The Bottom Line:
Zanubrutinib is more efficacious than ibrutinib and produces longer progression-free survival (PFS) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). It is also better tolerated with fewer cardiac side effects than ibrutinib.
Who Performed the Research and Where Was it Presented:
Dr. Jennifer Brown from Dana-Farber Cancer Institute and colleagues presented the results at the American Society for Hematology Annual Meeting in 2022 and a companion article published in the New England Journal of Medicine (NEJM).
Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib are very effective for treating CLL and SLL. However, Zanubrutinib is a next-generation BTK inhibitor that is much more specific for BTK than ibrutinib (meaning potentially fewer side effects). In addition, it was designed to continuously maintain drug levels in the body.
In this interview, Dr. Brian Koffman interviewed Dr. Jennifer Brown, Director of the CLL Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. They discussed the ALPINE trial, a phase 3 clinical trial directly comparing the efficacy of zanubrutinib vs. ibrutinib in patients with relapsed/refractory CLL / SLL.
Methods and Participants:
For this phase 3 clinical trial, patients with relapsed/refractory CLL / SLL who had received one or more prior therapies and had measurable disease were randomized to receive zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Approximately 650 patients from 15 countries were enrolled in the study.
- Most patients had been treated with one prior therapy (mostly chemoimmunotherapy), and the average age was 68 years.
- The treatment discontinuation rate was lower with zanubrutinib (26%) vs. ibrutinib (41%) due to lower rates of adverse events and lower rates of progressive disease.
- Cardiac safety was much better in the zanubrutinib group. In addition, the rate of atrial fibrillation (abnormal heart rhythm) was much lower with zanubrutinib (5%) vs. ibrutinib (13%).
- Cardiac deaths were 0 versus 6 (1.9%).
- After two years of treatment, 79% of patients in the zanubrutinib group were progression-free, compared with 67% in the ibrutinib group.
- This difference in favor of zanubrutinib was seen in all subgroups, including in patients with deletion 17p, where 77% of patients in the zanubrutinib group were progression-free after two years compared with 55% in the ibrutinib group.
- In the related article in the prestigious New England Journal of Medicine, released the same day as the ASH oral presentation, we learned this about the improvement in progression-free survival (PFS): ” sensitivity analyses… included evaluation for the possible effect of disease progression due to trial drug interruption.” This is saying that the improvement was not just because people were more likely to stay on zanubrutinib leading to longer PFS, but the improved PFS also applied to those still on the drug in both arms.
The results of this study are quite exciting. At the beginning of the trial, everyone expected zanubrutinib to have similar efficacy to ibrutinib (because they are in the same class of drugs) but with a better safety profile. Instead, we have strong evidence that suggests zanubrutinib improves progression-free survival compared to ibrutinib in all subgroups studied, including in high-risk, hard-to-treat patients like those with deletion 17p, and it is safer and better tolerated.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL / SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study
Take care of yourself first.
Ann Liu, PhD