Reviewing Long-Term CLL Treatment With BTK Inhibitor Zanubrutinib

Bruton kinase (BTK) inhibitors are a large part of modern chronic lymphocytic leukemia (CLL) treatment. During a virtual Case-Based Roundtable event, Mazyar Shadman, MD, MPH, professor of the Clinical Research Division, medical director for Cellular Immunotherapy and the Bezos Family Immunotherapy Clinic, and Innovators Network Endowed Chair at the Fred Hutchinson Cancer Center, highlighted the 5-year data from the SEQUOIA trial (NCT03336333). Shadman considered zanubrutinib's (Brukinsa) progression-free survival (PFS), including in patients with high-risk features like deletion 17p (del[17p]). He also emphasized the drug's safety profile.

Register today to join a Case-Based Roundtable near you.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What study showed data for zanubrutinib in previously untreated CLL?

Mazyar Shadman, MD, MPH: The SEQUOIA study was a larger study with different cohorts. The randomized cohort of the study is cohort 1 of patients who did not have del(17p) and were considered to be good candidates for bendamustine and rituximab [Rituxan; BR] under the old criteria, either being older than 65 or being unfit. So those patients were randomized to receive either zanubrutinib monotherapy until progression, or BR as a standard of care.¹

There was a cohort 2, which included patients with del(17p) and those patients received zanubrutinib as monotherapy, so there was no randomization. The idea was to give zanubrutinib to patients who are not eligible for the randomized portion of the study.

What were the long-term results for patient with CLL receiving zanubrutinib?

At 2024 American Society of Hematology meeting, we presented the 5-year follow-up of SEQUIOA cohort 1, and that was also published [in] 2025.² In cohort 1, the randomized portion of the study comparing zanubrutinib vs BR, zanubrutinib was superior to BR. That benefit of zanubrutinib over chemotherapy was present regardless of the IGHV mutational status.

Historically, patients with mutated IGHV did well with chemotherapy, so it was more difficult to show the benefit of a BTK inhibitor over chemotherapy in mutated IGHV because they did well with chemotherapy too. But we showed with the longer follow-up of SEQUIOA cohort 1 was that even in the mutated IGHV subgroup, zanubrutinib was superior to chemotherapy. So regardless of IGHV mutation, zanubrutinib had a better progression-free survival [PFS] compared with chemotherapy.

How did patients with CLL do on cohort 2 in terms of efficacy?

SEQUIOA had a cohort 2, which was also updated at the 2025 American Society of Clinical Oncology meeting, and showed that when patients with del(17p) received zanubrutinib, their PFS at 5 years was very similar to patients who received zanubrutinib on the randomized portion of cohort 1 of the study. This is important because cohort 2 of SEQUIOA is the largest prospective study that used a BTK inhibitor in patients with del(17p), in 111 patients.³

Regardless of the IGHV mutational status, it seems that, in the first-line setting at least, having a del(17p) or a mutated IGHV did not impact the outcomes, and that's why in patients with high-risk features, using zanubrutinib—you can extrapolate about [other] BTK inhibitors, but the data belongs to zanubrutinib—provides you with the same efficacy that somebody without del(17p) has.

When discussing with patients who have del(17p), they look it up, and they're always worried about having high-risk disease. It's nice to be able tell them that, depending on what treatment we use, for example, if you use zanubrutinib, their outcomes could be comparable with the current follow-up of 5 years. We have longer follow-up with other BTK inhibitors, although not in a single prospective study. It seems to be comparable to patients without del(17p).

The overall survival was looking pretty good for both cohort 1 and 2.^2,3 [In cohort 2, the 5-year overall survival rate was] at 85%. These patients are doing well on BTK inhibition.

What was the toxicity profile seen with zanubrutinib in cohorts 1 and 2?

In terms of the safety profile, when you look at the type of adverse events [AEs] that we expect with any of these novel agents, it has the AEs of interest, including diarrhea, but in the 20% range for all grades. A very small percentage of patients, only 2% of patients, had grade 3 or [higher]. There was no new safety signal with the longer follow-up that we showed with cohort 1: some infections, some cytopenias, and hypertension at the 20% range for zanubrutinib, vs 12% for arm B, which is chemotherapy. I would highlight that. With both atrial fibrillation and hypertension, when we did the analysis, the incidence was not different statistically between chemotherapy and zanubrutinib.⁴

The AEs of interest for BTK inhibitors were hypertension, atrial fibrillation/atrial flutter, and arterial myalgia with the initial report and also with the longer follow-up. If you look at these and do an unplanned, ad hoc analysis, the incidence rates were not statistically different.¹

Hypertension is something that we monitor with BTK inhibitors closely. Here we had 10% grade 1/2 and 8% grade 3 or more with zanubrutinib. This is looking at cohort 2, which is the zanubrutinib monotherapy.³

Register today to join a Case-Based Roundtable near you.

DISCLOSURES: Shadman previously reported employment with Bristol Myers Squibb; a consulting or advisory role with AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeOne Medicines Ltd, Bristol Myers Squibb/Celgene, MorphoSys, Kite, a Gilead company, Fate therapeutics, Lilly, Genmab, Merck, Nurix, and ADC Therapeutics; and patents, royalties, or other intellectual property with Koi Biotherapeutics Stock options.

REFERENCES

1. 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

2. Shadman M, Munir T, Robak T, et al. Zanubrutinib versus bendamustine and rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: median 5-year follow-up of SEQUOIA. J Clin Oncol. 2025;43(7):780-787. doi:10.1200/JCO-24-02265

3. Tam CS, Ghia P, Shadman M, et al. SEQUOIA 5-year follow-up in arm C: Frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). J Clin Oncol. 2025;43(suppl 16):7011. doi:10.1200/JCO.2025.43.16_suppl.7011

4. Shadman M, Munir T, Robak T, et al. Sustained superiority of zanubrutinib vs bendamustine + rituximab in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN CLL): 5-Year follow-up of cohort 1 from the SEQUOIA study. Blood. 2024;144 (suppl 1):3249. doi:10.1182/blood-2024-194864