Introduction <p>Our previous study has suggested a favorable progression-free survival (PFS) with zanubrutinib over orelabrutinib in patients with relapsed or refractory mantle cell lymphoma (R/R MCL). Here, we conducted an updated analysis to indirectly compare the long-term efficacy between zanubrutinib and orelabrutinib in patients with R/R MCL.</p> Methods <p>Individual patient data from the zanubrutinib study were adjusted to match the patient population profile of the orelabrutinib study. An unanchored matching-adjusted indirect comparison (MAIC) was performed to adjust for effect modifiers and prognostic variables. The efficacy outcomes included investigator-assessed PFS, overall survival (OS), and overall response rate (ORR). Response evaluations were only computed tomography (CT)-based assessments in the orelabrutinib study, while positron emission tomography (PET)- and CT-based assessment were both performed in the zanubrutinib study. The comparison of PFS assessed by CT between zanubrutinib and orelabrutinib was the primary result.</p> Results <p>After matching, the baseline characteristics were balanced between zanubrutinib and orelabrutinib, with an effective sample size of 70 in the zanubrutinib study. PFS assessed by CT was significantly longer in the zanubrutinib study vs. the orelabrutinib study (median PFS, not reached vs. 22.0&#xa0;months; hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.34–0.86; <i>P</i> = 0.009). With longer follow-up, OS continued to trend favorably for zanubrutinib, with OS rate at 24&#xa0;months numerically higher (83.7% vs. 74.3%); no statistical difference was observed (HR 0.68, 95%&#xa0;CI 0.36–1.27; <i>P</i> = 0.223). ORR was numerically higher in the zanubrutinib study (85.5% vs. 82.1%; odds ratio 1.28, 95%&#xa0;CI 0.56–2.94; <i>P</i> = 0.556).</p> Conclusion <p>MAIC results demonstrated that zanubrutinib had significantly longer PFS compared with orelabrutinib in the treatment of patients with R/R MCL.</p>