MAIC Analysis Reveals Long-Term PFS Benefit With Zanubrutinib Over Orelabrutinib in R/R MCL

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Updated findings from a matching-adjusted indirect comparison (MAIC) with longer-term follow-up demonstrated that zanubrutinib (Brukinsa) was associated with improved progression-free survival (PFS) outcomes compared with orelabrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).1

Findings published in Advances in Therapy showed that at a median follow-up of 35.3 months for the zanubrutinib arm and 23.8 months for the orelabrutinib arm, the median PFS for zanubrutinib was not reached (NR; 95% CI, 26.4-NR) before matching (n = 86) compared with 22.0 months (95% CI, 12.8-NR) for orelabrutinib (n = 106; HR, 0.61; 95% CI, 0.39-0.94). The 12- and 24-month PFS rates for zanubrutinib were 77.5% and 63.9%, respectively. These respective rates were 65.1% and 46.5% in the orelabrutinib arm.

After matching, the median PFS for patients in the zanubrutinib arm (n = 70) was NR (95% CI, 27.7-NR; HR vs orelabrutinib, 0.54; 95% CI, 0.34-0.86). The 12- and 24-month PFS rates were 80.1% and 67.3%, respectively, in the zanubrutinib group after matching.

“Although next-generation BTK inhibitors zanubrutinib and orelabrutinib both showed benefits for patients with relapsed/refractory MCL in China, and with recommendation in guidelines, a comparison between the 2 BTK inhibitors is lacking, and there is no consensus on the best treatment options in the second-line setting,” lead study author Lijuan Deng,

Previous findings from the MAIC at shorter follow-up showed that investigator-assessed PFS favored the zanubrutinib arm (HR, 0.77; 95% CI, 0.45-1.32).2 The 12-month PFS rate was 77.5% for zanubrutinib vs 70.8% for orelabrutinib.

MAIC Design

To conduct the MAIC, investigators gathered patient data for patients treated with zanubrutinib in the phase 2 BGB-3111-206 trial (NCT03206970) and those given orelabrutinib during the phase 1/2 ICP-CL-00102 trial (NCT03494179).1 Matching between the cohorts was intended account for effect modifiers and prognostic variables that varied between the 2 single-arm studies.

BGB-3111-206 was a multicenter, single-arm trial that enrolled 86 patients 18 to 75 years of age with relapsed/refractory MCL who received 1 to 4 prior lines of therapy, had measurable disease, and had an ECOG performance status of 0 to 2. Patients in this study were treated with zanubrutinib at 160 mg twice per day until progressive disease, unacceptable toxicity, death, or withdrawal of consent. Overall response rate (ORR) per independent review committee (IRC) assessment served as the trial’s primary end point. Secondary end points included investigator-assessed ORR, duration of response (DOR), and PFS, and overall survival (OS) was an exploratory end point.

ICP-CL-00102 included 106 patients 18 to 75 years of age with relapsed/refractory MCL who received 1 to 4 prior lines of therapy and had an ECOG performance status of 0 to 2. Patients in the first stage of the trial were randomly assigned to receive orelabrutinib at 100 mg twice per day or 150 mg once per day, and those included in the second stage received orelabrutinib at 150 mg once per day. IRC-assessed ORR was the primary end point, with secondary end points of investigator-assessed ORR, DOR, PFS, and OS.

After matching, the majority of patients in the effective sample size from the zanubrutinib cohort (n = 70) and those treated with orelabrutinib in ICP-CL-00102 (n = 106) were male (both arms, 79%) did not have bulky disease of at least 5 cm (61%), did not have bone marrow involvement (59%), had stage IV disease (74%), received at least 2 prior lines of treatment (55%). Twelve percent of patients in both groups had high-risk disease per simplified MCL International Prognostic Index criteria, 33% had intermediate-risk disease, and 8% underwent a prior autologous stem cell transplant.

Additional Efficacy Data

Updated findings from the MAIC also demonstrated that when assessed by CT scan after matching, the median PFS was NR for zanubrutinib vs 22.0 months for orelabrutinib (HR, 0.63; 95% CI, 0.40-0.99; P = .044). The 12- and 24- month PFS rates were 78.6% and 62.2%, respectively, for zanubrutinib, vs 65.1% and 46.5%, respectively, for orelabrutinib.

The median OS was NR in both arms, and although the difference was not statistically significant, a trend favoring the zanubrutinib arm was observed (HR, 0.68; 95% CI, 0.36-1.27; P = .223). The respective 12- and 24-month OS rates were 85.1% and 83.7% for zanubrutinib vs. 83.9% and 74.3%, respectively, for orelabrutinib.

Prior to matching, the ORR was 83.7% in the zanubrutinib group vs 82.1% in the orelabrutinib arm (odds ratio [OR], 1.12; 95% CI, 0.53-2.40; P = .764). After matching, the ORR was 85.5% in the zanubrutinib arm (OR, 1.28; 95% CI, 0.56-2.94; P = .556).

Findings from a sensitivity analysis showed that PFS outcomes continued to favor zanubrutinib (n = 48) over orelabrutinib (HR, 0.59; 95% CI, 0.36-0.97; P = .038), and no statistically significant difference was observed regarding OS (HR, 0.75; 95% CI, 0.37-1.51; P = .421). ORR outcomes were similar (OR, 0.92; 95% CI, 0.38-2.20; P = .850).

Study authors noted the MAIC was limited by the single-arm nature of both studies, the assumption that all prognostic factors were accounted for between both trials, and the lack of safety analysis due to differences in data collection.

References

1. Deng L, Song Y, Zhou K, et al. Indirect comparisons of efficacy of zanubrutinib versus orelabrutinib in patients with R/R MCL: an extended follow-up analysis. Adv Ther. 2025;42(6):2937-2949. doi:10.1007/s12325-025-03202-x
2. 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. Invest New Drugs. 2023;41(4):606-616. doi:10.1007/s10637-023-01376-1