BeOne Medicines (Nasdaq: ONC) reported 78-month follow-up data from the Phase III SEQUOIA trial at ASCO 2026, showing zanubrutinib (Brukinsa) maintained a progression-free survival rate of 71.8% at 78 months versus 31.0% for bendamustine-rituximab in treatment-naive chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) — the longest follow-up reported for any next-generation BTK inhibitor in this setting.
The SEQUOIA trial is a randomized, active-controlled Phase III study comparing zanubrutinib against bendamustine-rituximab in treatment-naive CLL/SLL patients. After a median follow-up of 84 months, the PFS gap between arms remained wide: 71.8% versus 31.0% at 78 months (95% CI, 65.3–77.3 vs. 24.3–37.9). The benefit held across genomic subgroups, with patients carrying unmutated IGHV — a marker of poor prognosis — achieving 70.4% PFS on zanubrutinib compared to 17.4% on bendamustine-rituximab. Time to next treatment also strongly favored zanubrutinib (HR 0.24; 95% CI, 0.16–0.35; P < 0.0001). A PFS2 analysis, which tracks outcomes through subsequent therapy, showed 81.3% versus 74.4% at 78 months, suggesting that the first-line treatment choice continues to influence disease trajectory well beyond initial progression. Of the 26 zanubrutinib-treated patients who progressed, 69.2% had not progressed again after more than three years of follow-up on subsequent therapy. Safety was consistent with prior reports, with no new signals emerging at this extended timepoint.
BeOne also presented three large real-world analyses spanning more than 250,000 patients. In a Medicare dataset of 10,523 frontline BTK inhibitor recipients, zanubrutinib was associated with a statistically significant reduction in the composite risk of death, advancing to next line, or discontinuation versus AbbVie's Imbruvica (ibrutinib) or AstraZeneca's Calquence (acalabrutinib). A separate Komodo database analysis of 16,788 treatment-naive patients showed longer time to next treatment (HR 0.88; P=0.009) and improved overall survival (HR 0.72; P < 0.001) with zanubrutinib. A retrospective cardiovascular safety analysis of 233,362 patients found a one-year atrial fibrillation rate of 11% for zanubrutinib versus 13% for acalabrutinib and 16% for ibrutinib (P < 0.0001).
Separately, BeOne presented Phase I/Ib data on the all-oral combination of zanubrutinib plus sonrotoclax (Beqalzi), its recently FDA-approved next-generation BCL-2 inhibitor, in treatment-naive CLL/SLL. After a median follow-up of approximately 34 months, the combination produced an overall response rate of 100%, with complete responses in 59.5% of patients. The best undetectable minimal residual disease (uMRD) rate reached 98.8%, and no patient who achieved uMRD4 status subsequently reverted to MRD positivity. In patients with TP53 mutation or del(17p) — among the highest-risk cytogenetic profiles in CLL — the best uMRD rate was 92.9% across two dose levels. Median time from combination initiation to uMRD4 was 4.5 months. No disease progression events were observed at the recommended Phase II dose of 320 mg sonrotoclax, including in patients who electively discontinued therapy.
The SEQUOIA data land at a moment when the first-line CLL treatment landscape is shifting toward fixed-duration, all-oral combinations. The February 2026 FDA approval of acalabrutinib plus venetoclax (AbbVie's Venclexta plus Calquence) — the first all-oral, time-limited regimen cleared for treatment-naive CLL in the US — established a new competitive benchmark. BeOne's zanubrutinib plus sonrotoclax combination is the most direct investigational challenger to that regimen, pairing a BTK inhibitor with a next-generation BCL-2 inhibitor that BeOne positions as more potent and selective than AbbVie and Genentech's Venclexta (venetoclax), with a shorter half-life and no drug accumulation. The uMRD response rates reported in the Phase I/Ib study are striking — 98.8% best uMRD4 in an unselected treatment-naive population is a number the field has not seen before — though cross-trial comparisons are limited by differences in patient populations, MRD assay sensitivity thresholds, follow-up duration, and study design. The Phase I/Ib dataset remains small and is not powered to establish superiority over any approved regimen. BeOne has indicated the data will be presented again at the European Hematology Association Congress in June 2026; a Phase III registration strategy for the zanubrutinib plus sonrotoclax combination in CLL/SLL has not been publicly confirmed.
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