Zanubrutinib Approval Underscores the Importance of Next-Generation BTK Inhibitors in CLL/SLL

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Lamanna discussed key efficacy and safety data with zanubrutinib from the SEQUOIA and ALPINE trials, the advantages of zanubrutinib compared with previous therapeutic options, and how the approval of the agent will affect the use of next-generation BTK inhibitors in chronic lymphocytic leukemia and small lymphocytic lymphoma .

Nicole Lamanna, MD

Nicole Lamanna, MD

With its increased selectivity, improved efficacy, and superior toxicity profile, the next-generation BTK inhibitor zanubrutinib (Brukinsa) may usurp first-generation agents as a preferred treatment option for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to Nicole Lamanna, MD.

On January 19, 2023, the FDA approved zanubrutinib for the treatment of patients with CLL or SLL, according to findings from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials.1

The SEQUOIA trial evaluated zanubrutinib vs bendamustine plus rituximab (Rituxan; BR) in previously untreated CLL and SLL, and the ALPINE study evaluated zanubrutinib vs ibrutinib (Imbruvica) in patients with relapsed/refractory CLL and SLL. Results from both trials showed that zanubrutinib provided a statistically significant progression-free survival (PFS) benefit and improved overall response rates (ORR). Adverse effects (AEs) that occurred in at least 30% of patients across trials included neutrophil count decrease, upper respiratory tract infection, platelet count decrease, hemorrhage, and musculoskeletal pain. Additionally, 3.7% of patients reported atrial fibrillation or flutter, and grade 3 or higher ventricular arrhythmias were observed in 0.2% of patients.

“Given some of the head-to-head studies [of BTK inhibitors] that have come out, [zanubrutinib’s approval] will certainly [be useful] for patients with this disease,” said Lamanna, who is an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Herbert Irving Comprehensive Cancer Center, Columbia University in New York, New York. “Long-term data from [these] studies [will likely] increase the frequency of zanubrutinib usage, both in the frontline and relapsed setting.”

In an interview with OncLive®, Lamanna discussed key efficacy and safety data with zanubrutinib from the SEQUOIA and ALPINE trials, the advantages of zanubrutinib compared with previous therapeutic options, and how the approval of the agent will affect the use of next-generation BTK inhibitors in CLL and SLL.

OncLive®: What is the significance of the recent FDA approval of zanubrutinib in CLL and SLL?

Lamanna: We’re very excited about the approval of zanubrutinib in both the frontline and relapsed setting for patients with CLL and SLL. This [approval] opens the door [to] yet another covalent BTK inhibitor in this space [that may show] some advantages.

Could you describe the mechanism of action for zanubrutinib and how it compares with other BTK inhibitors in the paradigm?

Zanubrutinib is a next-generation small molecule inhibitor of BTK. It forms a covalent bond with cysteine residues in the BTK active site, leading to the inhibition of BTK activity. Its mechanism is similar to [that of] ibrutinib and acalabrutinib [Calquence] but it’s more selective for BTK. With this [agent, there will hopefully be] fewer off-target effects [that lead to AEs]. [The agent] was also designed to have 100% BTK occupancy over 24 hours, [which may increase its] efficacy.

Please describe what was examined in the SEQUOIA trial. What data have been reported thus far from the different arms, and what are you excited to learn more about in the future?

SEQUOIA [was a multi-arm] study. Arms A and B [consisted of] frontline zanubrutinib vs the traditional chemoimmunotherapy [regimen], BR, in patients with untreated CLL. Data revealed that zanubrutinib [resulted in] a better PFS [than] BR. [Although] the comparison [arm] was chemoimmunotherapy, which we’re moving away from in the frontline setting, the benefit of zanubrutinib over chemoimmunotherapy [was successfully] demonstrated.

