Jennifer Brown, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, compared two Bruton tyrosine kinase inhibitors at the 64^th ASH Annual Meeting, and found that zanubrutinib may be more effective and safer than ibrutinib for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia.

Transcript

I'm Jennifer Brown, Director of the CLL Center and Institute Physician at Dana-Farber Cancer Institute, and the Worthington and Margaret Collette Professor of Medicine in Hematologic Oncology at Harvard Medical School. I have had the pleasure of presenting the ALPINE data at the 2022 ASH meeting.

As you know, B-cell receptor signaling is a key component of what drives chronic lymphocytic leukemia cells. And in the last decade, the treatment of CLL has been transformed by inhibitors of this B-cell receptor signaling, in particular inhibitors of the Bruton tyrosine kinase, or BTK.

The first-in-class drug inhibiting BTK, of course, was ibrutinib, which really was transformative and highly effective, but also hampered by significant drug discontinuations due to a variety of adverse events ranging as high as 20% of patients and including serious cardiac events. For this reason, second-generation BTK inhibitors have been developed, and they've been developed to both be more specific for BTK and also to maintain, in the case of zanubrutinib, drug levels throughout the dosing interval, so that if more BTK is made by the cell, the drug is still there to inhibit it.

Now, zanubrutinib has previously been studied in a frontline randomized trial compared to chemoimmunotherapy, where it was shown to improve progression-free survival. ALPINE is the relapse trial in which it goes head-to-head against ibrutinib, and the data that I'm presenting are the final progression-free survival analysis. The study enrolled about 650 patients with a median of one prior therapy. They were an all-comer early relapse population with about 25% of patients with p53-aberrant disease. They were randomized between zanubrutinib and ibrutinib one to one, and the randomization was stratified by 17p as well as age, geography, and refractory disease.

The primary endpoint was overall response rate, which has been previously been shown to be improved by zanubrutinib compared to ibrutinib. And here we report the progression-free survival analysis, which was event driven, when 205 events occurred, and the data cutoff was August 2022. We found that zanubrutinib significantly improved progression-free survival compared to ibrutinib with a hazard ratio of 0.65 and a 2-year landmark estimated PFS [progression-free survival] of 79% for zanubrutinib vs 67% for ibrutinib. This was true whether the data were assessed by investigators or by the independent review committee. And notably in the 17p population, we saw an even bigger effect, with a 2-year landmark of 78% with zanubrutinib vs 55% with ibrutinib.

In general, the benefit was sustained across all other disease features as well. Zanubrutinib was also safer with fewer adverse events, fewer drug holds, fewer drug discontinuations and drug interruptions. The cardiac safety was perhaps most notable with fewer cardiac SAEs [serious adverse events], only 1 drug discontinuation for cardiac events compared to 14 with ibrutinib, 0 events of cardiac death with zanubrutinib compared to 6 with ibrutinib, which was 2%, and atrial fibrillation was 5% with zanubrutinib compared to 13% with ibrutinib.

So overall, the study showed a significant improvement in progression-free survival for zanubrutinib compared to ibrutinib. This is the first study to demonstrate an improvement in efficacy with one BTK inhibitor compared to another in CLL. And then in addition, zanubrutinib is safer, particularly with fewer cardiac events. These data, I think, have wide-ranging practice-changing implications, suggesting that zanubrutinib is both more effective and safer than ibrutinib and should be really a standard of care in this setting.