Exploring the Utility of a Next-Generation BTK Inhibitor for the Treatment of Patients With Chronic Lymphocytic Leukemia

Since the approval of ibrutinib for the treatment of patients with chronic lymphocytic leukemia (CLL), the pursuit of Bruton tyrosine kinase (BTK) inhibitors with greater receptor selectivity has become a significant focus of research and development in recent years. Among newer-generation BTK inhibitors that have emerged for the treatment of CLL is zanubrutinib, a potent, irreversible BTK inhibitor with notable selectivity for inhibition of BTK versus off-target kinase receptors.^1,2 Zanubrutinib was granted accelerated approval in 2019 for the several other B-cell lymphomas, such as Waldenstrom’s macroglobinemia, mantle cell lymphoma (in adult patients who have received at least 1 prior therapy), and relapsed or refractory marginal zone lymphoma (in adults who have received at least 1 prior anti-CD20 treatment).^2,3

Zanubrutinib also is under investigation for the treatment of CLL and small lymphocytic lymphoma (SLL). Several studies have explored the potential of zanubritinib for CLL. The latest findings are expected to be presented at the upcoming American Society of Hematology (ASH) Annual Meeting later this month. As clinicians await the new data, ahead is a summary of key findings from several studies evaluating zanubrutinib for the treatment of CLL as both a monotherapy and in combination with other agents.

Zanubrutinib as Monotherapy

ALPINE. The phase 3 ALPINE trial is a head-to-head study comparing the efficacy of zanubrutinib vs ibrutinib in relapsed or refractory CLL or SLL (NCT03734016).⁴ Investigators randomized approximately 600 patients to receive zanubrutinib or ibrutinib, with a primary end point of ORR at 50 months. Notable secondary endpoints included PFS, duration of response (DOR), time to treatment failure, overall survival (OS), patient reported outcomes, and incidence of adverse events. Additionally, the correlation between prognostic and predictive biomarkers and clinical outcomes were exploratory outcomes.⁴ A preplanned interim analysis of the first 415 patients was presented at the June 2021 European Hematology Association Presidential Symposium and it showed a significantly higher ORR with zanubrutinib vs ibrutinib at 15 months (78.3% v 62.5%, P = .0006).⁵ Among patients with del(11q) and del(17p), the ORR was 83.6% for patients treated with zanubrutinib vs 69.1% for patients treated with ibrutinib. Zanubrutinib was also associated with higher rates of 12-month PFS (94.9% vs 84.0%) and OS (97.0% vs 92.7%), as well as lower rates of atrial fibrillation (afib) or flutter (2.5% vs 10.1%, P = .0014), major bleeding (2.9% vs 3.9%), and AEs leading to discontinuation (7.8% vs 13.0%) or death (3.9% vs 5.8%). However, the rate of neutropenia was shown to be slightly higher with zanubrutinib (28.4% vs 21.7%).⁵

SEQUIOA. The multicenter phase 3 SEQUOIA trial was designed to evaluate the efficacy and safety of zanubrutinib in patients with presence or absence of del(17p) aberrations and previously untreated CLL or SLL (NCT03336333).⁶ In Cohort 1 patients without del(17p) were randomized to receive zanubrutinib or rituximab and benamustine. Patients harboring del(17p) were randomized into the 2 remaining cohorts, receiving either zanubrutinib monotherapy (Cohort 2, Arm C) or zanubrutinib and venetoclax (Cohort 3, Arm D).⁶ All outcome measures were designated at 5 years with PFS between treatment groups in Cohort 1 as the primary endpoint; important secondary outcomes including: ORR, OS, DOR, and patient reported outcomes related to quality of life.^2,6 Safety outcome measures included the number of patients experiencing AEs and serious AEs.⁶ Interim results reported in April 2020 included data from 109 patients assigned to Arm C over a period of 18 months.² The ORR was 94.5% and was consistent across prespecified demographic and baseline disease characteristics, with a DOR of at least 12 months in 92.8% of patients.² Estimated rates of 18-month PFS and OS were 88.6% and 95.1%, respectively. Any-grade AEs of interest included infections (64.2%), bleeding (26.6%), bruising (24.8%), neutropenia (18.3%),diarrhea (15.6%), nausea (13.8%), arthralgia (11.0%), and fatigue (10.1%). Severe AEs occurred in 36.7% of patients that required dose reductions in 6 patients. Reported rates of major bleeding or afib/flutter with zanubrutinib were slightly higher than those observed in the ALPINE study (5.4% vs 2.5%; 2.8% vs 2.9%, respectively).² The results were indicative of favorable efficacy for CLL or SLL in patients with del(17p) who received zanubrutinib.

Updated results from the SEQUOIA trial will be presented at the 2021 ASH Annual Meeting.

Combination Trials With Zanubrutinib

In recent years, agents targeting B-cell lymphoma-2 protein (BCL-2), BTK, and phosphatidylinositol 3-kinase (PI3K) have been approved, significantly improving the ability to manage CLL disease progression. However, resistance associated with these targeted therapies remains a challenge.⁷ Several strategies have been pursued to minimize resistance, including combination therapy using BCL-2, BTK, and PI3K inhibitors, non-covalent BTKis, dose escalation, and sequenced or fixed-duration therapies.^7,8 Currently, several clinical trials are evaluating the use of zanubrutinib in combination with other agents, including zandelisib (PI3K inhibitor) and venetoclax (BCL-2 inhibitor).

