Transparency Submission

FDA Clearance: BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with: -Mantle cell lymphoma who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. -Waldenström’s macroglobulinemia. -Relapsed or refractory marginal zone lymphoma who have received at least one anti–CD20-based regimen. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. -Chronic lymphocytic leukemia or small lymphocytic lymphoma. -Relapsed or refractory follicular lymphoma, in combination with obinutuzumab, after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Rationale for Requested Change: BeiGene thanks the Committee for their consideration and review of the previous submission of the ROSEWOOD full publication and inclusion of zanubrutinib + obinutuzumab as an other recommended regimen for third line and subsequent treatment of classic follicular lymphoma. Zanubrutinib is now FDA approved for the treatment of relapsed or refractory follicular lymphoma, in combination with obinutuzumab, after two or more lines of systemic therapy. As described in the FDA-approved prescribing information, the efficacy of zanubrutinib in combination with obinutuzumab was evaluated in the ROSEWOOD study (BGB-3111-212, NCT03332017), an open-label, multicenter, randomized trial that enrolled 217 adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic treatments. Patients were randomized in a 2:1 ratio to receive either zanubrutinib plus obinutuzumab or obinutuzumab alone. Efficacy was based on overall response rate and duration of response, as determined by an independent review committee. The median time to response in the zanubrutinib combination arm was 2.8 months. The overall response rate was 69% with zanubrutinib + obinutuzumab, including complete responses in 39% of patients, and was 46% with obinutuzumab alone, including complete responses in 19% of patients. The median duration of response was not reached in the combination arm and was 14 months with obinutuzumab. The estimated duration of response rate at 18 months was 69% in the zanubrutinib combination arm and 42% in the obinutuzumab monotherapy arm. The safety of zanubrutinib in combination with obinutuzumab was evaluated in 143 adult patients with relapsed or refractory follicular lymphoma in the ROSEWOOD trial. The median duration of zanubrutinib treatment was 12 months, with 24% of patients treated for at least 2 years. Serious adverse reactions occurred in 35% of patients who received zanubrutinib in combination with obinutuzumab. Serious adverse reactions in 5% or more of patients included pneumonia (11%) and COVID-19 (10%). Fatal adverse reactions occurred in 4.2% of patients, with the leading cause of death being COVID-19 (2.1%). Adverse reactions led to permanent discontinuation of zanubrutinib in 17% of patients, dose reduction in 9%, and dose interruption in 40%. Adverse reactions leading to permanent discontinuation in 2% or more of patients were pneumonia, COVID-19, and second primary malignancy. The leading causes of dosage modification (42% of all patients) were pneumonia, COVID-19, thrombocytopenia, and neutropenia. The efficacy and safety results of this study, which led to the FDA approval of the indication, support our request for changing zanubrutinib + obinutuzumab to a preferred treatment option for third line and subsequent treatment of classic follicular lymphoma.