Final analysis of the MAGNOLIA trial: zanubrutinib in marginal zone lymphoma

The global, open-label, single-arm, phase II MAGNOLIA trial was designed to assess the next-generation BTK inhibitor zanubrutinib in patients with relapsed/refractory marginal zone lymphoma (MZL) who had previously received ≥ 1 CD20-directed regimen. After a median follow-up of 15.7 months, the overall response rate (ORR) according to independent review was 68.2 %, with complete remissions resulting in 25.8 % [1]. Median duration of response and median progression-free survival had not been reached yet. At both 12 and 15 months, 82.5 % of patients were alive and progression-free. Opat et al. presented the final analysis of the MAGNOLIA study at a median follow-up of 28 months at ASH 2022 [2]. The safety and efficacy popula­tions comprised 68 and 66 individuals, respectively. Thirty-one were continuing zanubrutinib treatment on the long-term extension study at the time of the analysis.

Zanubrutinib was generally well tolerated, and no new safety signals emerged. Contusion, diarrhea and constipation were reported as the most common treatment-emergent AEs (TEAEs), with almost all cases rated as mild or moderate. Neutropenia occurred in 16 %; here, 12 % of events were grade ≥ 3. TEAEs of clinical interest mainly included infections (all grades, 56 %; grade ≥ 3, 22 %) and hemorrhage (all grades, 41 %; grade ≥ 3, 1.5 %). Hypertension and atrial fibrillation/flutter were infrequent and showed lower rates than reported for ibrutinib [3]. All-grade second primary malignancies were noted in 7 %.

Zanubrutinib treatment gave rise to high response rates and durable disease control. The ORR according to PET and/or CT by independent review committee (i.e., the primary endpoint) was 68 %, with complete responses being achieved in 26 %. Median time to response was relatively short at 2.8 months. According to CT only, 67 % of pa­tients responded. Remissions were seen across MZL subtypes (Figure) as well as regardless of age, disease stage, presence of bone marrow involvement, and prior treatment. Median progression-free survival, median overall survival and median duration of response had not been reached. At 24 months, 86 % of patients in the entire group were alive, and 71 % were progression-free. In 73 % of cases, responses lasted through 2 years. For all of these endpoints, no obvious differences emerged across MZL subtypes.

Figure: Best overall responses across marginal zone lymphoma subtypes by independent review

REFERENCES

1. Opat S et al., The MAGNOLIA trial: zanubrutinib, a next-generation Bruton tyrosine kinase inhibitor, demonstrates safety and efficacy in relapsed/refractory marginal zone lymphoma. Clin Cancer Res 2021; 27(23): 6323-6332
2. Opat S et al., Long-term efficacy and safety of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma: final analysis of the
   MAGNOLIA (BGB-3111-214) trial. ASH 2022, abstract 234
3. Tam CS et al., Rate of atrial fibrillation in patients with B-cell malignancies who undergo treatment with zanubrutinib, 2022 Lymphoma, Leukemia and Myeloma Congress, abstract 1324736

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