impressive. 

What's even more important in some ways, because one of the unmet needs was for better tolerated or safer drugs, patients on zanubrutinib had fewer serious adverse events (AEs) and discontinuations due to AEs, particularly cardiac events. There were fewer adverse cardiac events with zanubrutinib, particularly atrial fibrillation. There was only 1 discontinuation due to zanubrutinib vs 14 with ibrutinib. There were no cardiac deaths in the zanubrutinib arm vs 6 with ibrutinib.

Not only did you have a gain in progression-free survival, but we also had a gain in safety and tolerability that I think is very important, considering the typical age of the population with CLL is over 70. In fact, I think the average age at time of diagnosis is somewhere around 74, if I have my statistics right. This is a group that's more at risk for cardiac disease, and this safety profile certainly speaks well for treating those patients.

In light of the findings from ALPINE, how do you think zanubrutinib's newly approved indication will impact patients, payers, or the CLL space?

If indeed the patient is a candidate for a BTK inhibitor, zanubrutinib is going to evolve into the drug of choice. That doesn't mean there's anything terribly wrong with ibrutinib. It was a standby for a long time. It has multiple indications other than CLL and still is a useful drug. 

I think NCCN Guidelines have already moved to make zanubrutinib the preferred agent in the setting of relapsed/refractory disease, which makes a lot of sense. Until we have data on newer competitors coming to market, zanubrutinib will probably evolve to the standard of care.

From a payer standpoint, where I work, this is an oral agent, so it's a specialty pharmaceutical agent. Payers will want to make sure there is a good pathway to get zanubrutinib approved and covered. The cost of treating CLL rose dramatically in the mid 2010s with the introduction of the BTK inhibitors, as well as things like venetoclax to treat some cases, and there's concern there by payers. But I think these drugs are now state-of-the-art and have demonstrated superiority in both efficacy and safety. 

In my opinion, zanubrutinib should be the first choice for those relapsed/refractory patients who are candidates for BTK inhibition.

Is there anything we haven't mentioned yet today that you wanted to add?

No, I think we covered it very, very well, except for the fact that what we're saying today may not always be the case. With multiple BTK inhibitors in the pipeline, not only for CLL, but mantle cell and other lymphomas, these data will continue to evolve. What is axiomatic today may not be the same in 2024.

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This transcript has been edited for clarity.