BOVen. A multicenter, phase 2 trial is currently investigating a combination therapy known as the BOVen regimen, including zanubrutinib, obinutuzumab, and venetoclax, in patients with previously untreated CLL or SLL (NCT03824483).⁹ The rate of minimum residual disease (MRD) undetectable response at 1 year was the primary endpoint, and was accessed via peripheral blood or bone marrow aspirate.⁹ Initial results from a 9 month follow-up were reported at the American Society of Clinical Oncology Annual Meeting in 2020 demonstrating that 70% and 62% of patients had achieved peripheral blood undetectable MRD and bone marrow undetectable MRD at 9 months, respectively.¹⁰ The most common TEAEs included neutropenia (49%), infusion reaction (41%), bruising (41%), diarrhea (39%) and thrombocytopenia (36%).¹⁰

Findings thus far indicate that this combination regimen is well-tolerated and achieves rapid undetectable MRD. Additional results from the BOVen trial will be presented at the ASH 2021 Annual Meeting.

ME-401. A non-randomized Phase 1b study is currently investigating the novel PI3Kδ inhibitor, zandelisib (ME-401) in combination with zanubrutinib or rituximab in patients with relapsed or refractory CLL, SLL or B-cell non-Hodgkin’s lymphoma without prior PI3Ki or BTKi therapy (NCT02914938).^11,12 The study design includes 177 patients assigned to 1 of 3 treatment arms:

• Arm 1: monotherapy with ME-401
• Arm 2: ME-401 in combination with rituximab
• Arm 3: ME-401 in combination with zanubrutinib

Primary endpoints include minimum biologically effective dose, maximally tolerated dose (MTD), dose limiting toxicities, and the safety and tolerability of mono- and combination therapies.¹¹ Various pharmacokinetic efficacy parameters for both mono- and combination therapy are included as secondary measures.¹¹ Study data from 20 participants was included in the initial results demonstrating complete or partial responses to therapy in 80% of patients (16 of 20).¹² Dose limiting toxicities occurred in 2 patients, with 1 successfully resuming therapy upon rechallenge.¹² Grade 3 AEs including neutropenia occurred in 3 patients with one of these also experiencing tumor lysis syndrome and thrombocytopenia.¹² Overall, combination therapy was well tolerated and produced promising results regarding patient response rates.

Future Directions

When considering the favorable study data supporting the accelerated approval of zanubrutinib for the treatment of other B-cell malignancies, the initial safety and efficacy data from trials investigating both mono and combination therapy support its potential as an alternative agent for CLL treatment and suggest a preferred toxicity profile relative to first-generation BTK inhibitors. While the incidence of high-grade AEs have been favorable with zanubrutinib, further investigation regarding low grade AEs associated with patient quality of life may be helpful in regards to long-term therapies using BTK inhibitors.

References

1. Hillmen P, Brown JR, Eichhorst BF, et al. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020;16(10):517-523. doi:10.2217/fon-2019-0844
2. Tam CS, Robak T, Ghia P, et al. Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. Haematologica. 2020;106(9):2354-2363. doi:10.3324/haematol.2020.259432
3. Brukinsa. Prescribing information. BeiGene; 2019. Accessed November 9, 2021. https://www.brukinsa.com/prescribing-information.pdf
4. A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia (ALPINE). ClinicalTrials.gov. Updated November 22, 2021. Accessed November 9, 2021. https://clinicaltrials.gov/ct2/show/NCT03734016
5. Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021. Accessed November 9, 2021. https://library.ehaweb.org/eha/2021/eha2021-virtual-congress/330170/peter.hillmen.first.interim.analysis.of.alpine.study.results.of.a.phase.3.html
6. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). ClinicalTrials.gov. Updated November 22, 2021. Accessed November 9, 2021. https://clinicaltrials.gov/ct2/show/NCT03336333
7. Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative analysis of BTK inhibitors and mechanisms underlying adverse effects. Front Cell Dev Biol. 2021;9(630942):1-19. doi:10.3389/fcell.2021.630942
8. Skånland SS, Mato AR. Overcoming resistance to targeted therapies in chronic lymphocytic leukemia. Blood Adv. 2021;5(1):334-343. doi:10.1182/bloodadvances.2020003423
9. Study of zanubrutinib, obinutuzumab, and venetoclax in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). ClinicalTrials.gov. Updated June 4, 2021. Accessed November 9, 2021. https://clinicaltrials.gov/ct2/show/NCT03824483
10. Soumerai J, Mato A, Carter J, et al. Initial results of a multicenter, investigator-initiated study of MRD driven limited time therapy with zanubrutinib, obinutuzumab and venetoclax. Presented at: European Hematology Association 2020 Virtual Congress; June 10-21, 2020. Accessed November 9, 2021. https://library.ehaweb.org/eha/2020/eha25th/294982/jacob.soumerai.initial.results.of.a.multicenter.in-vestigator-initiated.study.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Ase-arch%3Dsoumerai
11. A study of ME-401 in subjects with CLL/SLL, FL, and B-cell non Hodgkin’s lymphoma. ClinicalTrials.gov. Updated January 6, 2021. Accessed November 9, 2021. https://clinicaltrials.gov/ct2/show/NCT02914938
12. Soumerai JD, Jagadeesh D, Salman HS, et al. Initial results of the combination of PI3Kδ inhibitor zandelisib (ME-401) and the BTK inhibitor zanubrutinib in patients (pts) with relapsed or refractory (R/R) B-cell malignancies. J Clin Oncol. 2021;39(suppl 15):7553. doi:10.1200/JCO.2021.39.15_suppl.7553