Studies Use Real-World Data to Evaluate BTK Inhibitors in MCL, CLL; More Options Needed

Data to be presented at this week’s American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois, include retrospective, real-world analyses that compare the effectiveness of 2 second-generation Bruton tyrosine kinase (BTK) inhibitors in different indications. The ASCO annual meeting opens Friday and concludes Tuesday.

Companion studies to be presented Monday compare zanubrutinib (Brukinsa; BeOne Medicines) with acalabrutinib (Calquence; AstraZeneca) in 2 settings: first, as first-line monotherapy in treatment-naive patients with chronic lymphocytic leukemia (CLL) in the US,¹ and second, for treating patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), as the second line or later.² Abstracts for both data sets were released May 21, 2026, and both studies received support from BeOne Medicines.^1,2

Results for First-Line Treatment in CLL

Ryan W. Jacobs, MD, clinical director of the Lymphoma Division and an associate professor of medicine at Atrium Health Levine Cancer, Wake Forest University School of Medicine, led the CLL study, which used the Komodo Health claims database (January 2015–August 2025) to identify 16,788 eligible adult patients for this analysis: 5819 patients were treated with zanubrutinib and 10,969 with acalabrutinib. Both cohorts were demographically similar—predominately male and non-Hispanic White, with a median Charlson Comorbidity Index score of 2. The patients treated with zanubrutinib were slightly older (median 73.3 vs 71.8 years) and had a shorter median follow-up (12.8 vs 16.4 months). The primary end points were overall survival (OS) and time to next treatment (TTNT).¹ 

Data released in the abstract show that neither median OS nor median TTNT was reached in either cohort. However, both unadjusted and inverse probability of treatment weighting (IPTW)–adjusted analyses consistently favored zanubrutinib. After researchers adjusted for age, sex, region, treatment year, and comorbidity burden, zanubrutinib was associated with a 25% reduction in mortality risk (HR, 0.75; P < .001) and an 11% reduction in the risk of requiring subsequent therapy or death (HR, 0.89; P = .02) compared with acalabrutinib.¹

“In this real-world analysis, [zanubrutinib] monotherapy demonstrated significantly longer TTNT and improved OS compared with acalabrutinib monotherapy” in first-line CLL, the authors concluded. “These findings suggest that [zanubrutinib] may offer superior outcomes in the real-world setting.”

Treatment for Relapsed or Refractory MCL

Yucai Wang, MD, PhD, an associate professor of medicine and oncology at Mayo Clinic and a consultant in the Division of Hematology, led the retrospective, real-world study, which evaluates the effectiveness of zanubrutinib and acalabrutinib as second-line or later monotherapy in patients with R/R MCL, a rare, generally aggressive subtype of B-cell non-Hodgkin lymphoma.² 

Again using Komodo Health administrative claims data, researchers identified 2219 eligible adult patients: 931 treated with zanubrutinib and 1288 with acalabrutinib. The cohorts were demographically similar, again both predominantly male and non-Hispanic White, with a mean Charlson Comorbidity Index score of approximately 3.5; the zanubrutinib patients were marginally older (mean 72.3 vs 71.4 years) and experienced a shorter median follow-up (14.8 vs 18.2 months). Primary end points were OS and TTNT.²

Results consistently favored zanubrutinib. The median TTNT was notably longer for zanubrutinib (26.7 months) compared with acalabrutinib (20.8 months). The median OS was not reached for zanubrutinib and was 60.6 months for acalabrutinib. After IPTW adjustment for age, sex, region, treatment year, and comorbidity burden, zanubrutinib was associated with a 19% reduction in mortality risk (HR, 0.81; P = .03) and a 14% reduction in the risk of requiring subsequent therapy (HR, 0.86; P = 025).²

In this analysis, zanubrutinib monotherapy “demonstrated significantly longer” time to the next treatment and improved survival, the authors wrote, compared with acalabrutinib in patients receiving therapy in the second line or later for MCL. “These findings support [zanubrutinib] as an effective BTK inhibitor for R/R MCL,” they said.²

What Comes After Covalent BTK Inhibitors in MCL?

What happens after a patient with MCL progresses on a covalent BTK inhibitors? A retrospective, real-world study also scheduled to be presented Monday examines treatment patterns, time to treatment discontinuation, and health care resource utilization among patients who previously received a covalent BTK inhibitor (cBTKi) and subsequently required further therapy.³

The most commonly used second-generation, covalent BTK inhibitors in the US market are zanubrutinib and acalabrutinib; a noncovalent BTK inhibitor, pirtobrutinib (Jaypirca; Eli Lilly), was approved in early 2023 for patients who had received at least 2 prior lines of therapy, including a covalent BTK inhibitor.

Researchers led by Alvaro J. Alencar, MD, chief medical officer, Sylvester Comprehensive Cancer Center, University of Miami Health, employed the Symphony Integrated Dataverse claims database (January 2020–August 2025), to identify 571 eligible adult MCL patients out of a broader pool of 10,519 who had received a cBTKi in any line of therapy and then initiated a subsequent treatment. The cohort was predominantly older (median age 72, with 77% aged 65 or older), male (74%), non-Hispanic white (67%), and Medicare-insured (62%).

Of note, the most common next therapy following cBTKi discontinuation was another cBTKi (38%), followed by a noncovalent BTK inhibitor (ncBTKi, 32%). The next choices included chemotherapy, with or without immunotherapy (11%), a BCL2 inhibitor (9%), and chimeric antigen receptor (CAR) T-cell therapy (2%). This pattern of cBTKi re-exposure warrants further investigation, the researchers wrote, “highlighting the need for novel treatment options in the post-cBTKi setting.”

They noted that time to discontinuation was greatest in patients who received cBTKis (365 days) or ncBTKis (206 days) and shortest in those treated with BCL2 inhibitors (140 days). Health care resource utilization burden was lowest for patients who received cBTKis and highest for those treated with CAR T-cell therapy.

As with the companion studies, BeOne Medicines provided support for this research.

References

1. Jacobs RW, Suryavanshi M, Maglinte G, et al. Real-world treatment and survival outcomes for zanubrutinib (zanu) and acalabrutinib (acala) monotherapy among treatment-naïve patients with chronic lymphocytic leukemia (CLL) in the United States. J Clin Oncol. 2026;44:(suppl 16):abstr 7045. doi:10.1200/JCO.2026.44.16_suppl.7045

2. Wang Y, Suryavanshi M, Maglinte G, et al. A real-world comparison of treatment and survival outcomes with zanubrutinib (zanu) and acalabrutinib (acala) monotherapy among patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) in the United States. J Clin Oncol. 2026;44:(suppl 16):abstr 7062. doi:10.1200/JCO.2026.44.16_suppl.7062

3. Alencar AJ, Challagulla S, Yuan D, et al. Navigating the post–covalent Bruton tyrosine kinase inhibitor (cBTKi) landscape in mantle cell lymphoma (MCL): real-world insights on treatment patterns, discontinuation, and healthcare resource utilization (HCRU). J Clin Oncol. 2026;44(suppl 16):abstr 7058. doi:10.1200/JCO.2026.44.16_suppl.7058