Zanubrutinib Plus Obinutuzumab Granted Accelerated Approval for Follicular Lymphoma

The FDA has granted accelerated approval to zanubrutinib (Brukinsa®, BeiGene USA, Inc.) with obinutuzumab for relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This is the first approval of a Bruton tyrosine kinase (BTK) inhibitor for FL. 

Why it matters: “FL is an indolent subtype of non-Hodgkin’s lymphoma. While many attain complete remission with first-line treatment, the disease is characterized by a clinical course of serial relapses, with patients often becoming refractory to treatment or developing histological transformation to aggressive B-cell lymphoma over time,” said Alankrita Taneja, MD, a Hematology/Oncology Fellow at Roswell Park Comprehensive Cancer Center. “Therefore, there is a need to develop treatments for relapsed/refractory disease.”

Dr. Taneja added, “Rituximab, which is an anti-CD20 monoclonal antibody, is incorporated in the first-line treatment of FL. Per the GADOLIN trial (NCT01059630), the second-generation anti-CD20 monoclonal antibody, obinutuzumab, was approved for treatment of patients with rituximab-refractory FL in combination with chemotherapy. Zanubrutinib is a next-generation BTK inhibitor which has previously been used effectively to treat other types of B-cell non-Hodgkin lymphoma such as mantle cell lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, and chronic lymphocytic leukemia. To find effective and tolerable treatment for relapsed/refractory FL, zanubrutinib/obinutuzumab has been studied in a phase 2 randomized trial called the ROSEWOOD trial (NCT03332017) versus single-agent obinutuzumab.”

What they studied: Efficacy was measured in the ROSEWOOD trial, on which approval was based, in which 217 adult patients with relapsed or refractory FL with at least two prior systemic treatments were enrolled. The median number of prior lines of therapy was 3 (range 2-11). Patients were randomized 2:1 to receive either 160 mg of zanubrutinib orally, twice daily, until disease progression or unacceptable toxicity plus obinutuzumab, or obinutuzumab alone.

The primary efficacy end points studied were overall response rate and duration of response, determined by an independent review committee.

What they found: With a median follow-up of 19 months, the overall response rate was 69% in those receiving zanubrutinib plus obinutuzumab compared with 46% in those receiving obinutuzumab alone. The median duration of response was not reached in the zanubrutinib arm—with an estimated duration of response rate of 69% at 18 months—compared with 14 months in those receiving obinutuzumab alone.

Adverse events: The most common adverse events experienced by ≥30% of those receiving zanubrutinib plus obinutuzumab, including laboratory abnormalities, were decreased neutrophil counts and platelet counts, upper respiratory tract infection, hemorrhage, and musculoskeletal pain. Serious adverse reactions occurred in 35% of patients receiving zanubrutinib plus obinutuzumab with FL. 

Conclusion: “The benefit of zanubrutinib/obinutuzumab tends to be the ease of administration of an oral therapy with an infusion therapy as compared to cellular therapies which require hospitalization or frequent medical care,” concluded. Dr. Taneja. “Moreover, the side effect profile could be more tolerable and necessitate less frequent monitoring; therefore, it will be interesting to see how these therapies are sequenced.”

In addition, Dr. Taneja stated, “Previously, ibrutinib, a first-generation BTK inhibitor, failed to be successful for relapsed/refractory FL as per the phase 3 trial findings; therefore, it will be interesting to see the continued success of zanubrutinib/obinutuzumab in this space. Moreover, several chimeric antigen receptor (CAR) T-cell therapies have also been recently approved in the third-line setting for FL, such as tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®) with a higher response rate of 86% and 91%, respectively. As per the phase 2 TRANSCEND FL trial (NCT04245839), lisocabtagene maraleucel (Breyanzi®) also elicited a response rate of 97% and is under review by the FDA in the third-line setting for FL. Similarly, bispecific antibodies have also been approved in the third-line setting for FL with better response rates than zanubrutinib/obinutuzumab.”

Instructions: The recommended dosage is 160 mg of zanubrutinib taken orally, twice daily, or 320 mg taken orally, once daily, until disease progression or unacceptable toxicity.

For More Information

Zinzani PL, Mayer J, Flowers CR, et al (2023). ROSEWOOD: A phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol, 41(33):5107-5117. DOI:10.1200/JCO.23.00775 (2023). A study comparing obinutuzumab and BGB-3111 versus obinutuzumab alone in treating R/R follicular lymphoma (ROSEWOOD). NLM identifier: NCT03332017.

Brukinsa® (zanubrutinib) prescribing information (2024). BeiGene USA, Inc. Available at:

US Food and Drug Administration (2024). FDA grants accelerated approval to zanubrutinib for relapsed or refractory follicular lymphoma. Available at:

Image credit: Nephron. Licensed under CC BY-SA 3.

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