Zanubrutinib Displays Improved Efficacy Vs Orelabrutinib in Relapsed/Refractory CLL/SLL and MCL

Zanubrutinib (Brukinsa) demonstrated a significant improvement in progression-free survival (PFS) compared with orelabrutinib (ICP-022) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL), according to findings from an indirect comparison study presented at the 2022 Pan Pacific Lymphoma Conference.

“For relapsed/refractory CLL/SLL patients, zanubrutinib demonstrated a comparable objective response rate [ORR] but more favorable PFS compared with orelabrutinib. For relapsed/refractory MCL patients, zanubrutinib showed a higher complete response [CR] rate and favorable PFS compared with orelabrutinib,” the study authors wrote in the poster.

The next-generation BTK inhibitors zanubrutinib and orelabrutinib are approved in China for the treatment of patients with CLL/SLL or MCL who have received at least 1 prior therapy.

Because no head-to-head studies of the agents exist, investigators performed an unanchored matching-adjusted indirect comparison to establish the relative efficacy of zanubrutinib vs orelabrutinib in patients with relapsed/refractory CLL/SLL.

Within the CLL/SLL cohort, individual patient data from the phase 2 BGB-3111-205 trial (NCT03206918) with zanubrutinib (n = 91) were adjusted to match the aggregate baseline characteristics in the phase 1/2 ICP-CL-00103 trial (NCT03493217) with orelabrutinib (n = 80). The matched characteristics included age, sex, ECOG performance status, bulky disease, deletion 17p, TP53 mutation, deletion 11q, IGHV mutation, trisomy 12, and prior lines of therapy.

Within the MCL cohort, a naïve comparison of the phase 2 BGB-3111-206 trial (NCT03206970)with zanubrutinib (n = 86) and phase 1/2 ICP-CL-00102 trial (NCT03494179) with orelabrutinib (n = 106) was performed because of the different response assessment methodology in each study.

Pre-matched baseline characteristics of the CLL/SLL cohort demonstrated that patients in BGB-3111-205 had a higher percentage of IGHV unmutated disease, deletion 17p, or TP53 mutation, and lower percentage of patients under the age of 65 years vs those in the ICP-CL-00103 trial.

The median follow-up time in this cohort was 34 months with zanubrutinib vs 25.6 months with orelabrutinib.

After matching, the ORR per independent review committee (IRC) was comparable between zanubrutinib and orelabrutinib, at 86.6% (95% CI, 77.5%-93.0%) and 92.5% (95% CI, 84.4%-97.2%), respectively (risk difference, –5.9%; 95% CI, –15.8% to 3.8%). Similar investigator-assessed ORRs were also seen between zanubrutinib and orelabrutinib, at 90.1% and 93.8%, respectively (risk difference, –3.7%; 95% CI, –12.8% to 5.2%).

However, the CR rate was significantly lower with zanubrutinib vs orelabrutinib, at 5.7% (95% CI, 1.8%-13.0%) vs 16.3% (95% CI, 8.9%-26.2%), respectively (risk difference, –10.5%; 95% CI, –20.9 to –1.1).

Notably, zanubrutinib had favorable IRC-assessed PFS before (HR, 0.69; 95% CI, 0.36-1.31) and after matching (HR, 0.74; 95% CI, 0.37-1.47). The 18-month PFS rate with zanubrutinib was also superior both before (85.4% vs 78.7%) and after matching (82.9% vs 78.7%). Moreover, zanubrutinib showed favorable investigator-assessed PFS after matching, with a 30-month PFS rate of 73.6% vs 69.7% with orelabrutinib.

Within the MCL cohort, the median follow-up time was 18.4 months with zanubrutinib vs 16.4 months with orelabrutinib.

The ORRs were similar between zanubrutinib and orelabrutinib, at 83.7% (95% CI, 74.2%-90.8%) and 87.9% (95% CI, 79.8%-93.6%), respectively (risk difference, –4.2%; 95% CI, –14.8% to 6.0%). However, the CR rate was significantly higher with zanubrutinib vs orelabrutinib, at 77.9% (95% CI, 67.7%-86.1%) vs 42.9% (95% CI, 24.5%-62.8%), respectively (risk difference, 35.0%; 95% CI, 14.5%-53.7%).

Additionally, PFS was favorable with zanubrutinib vs orelabrutinib (HR, 0.77; 95% CI, 0.45-1.32). The 6-month PFS rate was 86.7% (95% CI, 77.2%-92.4%) with zanubrutinib vs 84.9% (95% CI, 76.1%-90.6%) with orelabrutinib; the 12-month PFS rates were 77.5% (95% CI, 66.6%-85.2%) and 70.8% (95% CI, 60.5%-78.9%), respectively.

Reference

Song Y, Zhou K, Yang S, et al. Indirect comparisons of efficacy of zanubrutinib versus orelabrutinib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or relapsed or refractory mantle cell lymphoma. Presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, HI. https://bit.ly/3aYMfQJ