Early Data Show High Responses With Zanubrutinib Plus Venetoclax in Treatment-Naive Del17p/TP53+ CLL/SLL

Alessandra Tedeschi, MD

The addition of venetoclax (Venclexta) to zanubrutinib not only appears to enhance the efficacy of this next-generation BTK inhibitor, but could also provide a safer alternative to standard ibrutinib (Imbruvica) plus venetoclax for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and select high-risk features, according to Alessandra Tedeschi, MD.¹

Previously reported data from the randomized portion of the phase 3 SEQUOIA (NCT03336333) supported the FDA-approval of zanubrutinib (Brukinsa) monotherapy for patients with CLL/SLL in January 2023.2

At the 2024 EHA Congress, investigators presented preliminary results from arm D of the trial, which evaluated the combination of zanubrutinib plus venetoclax in patients with previously untreated CLL/SLL harboring 17p deletions and/or TP53 mutations. At a median follow-up of 31.6 months (range, 0.4-50.5), the overall response rate (ORR) among evaluable patients treated with the combination (n = 65) was 100%. This comprised a complete response (CR) rate of 46%, a CR with incomplete count recovery (CRi) rate of 2%, a partial response (PR) rate of 51%, and a PR with lymphocytosis rate of 2%.1

“[The combination demonstrated] very deep responses, and prolonged PFS. This leads us to [favor the] the fixed-duration treatment,” Tedeschi explained.

In an interview with OncLive^®, Tedeschi, who serves as a consultant in hematology in the Department of Hematology at Niguarda Hospital, in Milan, Italy, discussed initial data from arm D of the SEQUOIA trial, expanded on the utility of zanubrutinib with venetoclax for patients with CLL/SLL harboring 17p deletions and TP53 mutations, and delved into the potential role this combination may have in the CLL/SLL treatment paradigm.

OncLive: What is the current role of zanubrutinib in CLL/SLL, and what was the rationale for combining this agent with venetoclax in the SEQUOIA trial?

Tedeschi: This combination [is being evaluated] in the treatment-naive population in the SEQUOIA trial. [Arms A and B of the trial involve a] comparison between zanubrutinib and immunochemotherapy. [Arm C evaluated] zanubrutinib monotherapy for high-risk patients, [including those with] 17p deletions. [The final arm assessed] the combination of zanubrutinib plus venetoclax.

These agents have a synergistic effect, and are now used as a fixed-duration combination in CLL. [Zanubrutinib] is also FDA approved [in this disease space]. This is a path toward a better combination, considering that zanubrutinib has fewer adverse effects [AEs], as well as fewer off-target [AEs compared with] ibrutinib.

What were the key characteristics of patients enrolled onto arm D of the study, and what regimen did they receive?

We saw the results and analysis of the higher-risk population, [such as] patients with 17p deletions. This was a sub-study of the bigger [SEQUOIA trial] that we will see [later] on in the other populations.

This population was characterized by the high-risk population, not only because they [harbored] 17p deletions, but because one-third of patients had complex karyotypes; this makes for a difficult-to-treat population.

Zanubrutinib was administered, followed by the addition of venetoclax to help reduce the risk of tumor lysis syndrome. We could then discontinue venetoclax if minimal residual disease [MRD] was achieved. We were allowed to continue zanubrutinib until the achievement of undetectable MRD.

What results from arm D were reported at the 2024 EHA Annual Meeting?

The efficacy was impressive, considering the high-risk population. We observed a 100% ORR, which is very high. PFS at 2 years was approximately 95%, one of the better PFS rates we have seen in patients with 17p deletions. We also observed a 59% rate of undetectable MRD, the highest [observed] in peripheral blood.

The most important thing is that the combination did not lead to an increase in toxicity. The toxicity profile of the 2 drugs was as expected and [similar to that of each individual agent]. Neutropenia was a little higher, but this is expected with the combination of zanubrutinib and venetoclax; there was not an excess of infections.

Based on these data, what role might zanubrutinib plus venetoclax have for patients with previously untreated CLL?

This is a very useful combination. [We are currently using] ibrutinib with venetoclax [in the space. However], zanubrutinib is a next-generation BTK inhibitor, [potentially] making [this] a safer combination. However, [we still] have to see data from patients with lower-risk CLL/SLL who do not harbor 17p deletions [to better elucidate its utility].

References

1. Ma S, Munir T, Lasica M, et al. Combination of zanubrutinib + venetoclax for treatment-naive CLL/SLL with del(17p) and/or TP53: preliminary results from SEQUOIA arm D. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S160.
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed August 29, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma