Indirect Comparison Associates Zanubrutinib With Improved PFS in Treatment-Naive CLL

Data from a post hoc indirect comparison linked zanubrutinib (Brukinsa) to improved progression-free survival (PFS) vs acalabrutinib (Calquence) plus venetoclax (Venclexta) in the frontline treatment of patients with treatment-naive chronic lymphocytic leukemia (CLL).¹

The indirect comparison focused on patients treated with zanubrutinib in the phase 3 SEQUOIA trial (NCT03336333) with those treated with acalabrutinib plus venetoclax in the phase 3 AMPLIFY study (NCT03836261). An unadjusted analysis included fit patients from SEQUOIA, defined as those who had a creatinine clearance of at least 50 mL/min, a cumulative illness rating scale (CIRS) score of 6 or lower, and no 17p deletions or TP53 mutations, mirroring the AMPLIFY trial population. An anchored matching-adjusted indirect comparison (MAIC) also looked at patients with CLL who did not harbor 17p deletions or TP53 mutations.

Findings published in Blood Advances showed that patients in the fit population from SEQUOIA who were treated with zanubrutinib (n = 123) experienced improved PFS compared with those treated with acalabrutinib plus venetoclax (n = 291) in AMPLIFY (HR, 0.47; 95% CI, 0.28-0.77; P = .003). In an unadjusted analysis, the investigator-assessed 3-year PFS rate was 89.2% with zanubrutinib vs 78.9% with acalabrutinib plus venetoclax. When adjusting for COVID-19, these respective rates were 91.5% (per investigator assessment) and 78.8% (per independent review committee assessment). The overall response rates (ORRs) were 97.6% for zanubrutinib vs 96.9% for acalabrutinib plus venetoclax; the respective complete response (CR) rates were 18.7% and 14.8%.

In the MAIC, which featured an effective sample size population of patients from SEQUOIA (n = 206), along with the AMPLIFY population (n = 581), zanubrutinib was again associated with improved PFS vs acalabrutinib plus venetoclax per investigator assessment (HR, 0.45; 95% CI, 0.23-0.88; P = .0197).

“Many of us, [in the absence of this type of indirect] analysis, would expect a continuous therapy [to] provide a better or longer PFS,” lead study author Mazyar Shadman, MD, MPH, said in an interview with OncLive. “Now I have this study as one of the resources for information that [we can] share with the patient, if [a patient] is someone who is more focused on efficacy and they’re willing to take a drug that is a continuous therapy until progression.”

Shadman is a professor in the Clinical Research Division, the medical director of Cellular Immunotherapy, and the Innovators Network Endowed Chair at Fred Hutchinson Cancer Center in Seattle, Washington.

What was the rationale and design of the indirect comparison between zanubrutinib and acalabrutinib/venetoclax in treatment-naive CLL?

In January 2023, the FDA approved zanubrutinib for the treatment of patients with CLL or small lymphocytic lymphoma (SLL), backed by data from SEQUOIA and the phase 3 ALPINE trial (NCT03734016).² Acalabrutinib plus venetoclax received FDA approval for the treatment of adult patients with CLL or SLL in February 2026, supported by data from AMPLIFY.³

With multiple Bruton tyrosine kinase inhibitor–based approaches approved in the frontline setting for CLL, along with continuous and fixed-duration strategies, investigators sought to compare the efficacy and safety of zanubrutinib vs acalabrutinib/venetoclax via an indirect comparison in the absence of head-to-head prospective data.¹

“The problem with comparing the 2 trials—SEQUOIA and AMPLIFY—is the fact that the patient populations are different,” Shadman said. “AMPLIFY, by definition, selected more fit patients and healthier patients.... You have to adjust for that."

To conduct the indirect comparison, patients from cohort 1 of SEQUOIA were split into 3 analysis groups, as follows:¹

• Fit patients following the AMPLIFY enrollment criteria (a creatinine clearance of ≥ 50 mL/min, a CIRS score of ≤ 6, and no 17p deletions or TP53 mutations)
• Patients who did not fit AMPLIFY criteria (outcomes were compared vs the fit SEQUOIA subgroup)
• An MAIC population, with individual patient data for those treated with zanubrutinib, reweighted to match population characteristics of AMPLIFY

The primary end point of the indirect comparison was investigator-assessed PFS. Secondary end points included ORR and CR rate. Regarding safety, data were compared between patients in the overall SEQUOIA population who received zanubrutinib and those vs the population treated with acalabrutinib plus venetoclax in AMPLIFY.

