An Indirect Comparison of Zanubrutinib vs Acalabrutinib Plus Venetoclax in Patients With Treatment-Naive CLL

In the phase 3 randomized SEQUOIA study (NCT03336333), zanubrutinib (arm A) demonstrated superior progression-free survival (PFS) compared with bendamustine-rituximab (BR; arm B) in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). In the phase 3 AMPLIFY study (NCT03836261), acalabrutinib-venetoclax with or without obinutuzumab demonstrated prolonged PFS vs chemoimmunotherapy (investigator's choice of fludarabine, cyclophosphamide, and rituximab [FCR] or BR) in patients with treatment-naive CLL without del(17p) or TP53 mutations. Compared with AMPLIFY, the patient population in SEQUOIA was unsuitable for FCR and included patients with TP53 mutations. The aim of this post hoc analysis was to investigate the efficacy of zanubrutinib in patients from SEQUOIA vs a clinically similar patient population treated with acalabrutinib-venetoclax in AMPLIFY. A numerically greater 3-year investigator-assessed PFS (PFS-INV) was observed with zanubrutinib (84.3%) in the SEQUOIA population acalabrutinib-venetoclax in AMPLIFY (78.9%). When matching SEQUOIA to the AMPLIFY population by FCR eligibility, a greater PFS benefit with zanubrutinib was reported (89.2% vs 78.9%, respectively). To support the comparison of zanubrutinib vs acalabrutinib-venetoclax, an anchored matching-adjusted indirect comparison was performed, which showed that zanubrutinib was associated with prolonged PFS-INV vs acalabrutinib-venetoclax when adjusted for various baseline characteristics. Zanubrutinib also demonstrated longer PFS whether adjusted for age (PFS-INV hazard ratio [HR], 0.26; 95% CI, 0.13-0.54; P<.0003) or unadjusted (PFS-INV HR, 0.45; 95% CI, 0.23-0.88; P=.0197). These results highlight zanubrutinib monotherapy as an effective treatment option for all patients with treatment-naive CLL/SLL, including patients who might otherwise be considered for more intensive fixed-duration combination regimens.