The ALPINE study was a phase III head-to-head randomised trial comparing zanubrutinib to ibrutinib. Ibrutinib has been a major game-changer in the treatment of chronic lymphocytic leukaemia with high effectiveness but because of adverse events some of the patients were not able to continue therapy. Zanubrutinib is a next generation BTK inhibitor; it’s more specific to BTK without much off-target effect, therefore less side effects are expected. In fact, in clinical studies before this study we observed lower rates of adverse events with zanubrutinib. Also because of the characteristics and pharmacologic characteristics of the drug, it was expected that efficacy could be higher, the exposure, the BTK occupancy and other characteristics of the drug would basically bring the hypothesis of maybe even more efficacy with zanubrutinib.

So the study was designed with a primary endpoint of non-inferiority and superiority of overall response in zanubrutinib compared to ibrutinib in patients with previously treated CLL and also had secondary endpoints of adverse events, mainly cardiac adverse events, and also progression free survival.

What were the key findings?

At the interim presentation of this study we knew that zanubrutinib had a superior overall response compared to ibrutinib, that’s a combination of complete response and partial responses. For this presentation we reported on the final analysis showing progression free survival comparison between zanubrutinib and ibrutinib. This was the key point of the presentation but I should also mention that we continue to see a better improved overall response of 86.2% with zanubrutinib compared to 75.7% with ibrutinib so that has continued to be seen and observed.

In terms of the progression free survival which was the main point of this presentation, patients treated with zanubrutinib had at 24 months with a median follow-up of more than 29 months had 79.5% progression free survival and that’s compared to 67.3%, this is all-comers, and the difference is statistically significant. Also focussing on a planned analysis of patients with del 17p and p53 mutations, which is, of course, an important subgroup of patients with CLL, zanubrutinib provided a two year PFS of 77.6% compared to 55.7% with ibrutinib and, of course, this was statistically significant.

So the efficacy – for the first time in CLL a drug showed an improved efficacy compared to ibrutinib and that’s why this study gained a lot of attention. It is important for clinical practice as we will discuss.

We also noted that fewer patients on the zanubrutinib arm had discontinuation of therapy because of side effects – 15.4% compared to 22.2% in the ibrutinib arm. Then focussing on cardiac side effects and the cardiac profile of the two drugs, basically atrial fibrillation with zanubrutinib was zero… I’m sorry, the adverse events that lead to the discontinuation – no patients on the zanubrutinib arm discontinued drug because of atrial fibrillation and five patients, or 1.5%, discontinued drug on the ibrutinib arm. In terms of cardiac events, the fatal cardiac events leading to death, no patients on the zanubrutinib arm and six patients in the ibrutinib arm, and that’s 1.9%. Overall the rate of atrial fibrillation and atrial flutter was also significant – lower in the zanubrutinib arm versus the ibrutinib arm with 5.2% versus 13.3%.

So, overall the study take-home points are that zanubrutinib continues to be effective and showing improved efficacy. As I said, this is the first time a head-to-head study showing that, both from the overall response standpoint and also progression free survival, over ibrutinib and also showing fewer side effects and significantly lower rates of atrial fibrillation and atrial flutter.

There are some other adverse events in which we did not observe a difference and one would be hypertension, that’s another adverse event of interest with BTK inhibitors. This study did not show any significant difference between the hypertension rate in zanubrutinib versus ibrutinib.

How can these results impact the future treatment of CLL and what does the future look like for this study?

These are important results and practice changing. Before this presentation we knew that zanubrutinib had a better safety profile but now with efficacy signal this is an important message and important point of discussion when we sit with patients and discuss treatments. Zanubrutinib is definitely superior to ibrutinib in terms of treatment of choice and this study is practice changing in that regard.

In terms of the future of this study, the study will continue to follow-up these patients; like any other randomised trial, long-term follow-up will be important both for efficacy and also some of the side effects and adverse events may increase over time or may decrease over time and the differences may change. So the study will continue and we will hopefully have long-term follow-ups.

In terms of the future of the drug in CLL, as we all know and saw at the ASH meeting, there’s a lot of activity and interest in combination studies using BCL2 inhibitors and BTK inhibitors, for example, in combination plus/minus anti-CD20 antibodies. So this drug will be a major player in the combination regimens and we will see more studies coming out with zanubrutinib combined with different types of BCL2 inhibitors. So really looking forward to having that data in upcoming meetings.