Zanubrutinib Continues to Show Safety, Efficacy in Relapsed/Refractory MCL


Zanubrutinib monotherapy continues to demonstrate durable responses with an acceptable toxicity profile in patients with relapsed or refractory mantle cell lymphoma.

Zanubrutinib (Brukinsa) monotherapy continues to demonstrate durable responses with an acceptable toxicity profile in patients with relapsed or refractory mantle cell lymphoma (MCL), according to updated data from the phase 2 BGB-3111-206 trial (NCT03206970) published in Blood.1

At a median follow-up of 35.3 months, the BTK inhibitor elicited an objective response rate (ORR) of 83.7% (95% CI, 74.2%-90.8%) per investigator assessment among 86 evaluable patients; this included a complete response (CR) rate of 77.9% and a partial response (PR) rate of 5.8%. Moreover, 1 patient achieved stable disease and 8 patients experienced disease progression.

Moreover, the median time to response was 2.7 months (range, 2.5-3.0), and the median time to CR was 2.8 months (range, 2.5-16.7). The median duration of response that had not yet been reached (range, 2.3-36.2+). Additionally, 57.3% (95% CI, 44.9%-67.9%) of responders were estimated to be event free at 30 months. The median progression-free survival (PFS) was 33.0 months (95% CI, 19.4–not estimable), and the median overall survival (OS) had not been reached.

“This phase 2 study…with extended follow-up continued to demonstrate a favorable benefit-risk profile of zanubrutinib monotherapy in relapsed/refractory MCL patients,” lead study author Yuqin Song, MD, PhD, of Peking University Cancer Hospital & Institute, and colleagues, wrote in the paper. “Approximately 50% of patients remain progression-free at 36 months.”

The single-arm, open-label, phase 2 trial enrolled patients between the ages of 18 years and 75 years with central pathologically confirmed MCL who had measurable disease, relapse or failure to achieve at least a PR to their last regimen received, and an ECOG performance status ranging from 0 to 2. These patients were enrolled at 13 sites throughout China.

Study participants received zanubrutinib at a twice-daily dose of 160 mg until disease progression, intolerable toxicity, death, or consent is withdrawn.

The primary end point of the trial was ORR. Secondary end points included investigator-assessed ORR, DOR, time to response, PFS, and safety. OS served as an exploratory end point of the research. Investigators also conducted a mutational analysis to evaluate the status of 175 hematological malignancy–related genes.

A total of 86 patients were enrolled to the trial and all of them received at least 1 dose of the BTK inhibitor, and thus, were determined to be evaluable for safety and efficacy. Patients had a median age of 61 years (range, 34-75), 77.9% were male, 83.7% had intermediate-/high-risk Combined MCL International Prognostic Index score, and 14.0% had blastoid variant disease.

Moreover, 90.7% of patients had advanced disease, 45.3% had bone marrow involvement, and 70.9% had extranodal disease. Approximately 8% (8.1%) of patients had bulky disease that was greater than 10 cm, and 43.0% had disease that was bigger than 5 cm. Patients had received a median of 2 prior lines of therapy (range, 1-4). Additionally, 52.3% of patients had refractory disease.

Additional data showed that that the estimated PFS event-free rate at 24 months with zanubrutinib was 58.3% (95% CI, 46.9%-68.2%); the rate at 36 months was 47.6% (95% CI, 36.2%-58.1%). The estimated OS rates at 24 months and 36 months were 80.4% (95% CI, 69.9%-87.5%) and 74.8% (95% CI, 63.7%-83.0%), respectively.

The median PFS had not yet been reached in those who achieved a CR with zanubrutinib (95% CI, 27.8–not evaluable [NE]). Those who achieved a PR with zanubrutinib had a median PFS of 16.6 months (95% CI, 5.3-NE) and those who did not respond had a median PFS of 2.6 months (95% CI, 0.8-2.9). A similar trend was observed for OS.

Findings from a subgroup analysis indicated that no apparent differences in response rates were observed across the subsets examined, including those with poor prognosis factors. DOR and PFS were comparable in those with and without blastoid histology, bulky disease, or refractory disease. In those with blastoid histology, the median DOR was 30.2 months and the median PFS was 25.0 months. Those with classic histology had a median DOR of 30.6 months and a median PFS of 27.8 months.

However, those with low-/intermediate-risk disease, lower Ki67 index, fewer prior lines of therapy, and TP53 wild-type disease were noted to have a prolonged DOR and PFS.

In those with TP53-mutated disease, the median PFS with zanubrutinib was 14.7 months (95% CI, 2.9-NE); in those with TP53 wild-type disease, the median PFS had not yet been reached (95% CI, 19.4-NE). The median OS in these subsets was 37.1 months (95% CI, 4.9-NE) and not reached (95% CI, NE-NE), respectively. ORRs were comparable between the 2 groups, at 80.0% (95% CI, 51.9%-95.7%) and 89.7% (95% CI, 75.8%-97.1%), respectively.

Regarding safety, the most common treatment-emergent adverse effects (TEAEs) included neutrophil count decreased (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), white blood cell count decreased (33.7%), and platelet count decreased (32.6%). The majority of toxicities observed were grade 1 or 2 in severity.

Fifty percent of patients experienced grade 3 or higher TEAEs, and they included neutrophil count decreased (18.6%), pneumonia (12.8%), platelet count decreased (7.0%), white blood cell decreased (7.0%), and anemia (5.8%).

No new safety signals were observed with extended follow-up.

Half of patients experienced all-grade neutropenia, and 19.8% experienced a grade 3 or higher event. No patients needed to discontinue treatment due to neutropenia, although 3 needed treatment to be interrupted. No patients experienced atrial fibrillation or flutter, grade 3 or higher cardiac effects, second primary malignancies, or tumor lysis syndrome.

No new deaths from toxicities were reported in the longer follow-up period. Twenty-one patients died, and 8 did so within 30 days of the last study treatment.

In November 2019, the FDA granted an accelerated approval to zanubrutinib for the treatment of adult patients with MCL who received at least 1 prior therapy. The decision was based on earlier data from BGB-3111-206.2


  1. Song Y, Zhou K, Zou D-h, et al. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood. Published online March 18, 2022. doi:10.1182/blood.2021014162
  2. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. News release. FDA; November 14, 2019. Accessed April 7, 2022.
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