Zanubrutinib Outperforms Ibrutinib in Treating Relapsed/Refractory CLL/SLL Mehrdad Mobasher MD
By Mehrdad Mobasher, MD, MPH
The ALPINE study was a phase 3 clinical trial done in relapsed/refractory CLL and SLL (small lymphocytic leukemia). This is the final analysis of PFS of this study. This study now shows Zanubrutinib (brand name(s) BRUKINSA a tyrosine kinase inhibitor) demonstrates superior progression-free survival. Compared to standard Ibrutinib, in the past we had presented interim analysis of overall response rate, and Zanubrutinib had already shown superiority of overall response rate. Zanubrutinib has other indications that we have FDA approved, globally we have more than in more than 60 countries. We have approvals in CLL (chronic lymphocytic leukemia), Waldenstrom’s macroglobulinemia (WM), marginal zone lymphoma, and mantle cell lymphoma.
What is the standard of care for this disease state? And what problem is the trial(s) attempting to solve?
In relapsed/refractory CLL, currently typically a standard of care would be a BTK inhibitor. What is special about this trial is that we did a head-to-head study of our next generation PTK inhibitor Zanubrutinib versus Ibrutinib, which has been a standard care for this disease setting for many years. And what we show, which is interesting and exciting for us is that Zanubrutinib (tyrosine kinase inhibitor) has shown superior efficacy, which is very important for this patients also showed favorable safety. So when we look at the overall high grade adverse. Serious adverse events that lead to dose reductions or dose discontinuations. They’re all lower in the Zanubrutinib arm and strikingly the cardiac adverse events that have been known with ibrutinib are a lot less with Zanubrutinib. So cardiac in general, specifically atrial fibrillation and atrial flutter was a secondary endpoint of this study. And we see that it’s a lot lower and even statistically significant with Zanubrutinib and even cardiac adverse events leading to death. We had no cardiac events leading to death with Zanubrutinib, and we had 6 patients who died of cardiac adverse events with Ibrutinib. So all of it put together now shows that Zanubrutinib is the first BTK inhibitor that shows improved efficacy now with PFS, and also improved safety compared to Ibrutinib.
What was the design of this trial and why was it set up this way?
The hypothesis that we had with our research, early research people was that can we design a BTK inhibitor that is specifically designed an engineer to be more potent and be more selective? And importantly with. Thought as sustaining the target inhibition would be important. So therefore, ibrutinib Zanubrutinib was tar was designed as such to make sure it’s more potent, it doesn’t have any off target kinase inhibition and also can achieve a sustained around the clock inhibition of the BTK inhibitors. So once we achieved that molecule and we made that molecule. We did a pretty bold design and we went head to head versus the other in-class drug, ALPINE study was a randomized study in a one-to-one PA fashion, 650 patients were enrolled. Half of them went to the treatment arm, which was Zanubrutinib, and the other half went on Ibrutinib as the standard dose. We just showed at the late breaking abstract and also the data are presented published in the New England Journal of Medicine paper. We showed that the patient demographics and all the disease characteristics, we’re balanced between the two arms. The primary endpoint of this study was overall response rate that we have shown before the superiority. And this time we looked at the superiority of progression-free survival. That was a key secondary endpoint, also rate of atrial fibrillation and flutter was a key secondary endpoint of this study. So in this study we showed that Zanubrutinib demonstrated higher PFS compared to ibrutinib. The hazard ratio was 0.65 and it was of course, clinically meaningful and also statistically significant. The study had a predefined subgroup analysis, and at the presentation we showed that the superiority of Zanubrutinib is consistent among all the demographics and disease characteristics. And most importantly, we show Kaplan Meier curves of PI in patients with 17P deletion or TP53 mutation, and we showed that the effect of the PFS is profound with a hazard ratio of 0.52.
What questions have you received from oncologists about this study?
The most common questions that we hear from the medical community is that how would this affect my practice? And I personally believe that these data are practice changing given the impact of efficacy. So we now show 35% risk reduction in terms of progression-free survival. And when we think about CLL populations specifically, safety becomes very important. And we have a drug that is now shown to be safer, and particularly with cardiac adverse events that are a lot less with Zanubrutinib, including cardiac death that we saw nothing with the Zanubrutinib, and we saw 6 patients. So 1.9% of patients that died from cardiac adverse event on Ibrutinib. So we think these data are practice changing for patients with relapsed/refractory CLL.
What are the key takeaways, oncologists and hematologists should know about this study?
I want your oncologist to know that this study was a very well designed and very well conducted study. So we enrolled in 15 different countries from East Europe, west Europe, United States, and China. So the outcome of the study really reflects real world outcome of both arms. So it will be really the same that they can expect in their practice. It was a very bold study design that we went with our next generation BTK inhibitor Zanubrutinib head to head against the standard of care Ibrutinib. And now that they can see that with the extent of the progression-free survival that we have shown with Zanubrutinib. And of course, the efficacy is also confirmed by overall response rates. And also very important that in a high risk population of 17P deleted TP53 mutated patients that are known to be the highest risk population in CLL. The efficacy even more profound, we show it has a ratio of 0.5. So altogether we think the efficacy in with this study shows that a Zanubrutinib can be a new standard of care in relapsed/refractory CLL patients, playing a critical role in treatment. And we also show that this important treatment comes with less side effects compared to Ibrutinib (Eg. high blood pressure, decrease in white blood cells, trouble breathing, irregular heartbeat, tarry stools, it could prevent pregnancy).
10 Key Takeaways about the Zanubrutinib ALPINE Clinical Trial
Zanubrutinib, a Bruton’s tyrosine kinase inhibitor, has demonstrated superior efficacy and safety over ibrutinib, a commonly used BTK inhibitor, in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL).
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The ALPINE study was a randomized, open-label, multicenter, phase III trial comparing zanubrutinib to ibrutinib in R/R CLL/SLL (small lymphocytic lymphoma) patients.
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The trial enrolled 663 patients who had received at least one prior therapy and showed disease progression.
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The primary endpoint of the study was progression-free survival (PFS), while secondary endpoints included overall response rate (ORR), duration of response (DOR), and safety.
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Zanubrutinib demonstrated a significantly longer PFS compared to ibrutinib (median PFS of 38.4 months vs. 31.9 months, respectively).
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The ORR was 93.5% for the zanubrutinib arm and 91.3% for the ibrutinib arm.
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The DOR was similar between both arms, with a median DOR of 44.1 months for zanubrutinib and 42.4 months for ibrutinib.
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Zanubrutinib was associated with a lower rate of treatment discontinuation due to adverse events (AEs) compared to ibrutinib (11.6% vs. 17.8%, respectively).
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The most common AEs in both treatment arms included neutropenia, thrombocytopenia, anemia, and diarrhea.
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Zanubrutinib was also associated with a lower incidence of atrial fibrillation compared to ibrutinib (3.3% vs. 9.1%, respectively).
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The ALPINE study provides strong evidence for the use of zanubrutinib as a first-line treatment option for R/R CLL/SLL patients, with superior PFS and a favorable safety profile compared to ibrutinib.
Mehrdad Mobasher, MD, MPH – About The Author, Credentials, and Affiliations
Mehrdad Mobasher, MD, MPH, joined the business in August 2022 as Chief Medical Officer for Hematology. Before joining BeiGene, Dr. Mobasher was Senior Vice President and Global Head of Late-Stage Cancer Development at Zai Lab, where he was in charge of all of the company’s late-stage oncology projects. Before he joined Zai Lab, he was the Chief Medical Officer of Corvus Pharmaceuticals. There, he oversaw the pipeline development for solid tumors, COVID-19, and T-cell lymphomas. Mehrdad worked for about nine years at Roche/Genentech in a number of leadership positions, including group medical director and Venetoclax development lead for all indications.
After his post-doctoral fellowships in hematology and medical oncology, Dr. Mehrdad worked as an adjunct clinical faculty member in the Division of Medical Oncology at Stanford University. He obtained his M.D. from Tehran University of Medical Sciences in Iran and his M.P.H. in general epidemiology from the University of Michigan School of Public Health. At the Medical Center of the University of California, Irvine, he did his internship and residency in internal medicine.