Indirect Comparison Favors Zanubrutinib vs Venetoclax Combo in CLL/SLL

Progression-free survival (PFS) and safety outcomes were superior with continuous zanubrutinib (Brukinsa) in the phase 3 SEQUOIA trial (NCT03336333) vs fixed-duration venetoclax (Venclexta) plus obinutuzumab (Gazyva) in the phase 3 CLL14 trial (NCT02242942) among patients with treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to an indirect comparison study published in Oncology and Therapy.¹

When matching and adjusting for baseline characteristics between trials, investigators reported significantly prolonged PFS with zanubrutinib vs venetoclax/obinutuzumab (HR, 0.66; 95% CI, 0.44-0.97; P = .0351). At 60 months, the PFS rates with each respective regimen were 73.9% (95% CI, 65.1%-80.7%) vs 63.0% (95% CI, 55.0%-69.0%). A similar PFS benefit with zanubrutinib occurred when adjusting for the COVID-19 pandemic. Additionally, data showed that PFS improved with zanubrutinib among patients with unmutated IGHV, with 60-month PFS rates of 70.1% (95% CI, 58.0%-79.3%) vs 56% (95% CI, 46%-65%) using venetoclax/obinutuzumab (HR, 0.63; 95% CI, 0.39-1.03; P = .0652).

The analysis also showed a trend towards prolonged overall survival (OS) with zanubrutinib vs the venetoclax combination (HR, 0.89; 95% CI, 0.55-1.46; P = .6468). This trend persisted even when adjusting for COVID-19 (HR, 0.74; 95% CI, 0.43-1.25; P = .2587).

“Findings from this study may help inform clinical treatment sequencing and patient preferences to optimize clinical decision-making and improve health economic modeling,” lead study author Talha Munir, MBChB, PhD, from Leeds Teaching Hospitals NHS Trust and St Jame’s Hospital in Leeds, UK, wrote with coauthors in the publication.¹ “On the basis of the efficacy and safety results of our analyses, continuous therapy with zanubrutinib in [patients who are] treatment naïve with CLL/SLL remains a valuable treatment option compared with fixed-duration venetoclax plus obinutuzumab.”

Investigators employed matching-adjusted indirect comparison (MAIC) propensity-score weighting to evaluate differences in PFS, OS, tolerability, and adverse effects (AEs) of special interest between patients who received zanubrutinib monotherapy or venetoclax plus obinutuzumab for CLL or SLL. MAIC matching occurred based on prognostic factors or effect modifiers, with relevant baseline characteristics for matching including demographics, genetics, ECOG performance status, disease stage, creatinine clearance, and time from diagnosis. Given that the SEQUOIA trial took place during the COVID-19 pandemic, investigators conducted additional analyses adjusting for COVID-19–related deaths.

The analysis included 352 patients in the unadjusted SEQUOIA trial population, 163 in the matched or adjusted SEQUOIA trial population, and 216 in the CLL14 trial population. Prior to matching, the median age was 70.0 years in the SEQUOIA trial and 72.0 years in the CLL14 trial; most patients from each group were male (66.2% vs 67.6%). In the unmatched SEQUOIA and CLL14 populations, respectively, most patients had an ECOG performance status of 0 (48.0% vs 45.8%), and a higher proportion of patients in SEQUOIA had B symptoms (57.1% vs 48.0%).

Any-grade treatment-emergent AEs (TEAEs) occurred in 96.3% of patients in the SEQUOIA trial (n = 351) during the overall period compared with 94.8% of those in CLL14 (n = 212) after a median of 170 weeks. Across both trial populations and periods, grade 3/4 toxicities occurred in 64.4% vs 70.8%, serious TEAEs in 57.0% vs 54.0%, TEAEs associated with discontinuation in 18.8% vs 15.6%, and TEAEs associated with death in 7.7% vs 9.0%.

Selected AEs of interest tended to be less frequent with zanubrutinib vs venetoclax/obinutuzumab, apart from grade 3/4 infections. When adjusting for grade 3/4 COVID-19 infections, zanubrutinib conferred significantly fewer high-grade infections at 104 weeks, although the incidence of grade 3/4 infection was comparable during the overall follow-up period.

According to the investigators, the study contains inherent MAIC limitations, such as trial design and characteristic differences that may limit the generalizability of the results. Additionally, they noted that the COVID-19 pandemic may have affected safety outcomes in the SEQUOIA trial that are not easily discernible compared with direct effects, which included deaths due to COVID-19.

How Was SEQUOIA Designed?

In the international, open-label, phase 3 SEQUOIA trial, patients with treatment-naïve CLL/SLL without del(17p) were randomly assigned to receive continuous treatment with zanubrutinib until progressive disease or unacceptable toxicity in arm A or 6 cycles of bendamustine (Treanda) plus rituximab (Rituxan) in arm B; those with del(17p) were eligible to receive continuous zanubrutinib in arm C. Investigators of the MAIC included data from arms A and C as part of their analysis.

The primary end point of the SEQUOIA trial was PFS per independent central review.² Secondary end points included overall response rate (ORR), OS, duration of response (DOR), and AEs.

How Was CLL14 Designed?

Investigators of the global, open-label, phase 3 CLL14 trial assessed treatment with 12 cycles of chlorambucil (Leukeran) plus obinutuzumab vs 12 cycles of venetoclax plus obinutuzumab among patients with treatment-naïve CLL or SLL. In the experimental arm of the trial, patients received venetoclax at doses ramping up from 20 mg daily to 400 mg once daily plus obinutuzumab at 100 or 1000 mg on day 1 of cycle 1, 1000 mg on days 8 and 15 of cycle 1, and 1000 mg on day 1 of all subsequent cycles until the end of the sixth cycle.³

The trial’s primary end point was PFS based on investigator evaluation per International Workshop on CLL criteria. Secondary end points included ORR, complete response rate, minimal residual disease negativity, OS, and event-free survival.

References

1. Munir T, Martinez-Calle N, Xu S, et al. Indirect comparisons of the efficacy and safety of zanubrutinib versus venetoclax plus obinutuzumab in treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma. Oncol Ther. Published online September 13, 2025. doi: 10.1007/s40487-025-00380-0
2. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). ClinicalTrials.gov. Updated March 7, 2025. Accessed September 26, 2025. https://tinyurl.com/nhjzadf9
3. Comparison of the treatments of obinutuzumab + venetoclax versus obinutuzumab + chlorambucil in patients with chronic lymphocytic leukemia. ClinicalTrials.gov. Updated May 28, 2025. Accessed September 26, 2025. https://tinyurl.com/skbuner9