Within the SEQUOIA fit population treated with zanubrutinib (n = 123) and AMPLIFY patients treated with acalabrutinib plus venetoclax (n = 291), the median ages were 71 years (range, 40-83) and 61 years (range, 31-84), respectively. Most patients in the SEQUOIA population (92.7%) were older than 65 years, the percentage was smaller in the AMPLIFY group (27.1%). The majority of patients in both groups were male (SEQUOIA, 65.9%; AMPLIFY, 61.2%), had an ECOG performance status of 0 or 1 (94.4%; 90.0%, respectively), and had unmutated IGHV (51.2%; 57.4%). Median CIRS scores were not reported for the SEQUOIA population; in the AMPLIFY population, the median was 2 (range, 1-4). Patients in the SEQUOIA fit population had a median creatinine clearance of 75 mL/min (range, 51-150), but this value was not reported for AMPLIFY patients. Creatine clearance of less than 60 mL/min was reported in 19.5% of patients in the SEQUOIA fit group vs 13.1% in the AMPLIFY group. At least 3 cytogenetic abnormalities were reported in 8.9% of patients in the SEQUOIA group vs 15.5% in the AMPLIFY group; data on karyotype status were missing for 31.7% of patients in SEQUOIA vs 5.5% in AMPLIFY.

What outcomes were reported for zanubrutinib vs bendamustine plus rituximab (Rituxan; BR) among the fit population in SEQUOIA?

In the fit population of SEQUOIA, the median PFS was not reached for those treated with zanubrutinib or those treated with BR (n = 129) at a median follow-up of 40.3 months (range, 39.4-43.9). However, PFS was improved in the zanubrutinib arm (HR, 0.23; 95% CI, 0.13-0.40; P = .0001). The 36-month PFS rates were 89.2% for zanubrutinib vs 57.9% for BR; the respective 42-month PFS rates were 87.1% and 50.0%. The ORRs were 97.6% for zanubrutinib and 88.4% for BR, with respective CR rates of 18.7% and 24.8%.

Furthermore, when comparing outcomes for zanubrutinib in the SEQUOIA fit population vs those who did not fit the AMPLIFY inclusion criteria, the 36-month PFS rates were 89.2% and 79.1%, respectively. When adjusting for COVID-19, these respective rates were 91.5% and 87.1%.

What was reported regarding the safety of zanubrutinib vs acalabrutinib plus venetoclax?

The median treatment duration with zanubrutinib in SEQUOIA (n = 240) was 43.3 months vs 12.9 months for acalabrutinib plus venetoclax in AMPLIFY (n = 291). Any-grade treatment-emergent adverse effects (TEAEs) occurred in 94.6% of patients treated with zanubrutinib vs 92.8% of patients treated with acalabrutinib plus venetoclax; the respective rates of grade 3 or higher TEAEs were 61.3% and 53.6%. Serious TEAEs were reported in 47.5% of patients treated with zanubrutinib vs 24.7% of those receiving acalabrutinib plus venetoclax.

Among patients treated with zanubrutinib during SEQUOIA, TEAEs led to death, treatment discontinuation, dose interruption, and dose reduction in 7.1%, 15.0%, 57.5%, and 10.8% of patients, respectively. These respective rates were 3.4%, 7.9%, 49.8%, and 14.1% for acalabrutinib plus venetoclax in AMPLIFY.

“As the number of [treatment] options increases, we need to have data to support our colleagues who are maybe less focused on CLL,” Shadman said. “No single study would give us [a complete] answer. [Treatment decisions involve] putting all these pieces together and coming up with the best strategy.”

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. 2026;10(8):2599-2607. doi:10.1182/bloodadvances.2025018536
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed March 31, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. FDA approves acalabrutinib with venetoclax for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. Updated February 20, 2026. Accessed March 31, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-venetoclax-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma