ALPINE Trial of Zanubrutinb Improves PFS vs Ibrutinib in CLL and SLL

In an interview with Targeted Oncology, Jennifer R. Brown, MD, PhD, discussed the findings from the ALPINE study and the effectiveness of zanubrutinib when used for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Treatment with zanubrutinib (Brukinsa) reduced the risk of progression or death by 35% vs ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to findings from the phase 3 ALPINE study (NCT03734016).1

A presentation given at the 2022 ASH Annual Meeting and data simultaneously published in the New England Journal of Medicine showed that the study met the criteria for noninferiority and superiority for zanubrutinib vs ibrutinib for objective response rate (ORR) and progression-free survival (PFS) by independent review committee (HR, 0.65; 95% CI, 0.49-0.86; P = .0024).

In the trial, the 24-month PFS rate was 79.5% with zanubrutinib and 67.3% with ibrutinib. For the primary end point, objective response rate (ORR) was 86.2% with zanubrutinib vs 75.7% for ibrutinib (P = .0007).

For the secondary end point of fibrillation/flutter, rates (P = .0004) were significantly less common with zanubrutinib (5.2%) compared with ibrutinib (13.3%).

Regarding safety, fewer adverse events (AEs) leading to treatment discontinuation were seen in patients administered zanubrutinib (15.4%) compared with those given ibrutinib (22.2%). There were no fatal cardiac events reported with ibrutinib compared with 6 events in the ibrutinib arm.

In an interview with Targeted OncologyTM, lead study author Jennifer R. Brown, MD, PhD, from the Dana-Farber Cancer Institute, discussed the findings from ALPINE and the effectiveness of zanubrutinib when used for patients with CLL or SLL.

How does zanubrutinib differ from other Bruton’s tyrosine kinase inhibitor (BTK) inhibitors? What may make it more effective?

The covalent BTK inhibitors were the first group where ibrutinib was the first-in-class drug. Then zanubrutinib and acalabrutinib are second generation covalent inhibitors. Zanubrutinib is much more specific for BTK than ibrutinib is. Acalabrutinib is also more specific for BTK. That doesn't distinguish them that much, but 1 thing that does distinguish zanubrutinib from both of them is its pharmacokinetic [PK] properties. The drug remains present in the bloodstream throughout the entire dosing interval so that if new BTK is generated by the cells, the drug can still inhibit BTK and it's available to inhibit it again.

This is not true of ibrutinib and acalabrutinib. After they do their initial inhibition covalently, they don't stay in the bloodstream, so new BTK would not be inhibited until the next dose. That's perhaps the main biological rationale for why zanubrutinib could be more effective than ibrutinib. The other would be that the dosing was optimized to maintain BTK occupancy. Part of that's the PK but part of it's also the dose and schedule.

What did investigators of the ALPINE study look to evaluate?

The ALPINE trial is a randomized phase 3 trial comparing the second generation BTK inhibitor zanubrutinib to the first generation one, ibrutinib in relapsed/refractory patients with CLL. This was an all-comers type population, and patients had a median of 1 prior therapy. About 23% had a 17p deletion or TP53 mutations, and they were randomized between zanubrutinib and ibrutinib until progression or intolerance.

Can you explain the findings from the trial which were presented at ASH 2022?

The study showed that zanubrutinib had a significant progression-free survival benefit compared with ibrutinib, as measured by both the independent review committee and the investigators for the hazard ratio .65. The 2-year landmark estimates of PFS were 79% for zanubrutinib and 67% for ibrutinib.

Furthermore, even in the highest risk group of patients with del(17p) and/or aberrant TP53, a pre-planned analysis of zanubrutinib significantly improved the progression-free survival by 22%, by a larger amount, even in the all-comer population. The finding was consistent across all different types of patient characteristics.

There was also a significant safety improvement. Patients on zanubrutinib had fewer serious adverse events, fewer adverse events leading to dose reduction or discontinuation, or interruption, and cardiac events were less as well. There were fewer cardiac serious adverse events, fewer cardiac events leading to drug discontinuation, only 1 on zanubrutinib vs 14 on ibrutinib. There were no cardiac deaths was zanubrutinib vs 6 with ibrutinib. Overall, the study showed that zanubrutinib was more efficacious and safer than ibrutinib.

As this was the extended follow-up of the study, how do these results differ from the previous phase 3 results that were released?

The primary end point of the study is overall response rate defined as complete response and partial response comparing zanubrutinib and ibrutinib. Those data were released at EHA in 2021, showing that zanubrutinib had significantly improved overall response rate compared with ibrutinib. That was an interim overall response rate analysis. Since then, there's been a final overall response rate analysis and both of those showed superiority for zanubrutinib compared with ibrutinib. That paved the way for testing progression-free survival difference by hierarchical statistical testing once 205 events had occurred, and that happened in August of 2022. The overall response rate is still improved by zanabrutinib compared with ibrutinib now. We don't have the formal quality-of-life data as yet, but in general, if patients have a better response to their disease, they feel better. That's been a consistent finding.

What ongoing studies are also evaluating these agents? What are the next steps?

I'm doing a study of zanubrutinib and venetoclax [Venclexta] combination in relapse. There's ongoing data from the frontline SEQUOIA trials [NCT03336333]. We'll probably see, not only for the follow-up of this trial for long-term follow-up of zanubrutinib of single agent, but we'll start to see some studies of zanubrutinib and venetoclax in combination as well.

Zanubrutinib improved efficacy and safety compared with ibrutinib, so I think people should strongly consider using zanubrutinib as the potential standard of care BTK inhibitor in CLL. It's not yet approved by the FDA, but we are expecting that hopefully in January, It is already in the NCCN guidelines as a preferred treatment option for CLL

What unmet needs still exist in the CLL space?

The del(17p) and/or aberrant TP53 group of patients remains a significant unmet need. They are more likely to relapse sooner on all our therapies. Richter's transformation is also a major unmet need. That's where CLL becomes an aggressive lymphoma and that's historically been hard to treat. Even the IGVH-unmutated patients, particularly if they're very young, is a significant unmet need, because this group tends to progress more rapidly to treatment and then tends to relapse sooner, certainly on time-limited therapies. If we're going to get them to their natural lifespan, we need more than BTK inhibitors and venetoclax.

What else in the CLL space excites you? Do you have any predictions on what we can see in this upcoming year?

There was a lot of data at this ASH about the ibrutinib and venetoclax combination with longer term follow-up. That combination is also not yet FDA approved, but I think there's a lot of interest in seeing what the longer follow-up of many of these studies show. Then, newer studies that are comparing a BTK inhibitor/BCL2 inhibitor combination to venetoclax are of great interest. Then Matthew S. Davids, MD, MMSc, from my group is leading a study with acalabrutinib [Calquence] and venetoclax vs venetoclax. It's going to be a crucial set of data for us to understand and think about how best to treat our patients going forward.

Pirtobrutinib [LOXO-305] is also a drug to keep one's eye on. That is a novel non-covalent BTK inhibitor, which has now treated almost 300 patients with CLL who were previously treated with a covalent BTK inhibitor. We heard at this [recent] ASH that the median PFS was a little over 19 months for those patients, even if they progressed on a prior covalent BTK inhibitor. Even if they carried the C481 mutation that makes them unresponsive to covalent inhibitors. That drug is in multiple phase 3 registration trials and will hopefully add an additional line of therapy or extend the benefit of BTK inhibitor therapy for our patients.

1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study. Blood. 2022;140(suppl 2):LBA-6. doi:10.1182/blood-2022-171538