Although ibrutinib, a first-generation Bruton’s Tyrosine Kinase inhibitor (BTKi), has become standard therapy for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) off-target effects can limit its use. Comparatively, zanubrutinib, a next-generation BTKi, has improved BTK occupancy across disease-relevant tissues with greater kinase selectivity. In the first study to demonstrate progression-free survival (PFS) superiority in a head-to-head comparison of BTKis, zanubrutinib demonstrated proven superiority to ibrutinib in both overall response rate (ORR) and PFS in patients with relapsed/refractory (RR) CLL/SLL.

Jennifer R Brown, MD, PhD, spoke on this data in the late-breaking abstract presentation, “Zanubrutinib demonstrates superior progression-free survival compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: Results from final analysis of ALPINE randomized phase 3 study,” at the 64th American Society of Hematology Annual Meeting and Exposition. 

ALPINE (NCT03734016) included 652 patients from 15 countries with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease. Patients were randomized 1:1 to receive zanubrutinib (n = 327) or ibrutinib (n = 325) until disease progression or unacceptable toxicity. Demographic and disease characteristics were similar between the zanubrutinib vs ibrutinib treatment groups: age ≥65 years (61.5% vs 61.5%), male (65.1% vs 71.4%), unmutated immunoglobulin heavy chain gene (IGHV; 73.1% vs 73.5%), del(17p) (13.8% vs 15.4%), and TP53 mutated without del(17p) (9.2% vs 7.7%), respectively. Additionally, median prior lines of therapy was one in both treatment arms.

ORR was greater in zanubrutinib than ibrutinib. PFS was tested for noninferiority when 205 PFS events were observed. According to Dr Brown and colleagues, if PFS noninferiority between zanubrutinib and ibrutinib was demonstrated, superiority of zanubrutinib vs ibrutinib could be tested and claimed if the 2-sided P <.4996.

With a median follow-up of 29.6 months, zanubrutinib PFS assessed by independent review committee (PFS_IRC) was superior to ibrutinib in the intent-to-treat population (hazard ratio [HR]: 0.65 [95% CI, 0.49–0.86]; 2-sided P = .0024). “These results are by IRC, but the investigator determined results are extremely concordant,” stated Brown.

In a predefined subgroup of patients with del(17p)/TP53 mutation, longer PFS_IRC was demonstrated with zanubrutinib than ibrutinib; PFS, regardless of assessment, consistently favored zanubrutinib across other major predefined subgroups, including IGHV status. Compared with ibrutinib, zanubrutinib also had a higher ORR_IRC (86.2 vs 75.7%, nominal 2-sided P = .0007).

Treatment discontinuation rate was lower with zanubrutinib vs ibrutinib (26.3% vs 41.2%), mostly due to adverse events (AEs; 16.2% vs 22.8%) or progressive disease (7.3% vs 12.9%).  Grade ≥3 AEs (67.3% vs 70.4%), serious AEs (42.0% vs 50.0%), dose interruption (50.0% vs 56.8%), and dose reduction (12.3% vs 17.0%) were lower with zanubrutinib vs ibrutinib, respectively, as was rate of atrial fibrillation/flutter (5.2% vs 13.3%). Death occurred in 48 (14.7%) patients treated with zanubrutinib and 60 (18.5%) patients treated with ibrutinib (OS HR: 0.76 [95% CI, 0.51–1.11]).

“ALPINE is, therefore, the first study to demonstrate progression-free survival superiority in a head-to-head comparison of BTK inhibitors in patients with relapsed/refractory CLL/SLL,” Brown concluded. “Zanubrutinib has now proven superiority to ibrutinib in both progression-free survival and overall response rate.”

Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: Results from final analysis of ALPINE randomized phase 3 study. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022. Abstract LBA-6.