I had the pleasure of presenting the final results of the progression free survival analysis of the ALPINE study as a late breaking abstract at ASH this year. The ALPINE study is a head-to-head trial comparing zanubrutinib to ibrutinib in CLL patients. Ibrutinib, as you know, is the first in class BTK inhibitor approved some time ago for CLL. Zanubrutinib is a next generation BTK inhibitor which was designed to be more specific for BTK and then it also has another property – in addition to being a covalent inhibitor of BTK, it maintains drug levels throughout the dosing interval so that if BTK is resynthesized there is zanubrutinib around to inhibit it.  As a result of these properties, BTK activity is very, very high with zanubrutinib, so, based on this rationale, it was hypothesised that zanubrutinib would be potentially more efficacious and safer than ibrutinib and hence this study was performed.

What was the design of the study?

As I mentioned, it was a phase III randomised trial, it was open label. Patients with relapsed/refractory CLL, more or less all comers, were eligible for enrolment. They had to have measurable lymphadenopathy. It turned out to be a fairly representative relapsed population with a median age of 67-68 and a median of one prior therapy which was chemoimmunotherapy in most cases. The randomisation was stratified by age, geography, refractory disease status and deletion 17p. Then treatment was until progression or intolerable toxicity.

The primary endpoint was actually overall response rate defined as partial and complete response and there was an interim and final analysis of overall response rate previously where non-inferiority was established and then superiority was established. So this was an event-triggered analysis of progression free survival as a key secondary endpoint at the time that 205 events were observed. The data cut-off was August of 2022.

What were the key findings?

The key finding is that zanubrutinib improves progression free survival compared to ibrutinib with a hazard ratio of 0.65 and a median follow-up of about 30 months. The two-year landmark difference in progression free survival was 79% with zanubrutinib compared to 67% with ibrutinib, so a 12% difference. In a pre-planned analysis we also looked at the highest risk 17p deleted patients and their two-year landmark was actually 22% improved by zanubrutinnib which was 78% with zanubrutinib versus 55% with ibrutinib.

So those results are extremely significant but, in addition, zanubrutinib was also safer. There were fewer serious adverse events, fewer adverse events leading to treatment discontinuation or dose holes, fewer adverse events leading to discontinuation and there were many fewer cardiac events – fewer cardiac serious adverse events, only one cardiac event leading to discontinuation on zanubrutinib compared to 14 with ibrutinib and no cardiac deaths with zanubrutinib compared to six with ibrutinib, which was 1.9%. So zanubrutinib was both more effective and safer than ibrutinib.

What do you think will be the clinical impact of these results?

These results, as I said, establish that zanubrutinib is both more effective and safer than ibrutinib so it should really be the drug of choice over ibrutinib. If you have access to zanubrutinib I would certainly choose it over ibrutinib in all cases. Acalabrutinib is also a next generation inhibitor so also safer than ibrutinib. In the head-to-head study acalabrutinib did not demonstrate superiority, however. So we will never have comparisons between acalabrutinib and zanubrutinib but acalabrutinib would also be a reasonable choice but doesn’t have this level of data compared to ibrutinib.