Arms C and D [contained] patients with high-risk disease and 17p deletions. Patients [in] arm C [received] zanubrutinib monotherapy, and patients in arm D [received] zanubrutinib plus the BCL-2 inhibitor venetoclax [Venclexta]. Although [data from] these arms are still maturing, the ORR demonstrated in our high-risk patients was [above] 90% and the PFS [was also] very good. [We are] looking forward to longer follow-up. These data are important for patients with high-risk disease. [Arm C is likely] the largest cohort of patients with 17p deletions receiving up-front treatment in CLL, which will be historic.

What is unique about the efficacy data from the ALPINE trial?

Head-to-head data from the ALPINE study made a splash at the 2022 ASH Annual Meeting. [ALPINE was] a phase 3 trial that directly compared zanubrutinib with ibrutinib in patients with relapsed/refractory CLL and SLL who have had at least 1 prior therapy. [A total of 652] patients from 15 countries enrolled in this study, and the average age was approximately 68 years. The median [number of] prior therapies received was 1. The study [showed] a lower rate of treatment discontinuation and typical BTK[-associated] AEs, particularly cardiac arrhythmias and cardiac issues, with zanubrutinib vs ibrutinib.

A [previous] head-to-head study of ibrutinib vs acalabrutinib noted that these agents were equally efficacious, but there were decreased [AEs] with acalabrutinib. Everyone was expecting similar results with zanubrutinib and ibrutinib in ALPINE. [However,] surprisingly, PFS was also increased with zanubrutinib vs ibrutinib in earlier data presented at the 12-month mark as well as in the 24-month [analysis].

Based on the efficacy and toxicity data reported with zanubrutinib, in what scenarios would you choose this drug over other therapeutic options?

With the [development of] next-generation BTK inhibitors, we’re seeing a shift away from [using] ibrutinib [in practice]. Ibrutinib is a great drug that changed the [treatment] landscape for patients with CLL but it was the first to market. Acalabrutinib and zanubrutinib [are] more specific for BTK, and head-to-head data on zanubrutinib [from ALPINE] shows that [it led to] less cardiac [AEs than ibrutinib]. Patients who are newly started on a BTK inhibitor will probably look to [receive] a newer, next-generation BTK inhibitor.

[Notably], the incidence of hypertension seems to be similar with zanubrutinib vs ibrutinib and [decreased] with acalabrutinib vs ibrutinib. If someone had uncontrolled or poorly controlled hypertension, [these data could influence treatment selection]. [However], these 2 studies are separate and you’re picking between apples and oranges. If somebody recently had a major bleeding issue, subdural hematoma, or cardiac event, you might avoid the class of BTK inhibitors altogether and choose a BCL-2 inhibitor. In general, the safety profile of next-generation BTK inhibitors seems better [than ibrutinib], and the data [support] choosing zanubrutinib [over ibrutinib] in this setting.

How will the approval of zanubrutinib affect the overall treatment landscape for patients with CLL and SLL?

It’s an exciting time for patients with CLL. Having BTK inhibitors has [allowed for] a remarkable change in how we treat our patients. If physicians [plan] to treat their patient with a BTK inhibitor, they are going to choose a next-generation BTK inhibitor. Given the PFS and head-to-head data from [ALPINE and SEQUOIA], there will [also] be a shift [in the treatment paradigm] for patients [who are] higher risk with 17p deletions. Albeit more long-term follow-up [is needed] to see if that PFS [benefit] holds true.

We [hope to] see more long-term follow-up from studies of zanubrutinib combinations, such as arm D of the SEQUOIA trial. These [data] will increase the usage of zanubrutinib—not only as a monotherapy, but in combination [with agents] like venetoclax. [Overall,] we’re going to see more patients being treated with zanubrutinib in both the frontline and relapsed setting.

Disclosures: Dr Lamann provides research support to the Institution/ P.I.: AbbVie, AstraZeneca, BeiGene, Eli Lilly/Loxo, Genentech, MingSight, Octapharma, Oncternal, TG Therapeutics. Consultant / Scientific Advisory Board: Abbvie, AstraZeneca, BeiGene, Eli Lilly/Loxo, Genentech, Jannsen/Pharmacyclics


FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed January 19, 2023.

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