Zanubrutinib Continues to Provide PFS Benefit Vs Ibrutinib in Relapsed/Refractory CLL/SLL

Jennifer R. Brown, MD, PhD

There continues to be an improvement in progression-free survival (PFS) with the next-generation BTK inhibitor zanubrutinib (Brukinsa) vs treatment with ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), as seen in findings from the phase 3 ALPINE trial (NCT03734016), according to Jennifer R. Brown, MD, PhD.¹

Data from the extended follow-up of the trial was presented at the 2023 ASH Annual Meeting, which demonstrated that treatment with the study drug reduced the risk for disease progression or death by 32% compared with ibrutinib at a median follow-up of 39.0 months (HR, 0.68; 95% CI, 0.53-0.86; P = .0011).

“Zanubrutinib is the only BTK inhibitor that has shown an efficacy benefit compared with another BTK inhibitor. Therefore, that seems like a good reason to choose it,” Brown emphasized.

In an interview with OncLive, Brown discussed the clinical implications of the ALPINE study and highlighted a subgroup analysis of acquired mutations in patients with CLL, demonstrating which mutations were associated with resistance to covalent BTK inhibitors.

Brown is the director of the Chronic Lymphocytic Leukemia Center in the Division of Hematologic Malignancies, and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School, both in Boston, Massachusetts.

OncLive: At the 2023 ASH Annual Meeting, you highlighted data from extended follow-up of the phase 3 ALPINE study. Could you provide some background on this trial?

Brown: The ALPINE study was a head-to-head comparison of the next-generation BTK inhibitor zanubrutinib against the first-generation inhibitor ibrutinib in patients with relapsed/refractory CLL. The enrolled patients had a median of 1 prior therapy.

What findings from ALPINE were presented at the 2023 ASH Annual Meeting?

We now have a median follow-up of 39 months on this study, and we showed, just as we did last year, that zanubrutinib improves PFS compared with ibrutinib by approximately 10%—in this case at 3 years at [approximately] 65% vs 55%. In the very high-risk 17p deletion subgroup, [the difference was] even more at 18%.

How might these findings impact treatment recommendations across patient subsets?

This is the first study that showed an efficacy benefit in a head-to-head comparison of BTK inhibitors. In that sense, clearly zanubrutinib would be preferred to ibrutinib because it's more effective and it has less toxicity. How it applies to choosing zanubrutinib over acalabrutinib [Calquence] is a little bit less clear; we're not going to have that head-to-head trial.

The acalabrutinib vs ibrutinib trial showed equivalence, but better safety. The overall data presented showed superiority and was of higher quality than what we have for acalabrutinib. However, those are both very good drugs, and reasonable to use. The safety profiles are fairly similar.

How does the sustained superiority of zanubrutinib observed in this study align with real-world effectiveness and experiences in the management of this disease?

We don't have much real-world experience with zanubrutinib yet. We know from the real-world experiences with ibrutinib that there were a lot of early discontinuations due to toxicity.

In fact, patients sometimes only stayed on for 6 months. That's gotten better as physicians learn more how to manage it.

However, it's really a sea change with acalabrutinib and zanubrutinib. They are both much better tolerated.

I do hope zanubrutinib becomes more widely used in any line of therapy in CLL. Acalabrutinib is also a good choice. However, people really should not use ibrutinib—in my view, given its toxicity profile—[especially with] the fact that 2 head-to-head trials have shown other drugs are better.

What unmet needs would you like to see addressed in the CLL treatment landscape?

The 17p and p53 aberrant population is still a substantial unmet need. They're the patients who relapse earliest and develop most refractory disease. We also have an issue with our young and fit patients, who we need to get through decades of life and we don't really have enough therapies to do that yet. Immune therapy, bispecifics, and CAR T-cell therapy are an area of interest.

CAR T-cell therapy hasn't worked as well in CLL, although we did hear an update on lisocabtagene maraleucel [Breyanzi; liso-cel] at this 2023 ASH Annual Meeting. Hopefully we'll figure out how to better harness some of those therapies for the benefit of patients with CLL. New categories of drugs may be coming along to new targets.

What would you like your colleagues to take away from this research?

Zanubrutinib continues to show an excellent cardiac safety profile compared with ibrutinib. There are less cardiac adverse events [AEs], less cardiac serious AEs, less cardiac hospitalizations, and less discontinuations due to cardiac events. Atrial fibrillation was 7% vs 16% with ibrutinib and no cardiac deaths with zanubrutinib vs 6 with ibrutinib.

You also launched a subgroup analysis of the ALPINE study on acquired mutations in these patients.² Could you elaborate on the methods used to identify these mutations?

[In ALPINE], we collected the samples [at disease] progression for some patients; we had about 52 patients who did have progression samples.

Their peripheral blood cells, which reflects CLL, were subjected to next-generation sequencing to look at BTK and PLCG2 mutations, as well as additional mutations, but the depth of sequencing was higher for the BTK and PLCG2.

What is the clinical significance of evaluating these acquired mutations in CLL?

We know that with covalent BTK inhibitors, C481 mutations that abrogate the covalent binding of the inhibitor to BTK, are the most common mechanism of resistance. The interesting thing is that in this study, we only saw [C481] in approximately 17% to 18% of the patients. The reason for that is not entirely clear, though it may be because many of these were early relapses. It does tend to be the case that the C481 appeals to PLCG2 mutations developed at later times.

Eventually, we may end up potentially choosing different inhibitors in relation to mutations, but we're not there yet.

What were the indications of certain mutations conferring resistance to specific therapies or drug classes?

We tend to assume that if we see that a mutation is not present at baseline, and that it's acquired in association with resistance, that probably means it's associated with resistance, particularly if it's an unknown gene of importance to the target. In the case of BTK, many of these mutations have been studied ex vivo or in vitro to demonstrate that they confer resistance to the drug in question.

Are there research efforts on developing tailored therapeutic strategies that coincide with what was seen within this trial?

In terms of BTK mutations, in general, there is a huge amount of activity, looking at non-covalent inhibitors, which will bind regardless of whether the C481 site is cysteine, serine, or anything else.

There are also BTK degraders coming along, which would work against any of the mutations because we also know that there are other mutations at C474, and 528W that turn up occasionally with covalent inhibitors, but are more common with non-covalent inhibitors. The degraders would potentially target all of those. We're looking at several classes of BTK inhibitory drugs as we move to the future.

Is there anything else you would like to convey on this mutational research?

The interesting aspect of this research is that BTK mutations are not the primary mechanism of resistance in this cohort. There is still a lot of work to do to identify the other mechanisms of resistance.

We did see some evolution of driver mutations, but most of the patients that we studied, we still don't have a mechanism of resistance. Therefore, there is a lot of work still to be done.

References

1. 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 vs 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.
2. Brown JR, Li J, Eichhorst BF, et al. Acquired mutations in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) that progressed in the ALPINE study. Blood. 2023;142(suppl 1):1890. doi:10.1182/blood-2023-173547