Alexey Danilov, MD, PhD

Although these results are certainly exciting, a few questions remain.

First, one might suggest that ibrutinib underperformed in this study. The ibrutinib PFS in this study is comparable to that seen in RESONATE-17 (63% at 24 months), a study restricted to patients with TP53 aberrations who underwent a median of two prior therapies. In RESONATE, which compared ibrutinib with ofatumumab (Arzerra, Novartis), PFS was not reached among ibrutinib-treated patients who had received one to two prior therapies, and 24-month PFS approximated 80%. In the ALPINE study, median number of prior therapies was one for both arms.

Second, a relatively high proportion of patients in ALPINE discontinued both drugs. As reported, 26.3% of patients discontinued zanubrutinib, mostly due to adverse events (16.2%). Meanwhile, 41.2% of patients discontinued ibrutinib (22.7% due to adverse events). Contrast this with the SEQOUIA study, in which 8.3% of patients discontinued zanubrutinib due to adverse events over a similar follow-up period of 26 months.

Ibrutinib toxicity-related discontinuation rates range between 10% and 20% in clinical trials, depending on the length of follow-up. Why an additional 20% of patients discontinued ibrutinib early should be further detailed.

Third, this study does not help clarify whether zanubrutinib is preferable to acalabrutinib, a selective BTK inhibitor FDA-approved for treatment of CLL that is associated with a more favorable toxicity profile compared with ibrutinib. Of note, PFS benefit was not observed in ELEVATE-RR, a randomized study that compared acalabrutinib (Calquence, AstraZeneca) with ibrutinib among patients with relapsed/refractory CLL. Unlike ELEVATE-RR, ALPINE was not restricted to high-risk patients, thus it is not possible to conduct a faithful comparison between these two trials.

Finally, resistance to zanubrutinib is an emerging question. A recent study reported that patients treated with zanubrutinib can gain BTK mutations, such as Leu528Trp, that can potentially confer resistance to noncovalent BTK inhibitors (ie, pirtobrutinib [LOXO-305, Eli Lilly, Loxo Oncology]). The true prevalence of these mutations among zanubrutinib- (and acalabrutinib-) treated patients and how they may affect efficacy of subsequent therapies remains to be seen.

Despite these caveats, the ALPINE study results are exciting and zanubrutinib, now incorporated in the NCCN compendium, is a fine therapeutic option for patients with CLL. One hopes that future scientific studies will help shed light on the biologic rationale behind improved efficacy of zanubrutinib seen in ALPINE.

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Tam CS, et al. Lancet Oncol. 2022;doi:10.1016/S1470-2045(22)00293-5.

Lee Greenberger, PhD

This was a very aggressive effort, comparing zanubrutinib with ibrutinib head to head in a large phase 3 trial. These are important studies to do because they tell us if there are real differences between therapeutics. Quite often, the approvals of these therapies are based on no comparator — simply OS or PFS in the case of BTK inhibitors. But we need to understand if they truly are better than existing therapies. The best way to do that is to conduct a large phase 3 comparator trial in which patients are equally matched.

In this comparison, zanubrutinib statistically outperformed ibrutinib and provided longer PFS. It also is associated with less atrial fibrillation, which has been an issue with BTK inhibitors — particularly ibrutinib. Because there is less atrial fibrillation and fewer side effects, there potentially will be fewer patients going off therapy, so this appears to be practice changing.

The OS data are immature so, although zanubrutinib can improve PFS, it may or may not show a statistical difference in OS. That is really what we’re after because, as best as we can tell, patients need to be on these drugs every day for the rest of their lives.

We need to learn how to combine these therapies with other agents for a defined duration so patients can stop taking them because the disease (A) is molecularly cleared and (B) doesn't come back. it's going to take time to learn how to do that — specifically what the combination should be, what the duration should be and which patients are going to derive the most benefit.

Patients who have a P53 deletion or mutation tend to be the most difficult to treat. All BTK inhibitors actually can work for those patients, so that is encouraging. They don't work quite as well for patients who don't have P53 mutations. This concept of the ‘worst-case’ patients — how to treat them, when to treat them, what combinations to use and when we can stop treatment — needs to be looked at.

Regardless of the agent — whether it be covalent inhibitors like zanubrutinib or ibrutinib, or noncovalent inhibitors such as pirtobrutinib (Jaypirca, Eli Lilly), or even the so-called BTK degraders that actually will destroy the protein by a molecular mechanism inside the cells — we’re going to have to learn how to use them in combination to ultimately achieve cure, and that is going to take some time.