The implementation of zanubritinib as treatment for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) yielded superior progression free survival (PFS) and overall remission rates (ORR) when compared to ibrutinib, according to a final analysis of the ALPINE randomized phase 3 study. 

At the 2022 ASH Annual Meeting and Exposition in New Orleans, Louisiana, Jennifer R. Brown, Dana-Farber Cancer Institute, Boston, Massachusetts, presented the data from this randomized phase 3 study. 

“While ibrutinib, a first-generation Bruton tyrosine kinase (BTK) inhibitor, has become standard therapy, it has well-described off-target effects that can limit use,” Brown and colleagues wrote, “Compared with ibrutinib, zanubrutinib, a next-generation BTK [inhibitor], provides improved BTK occupancy across disease-relevant tissues with greater kinase selectivity.”

652 patients from 15 countries with R/R CLL/SLL who had received at least one previous therapy and had measurable disease were randomized 1:1 into 1 of 2 cohorts, to either receive zanubrutinib (n=327) or ibrutinib (n=325) until disease progression or toxicity. The patients were arranged based on age, refractory status, geographical region, and del(17p)/TP53 mutation status. The median age was 68 years (age ≥ 65 [61.5% vs 61.5%]) and primarily male (65.1% vs 71.4%). Both cohorts included patients with unmutated immunoglobulin heavy chain variable (IGHV) (73.1% vs 73.5%), del(17p) (13.8% vs 15.4%), and TP53 mutated without del(17p) (9.2% vs 7.7%). 

Zanubritinib demonstrated superior PFS compared to ibrutinib at a median follow up of 29.6 months (HR: 0.65 [95% CI, .49 to .86]; p=.0024). The median PFS was 35 months for patients who received ibrutinib, and was not reached for patients who received zanubritinib. ORR was higher in the zanubritinib cohort (86.2% vs 75.7%; p=.0007). The treatment discontinuation rate was lower in the zanubritinib cohort (26.3% vs 41.2%), as were rates of grade ≥3 adverse events, serious adverse events, dose interruption, and dose reduction. Likewise, atrial fibrillation/flutter rate was lower in the zanubritinib cohort (5.2% vs 13.3%). 

Brown et al concluded, as the study endpoints were met, “zanubrutinib is more efficacious and better tolerated than ibrutinib as treatment for R/R CLL/SLL.” 

Source:

Brown J, Eichhorst J, Hillmen P, et al. 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. Presented at ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract LBA -6.