Indirect Comparison Supports Zanubrutinib Monotherapy in CLL/SLL Care

Zanubrutinib (Brukinsa) monotherapy may be an effective option over acalabrutinib (Calquence) plus venetoclax (Venclexta) among patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to findings from an indirect comparison study published in Blood Advances.¹

When matching outcomes from the phase 3 SEQUOIA trial (NCT03336333) assessing zanubrutinib alone with results from the phase 3 AMPLIFY trial (NCT03836261) evaluating zanubrutinib/acalabrutinib, the estimated 3-year progression-free survival (PFS) rate was 89.2% vs 78.9% in each respective population.^2,3 COVID-19–adjusted analyses revealed PFS rates of 91.5% per investigator assessment in SEQUOIA compared with 78.8% per independent review committee evaluation in AMPLIFY. In the fit subgroup analysis, the objective response rate (ORR) was 97.6% vs 96.9% in each respective trial, with complete response (CR) rates of 18.7% vs 14.8%.

Matching-adjusted indirect comparison (MAIC) evaluations showed improved investigator-assessed PFS with zanubrutinib vs acalabrutinib/venetoclax (HR, 0.45; 95% CI, 0.23-0.88; P = .0197). Investigators observed similar results when adjusting for age based on patients in SEQUOIA who lacked del(17p) or TP53 mutations and with CLL only (HR, 0.26; 95% CI, 0.13-0.54; P <.003). Similar HR values were achieved across all sensitivity models for zanubrutinib vs acalabrutinib/venetoclax regardless of prognostic factors like del(11q), unmutated IGHV, and complex karyotypes.

“Overall, these results demonstrate that continuous treatment with zanubrutinib in treatment-naive fit patients with CLL resulted in prolonged PFS compared with fixed-duration acalabrutinib/venetoclax. This unadjusted indirect comparison analysis between the SEQUOIA and AMPLIFY patient populations was supported by both anchored and the unanchored MAIC results, which utilized multiple sensitivity analyses to control for potential bias,” lead study author Mazyar Shadman, MD, MPH, a professor in the Clinical Research Division, medical director of Cellular Immunotherapy, and Innovators Network Endowed Chair at Fred Hutch Cancer Center, wrote with coauthors in the publication.¹ “In conclusion, these results highlight zanubrutinib monotherapy as an effective treatment option for all patients with treatment-naive CLL/SLL, including fit patients who might otherwise be considered for more intensive fixed-duration combination regimens.”

Investigators of this post hoc analysis compared outcomes among patients who received zanubrutinib in the SEQUOIA trial with those of patients who received acalabrutinib plus venetoclax in the AMPLIFY trial based on an unadjusted analysis of the fit population and a supporting analysis with a MAIC strategy. The unadjusted analysis identified fit patients from the SEQUOIA trial—defined as having a creatinine clearance of at least 50 ml per minute, a CIRS score of no more than 6, and no del(17p) or TP53 mutation—to compare them with the AMPLIFY trial population.

The study’s primary efficacy end point was PFS per investigator assessment. Other key efficacy end points included ORR and CR rate. The study authors also evaluated treatment-related adverse effects (TRAEs) across the trial populations.

Between 123 patients who were fit and received zanubrutinib monotherapy in the SEQUOIA trial and 291 who received acalabrutinib/venetoclax in the AMPLIFY trial, the median age was 71 years (range, 40-83) and 61 years (range, 31-84). Of note, more patients in the SEQUOIA population were older than 65 (92.7%), while more in the AMPLIFY population were 65 years or younger (72.9%). Most patients in each population had an ECOG performance status of 0 (53.7% vs 90.0%), bulky disease of 5 cm or larger (23.6% vs 38.8%), and unmutated IGHV (51.2% vs 57.4%).

With a median follow-up of 40.3 months (range, 39.4-43.9), PFS in the SEQUOIA trial improved with zanubrutinib vs bendamustine (Treanda) plus rituximab (Rituxan; HR, 0.23; 95% CI, 0.13-0.40; P = .0001). In the fit subgroup from the SEQUOIA trial, data revealed an ORR of 97.6% vs 88.4% with zanubrutinib vs bendamustine/rituximab, respectively; the CR rates were 18.7% vs 24.8%.

Among all 240 patients who received zanubrutinib in the SEQUOIA trial, 94.6% (n = 227) experienced any-grade treatment-emergent AEs (TEAEs) compared with 92.8% (n = 270/291) of those who received acalabrutinib/venetoclax in the AMPLIFY trial. Grade 3 or higher TEAEs occurred in 61.3% and 53.6% of patients in each respective population, and serious TEAEs of any grade were reported in 47.5% vs 24.7%.

References

1. Shadman M, Tam CS, Brander DM, et al. An indirect comparison of zanubrutinib vs acalabrutinib plus venetoclax in patients with treatment-naive CLL. Blood Adv. Published online January 26, 2026. doi:10.1182/bloodadvances.2025018536
2. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5. Erratum in: Lancet Oncol. 2023;24(3):e106. doi:10.1016/S1470-2045(23)00073-6
3. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi: 10.1056/NEJMoa2409804