TOPLINE: 

In indirect post hoc comparisons of data from two phase 3 trials, zanubrutinib monotherapy was associated with improved progression-free survival (PFS) over fixed‑duration acalabrutinib-venetoclax in a fit subgroup, treatment‑naive patients with chronic lymphocytic leukemia (CLL) after adjusting for baseline differences. Overall rates of adverse events were similar between the two treatment groups, but zanubrutinib was associated with higher rates of serious adverse events.

METHODOLOGY: 

• In the phase 3 SEQUOIA trial, zanubrutinib was associated with improved PFS compared with bendamustine-rituximab in treatment‑naive patients with CLL. In AMPLIFY, fixed‑duration acalabrutinib-venetoclax with or without obinutuzumab prolonged PFS compared with chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab or bendamustine-rituximab) in treatment‑naive patients with CLL.
• To try to determine which treatment option is better, researchers conducted a post hoc analysis comparing treatment-naive patients with CLL who received zanubrutinib in the SEQUOIA trial with those who received acalabrutinib-venetoclax in the AMPLIFY trial.
• To align with AMPLIFY trial eligibility criteria, investigators defined a “fit” subgroup within SEQUOIA trial (n = 252; median age, 71) and compared this subgroup with AMPLIFY using both an unadjusted analysis and a matching-adjusted indirect comparison, reweighting SEQUOIA patient-level data to AMPLIFY trial populations (n = 581; median age, 61).
• The primary efficacy outcome was PFS. Other efficacy outcomes included overall response and complete response. The median follow-up duration was 43.9 months for SEQUOIA and 41.0 months for AMPLIFY.

TAKEAWAY: 

• Zanubrutinib was associated with improved PFS in both unadjusted and adjusted analyses. In the unadjusted comparison, 3-year PFS was 89.2% vs 78.9%, respectively. In a sensitivity analysis adjusting for COVID-related disruptions, estimates were 91.5% vs 78.8%.
• In the matching‑adjusted indirect comparison, zanubrutinib was associated with improved PFS compared with acalabrutinib-venetoclax (hazard ratio [HR], 0.45; P = .0197), with a stronger effect after adjusting for age (HR, 0.26; P < .0003).
• Overall response rates were similar between patients receiving zanubrutinib and those receiving acalabrutinib-venetoclax (97.6% vs 96.9%), as were complete response rates (18.7% vs 14.8%).
• Overall rates of adverse events were similar between the zanubrutinib and acalabrutinib-venetoclax groups; however, zanubrutinib was associated with higher rates of serious adverse events (47.5% vs 24.7%) and grade ≥ 3 events (61.3% vs 53.6%).

IN PRACTICE:

“These results highlight zanubrutinib monotherapy as an effective treatment option for all patients with treatment-naive CLL/[small lymphocytic leukemia], including patients who might otherwise be considered for more intensive fixed-duration combination regimens,” the authors concluded.

SOURCE:

The study, led by Mazyar Shadman, Fred Hutchinson Cancer Center in Seattle, was published online in Blood Advances.

LIMITATIONS: 

The comparisons were post hoc and indirect and not powered to detect differences between zanubrutinib and acalabrutinib‑venetoclax or to compare fit vs nonfit subgroups. Matching‑adjusted indirect comparison limitations — including cross‑trial variations in eligibility, assessments, treatment duration, and follow‑up — reduced comparability and may have biased PFS estimates, limiting generalizability and causal inference.

DISCLOSURES:

This study was funded and sponsored by BeOne Medicines. Shadman disclosed serving as a consultant for AbbVie, Genentech, AstraZeneca, Genmab, Janssen, BeOne Medicines, Bristol Myers Squibb, MorphoSys/Incyte, Kite Pharma, Lilly, Fate Therapeutics, Nurix, and Merck; receiving research funding from Mustang Bio, Genentech, AbbVie, BeOne Medicines, AstraZeneca, Genmab, MorphoSys/Incyte, and Vincerx; holding stock in Koi Biotherapeutics; and reporting spousal employment in Bristol Myers Squibb. Seven authors reported being employed and holding stocks with BeOne Medicines. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.