Zanubrutinib: Superior PFS in CLL Jennifer Brown, MD – ASH 2022
By Jennifer Brown, MD
I’ll be discussing the alpine study today. By way of background, we note that Bruton tyrosine kinase inhibition and CLL has been transformative. Of its therapy because B-cell receptor signaling is required for tumor expansion and proliferation in CLL and B-cell lymphomas, and that B-cell receptor signaling is dependent on btk.
Ibrutinib is the first in class covalent BTK inhibitor. Which did transform CLL therapy, but has properties that limit its use, particularly treatment discontinuation from toxicities with discontinuing rates of 16 to 23% across many studies. Also, exposure coverage between the dosing intervals falls below the IC 50 and variable btk.
Occupancy at Trough has been observed. Zanubrutinib is a second generation Bruton tyrosine kinase inhibitor designed to have greater BTK specificity than ibrutinib, and to maintain exposure coverage above its IC 50. Throughout the dosing interval, this higher drug concentration to IC 50 ratio would be expected to lead to more sustained and complete BTK in inhibition, which could potentially improve.
Effacy Zanubrutinib has demonstrated superior progression-free survival by IRC over chemo immunotherapy in treatment-naive cll SLL patients without deletion 17 P. And here we are presenting the out results of the Alpine study in which Zanubrutinib demonstrates superior progression-free survival compared with ibrutinib in relapse refractory c.
This study enrolled patients with relapse refractory CLL sll with at least one prior therapy and measurable lymphadenopathy. Key exclusion criteria included prior BTK inhibitor therapy and treatment with warfarin or other vitamin K antagonists. Although other anticoagulants were permitted, patients will randomize one-to-one between Zanubrutinib one 60 milligrams twice per day, or ibrutinib four 20 milligrams.
Until disease progression or unacceptable toxicity. The randomization was stratified by age, geographic region, refractoriness and deletion, 17 P or P 53. The primary endpoint was overall response rate, non-inferiority and superiority by investigator, which has been previously met. In the interim and final analysis, the key secondary endpoint of progression-free survival is now presented.
652 patients were randomized, 327 Zanubrutinib, and 325 to ibrutinib. You can see that only three patients on the Zanubrutinib arm and one on the ibrutinib arm were not treated. At time of data cutoff, 86 patients had discontinued on Zanubrutinib versus 134 on ibrutinib. This is balanced between adverse events and progressive disease with 53 patients stopping for adverse events on Zanubrutinib compared to 74 with ibrutinib and 24 stopping for progressive disease on Zanubrutinib versus 42 with ib.
At this time, treatment is ongoing for 73% of Zanubrutinib patients and 58% of ibrutinib patients. Here you can see the progression-free survival curve by IRC with a median follow up of 29.6 months demonstrating that Zanubrutinib is significantly superior to ibrutinib. With a hazard ratio of 0.65, the two year landmark estimated pfs is 79.5% with Zanubrutinib versus 67.3% with ibrutinib.
And very similar results were seen by investigator in our highest risk subgroup of disease patients with deletion 17 P or P 53 mutation, which was a pre-planned analysis. We see an even larger difference with a 77.6% two-year landmark pfs in Zanubrutinib versus 55.7% two-year landmark pfs in I Brutin.
The median treatment duration was 28 months with X ibrutinib, and 24 months with ibrutinib. Overall safety was improved with Zanubrutinib with serious adverse events reduced with X ibrutinib and adverse events leading to dose reduction, dose interruption, and treatment discontinuation all lower with Zanubrutinib compared to ibrutinib, we focused particularly on the cardiac profile in which X ibrutinib had fewer serious cardiac adverse.
At 1.9% versus 7.7% with ibrutinib and fewer cardiac adverse events leading to treatment discontinuation, one with Zanubrutinib versus 14 with ibrutinib. Atrial fibrillation occurred in 5% of patients on the ibrutinib arm versus 13% on the Zanubrutinib arm. There were no fatal cardiac events in patients treated with eza ibrutinib versus six events in patients treated with ibrutinib, which was 1.9% in the ibrutinib.
In conclusion Zanubrutinib demonstrated superior progression-free survival over ibrutinib in patients with relapsed refractory cll, and this pfs benefit was seen across all major subgroups including the deletion. 17 P P 53 mutant population Zanubrutinib as a favorable safety profile compared with ibrutinib with lower rates of grade three or higher in serious adverse.
Fewer adverse events leading to treatment, discontinuation and dose reduction. Zanubrutinib also has a better cardiac profile than ibrutinib with lower rates of atrial fibrillation, serious cardiac events, cardiac events leading to treatment, discontinuation and fatal cardiac events. Alpine is the first study to demonstrate progression-free survival superiority in a head-to-head comparison of BTK inhibitors in patients with relapsed refractory cll.
CLL Zanubrutinib has now proven superiority to ibrutinib in both progression-free survival and overall response rate. Thank you for your attention.