Transparency Submission

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

Rationale for Requested Change: BeiGene thanks the Committee for the inclusion in Version 2.2024 of the B-cell lymphoma guidelines of zanubrutinib/obinutuzumab/venetoclax (BOVen, suitable for all patients) as a category 2A recommendation for Stage II bulky noncontiguous, Stage III, or Stage IV classical TP53 mutated mantle cell lymphoma in the absence of a clinical trial (MANT-3). For consistency within the guidelines and clarity for readers, BeiGene respectfully requests that the BOVen regimen be listed on both the current page MANT-3 (Management and Follow-Up) and page MANT-A (Suggested Treatment Regimens). Zanubrutinib/obinutuzumab/venetoclax treatment achieved high response rates, high rates of undetectable minimal residual disease (MRD), and promising preliminary progression-free survival (PFS) and overall survival (OS) results in 25 previously untreated patients with TP53-mutant mantle cell lymphoma at an interim analysis of the Phase 2, multicenter, investigator-initiated BOVen trial (NCT03824483). BOVen is administered in 28-day cycles of zanubrutinib daily starting with cycle 1, obinutuzumab for cycles 1-8, and venetoclax daily starting with ramp-up in cycle 3. Treatment is continued for a minimum of 24 cycles, at which point zanubrutinib and venetoclax can be discontinued if MRD undetectable complete remission (CR) is achieved. At a median follow-up of 16.1 months, the 16-month PFS and OS rates were 75% (95% CI, 60-95) and 87% (95% CI, 75-100), respectively. The overall response rate was 95% (24/25), including 88% (22/25) with a CR. Of 7 patients who completed 24 cycles of treatment, all were in complete response and 5 (71%) had undetectable MRD and so discontinued treatment. The remaining 2 patients (29%) had detectable MRD and continued on therapy. Adverse events in 20% or more of patients were diarrhea (52%), neutropenia (28%), infusion-related reaction (24%), and nausea, bruising, COVID 19 infection, thrombocytopenia, and rash (20% each). Grade 3+ treatment related adverse events included neutropenia (12%), infusion-related reaction (8%), COVID-19 (8%), diarrhea (4%), transaminitis (4%), thrombocytopenia without bleeding (4%), and rash (4%). Five progressions and 4 deaths occurred on study. Two deaths were COVID-related, 1 was due to post-operative aspiration pneumonia, 1 had unknown cause.