Phase II MAGNOLIA trial: Efficacy and safety of zanubrutinib in marginal zone lymphoma

Bruton’s tyrosine kinase (BTK) inhibitors provide a highly selective mechanism of action in marginal zone lymphoma (MZL), targeting B-cell receptor signaling within malignant B cells. This mechanism appears to produce deep responses; however, off-target effects with the currently approved BTK inhibitor ibrutinib are associated with high toxicity and high discontinuation rates. Zanubrutinib is an alternative BTK inhibitor that is highly specific, which may limit toxicity. It was recently granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory (R/R) MZL who have had at least one prior treatment with an anti-CD20-based regimen.

This approval resulted from the phase II MAGNOLIA trial, which was recently published in Clinical Cancer Research, investigating the efficacy and safety of zanubrutinib in patients with R/R MZL.¹ We summarize key results below.

Study design

The phase II MAGNOLIA II trial was a single-arm, open-label study conducted at 31 sites in nine countries. All patients were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity.

Inclusion criteria

• Aged ≥18 years old
• Histologically confirmed diagnosis of MZL, including nodal MZL, splenic MZL, and extranodal subtypes
• Previously received one or more lines of therapy
• Eastern Cooperative Oncology Group (ECOG) score of 0–2
• Adequate organ function characterized by:
  • Neutrophil count ≥1.0 × 10⁹/L
  • Platelet count ≥75 × 10⁹/L
  • Creatine clearance ≥30 mL/min
  • Aspartate aminotransferase and alanine aminotransferase levels ≤2.5 times the upper limit of normal
  • Total bilirubin <2 times the upper limit of normal

Exclusion criteria

• Previous exposure to a BTK inhibitor
• Central nervous system involvement by MZL
• Known transformation to aggressive lymphoma
• Clinically relevant cardiovascular disease
• Active infection
• Requirement of concurrent strong CYP3A inhibitors

Study endpoints

The primary efficacy endpoint was overall response rate (ORR), which was defined as the proportion of patients achieving a best overall response of partial response or complete response (CR).

Secondary endpoints included ORR by investigator assessment, progression-free survival (PFS), duration of response, overall survival, and safety.

Results

Patient characteristics for the treated cohort (n = 68) are summarized in Table 1.

Table 1. Patient characteristics*

Efficacy

A total of 66 patients were evaluable for efficacy using an independent review committee (IRC); two patients were excluded after central pathology review showed transformation of MZL to diffuse large B-cell lymphoma. Zanubrutinib demonstrated an ORR of 68.2% (95% confidence interval, 55.56–79.11), which was largely consistent across subtypes of MZL, excepting the unknown group (Table 2). The median time to response was 2.8 months (range, 1.7–11.1 months).

Zanubrutinib also produced a partial response rate of 42.4% (28/66) and CR rate of 25.8% (17/66). One out of the 17 patients with CR had disease progression and 13 patients remain on study treatment. When comparing by subtype, CR rates were highest in extranodal and lowest in splenic MZL (Table 2).

Table 2. Efficacy data for zanubrutinib*

Five out of 13 patients with a best response of stable disease remain on zanubrutinib.

IRC-analyzed median PFS was not reached at 15.7 months nor in any subgroup except those with above normal lactate dehydrogenase (n = 15; PFS, 15.5 months).

A total of seven patients died, and three deaths were attributed to adverse events (AEs), including COVID-19 pneumonia (n = 2) and myocardial infarction (n = 1).

A subgroup of older patients aged ≥75 years (n = 18) demonstrated an IRC-assessed ORR of 94.4%.

Safety

In total, 95.6% (n = 65) of patients experienced at least one any grade AE, 39.7% (n = 27) of patients experienced at least one Grade ≥3 AE, and 38.2% (n = 26) of patients experienced a serious AE. Grade ≥3 or serious AEs reported in more than one patient are summarized in Table 3.

Table 3. Grade ≥3 AEs, serious AEs, and infections reported in at least two patients*

Two out of four patients with COVID-19 pneumonia died, however none of these cases were related to zanubrutinib treatment.

In terms of hematologic events, 13.2% (n = 9) of patients experienced neutropenia, with two of these patients experiencing treatment interruption. Other notable Grade 3 events included atrial fibrillation (n = 1) and hypertension (n = 1).

Zanubrutinib was well tolerated, and 29.4% (n = 20) of patients had a dose interruption due to AEs, while no patients required a dose reduction. Four patients permanently discontinued zanubrutinib, each due to events unrelated to the study treatment.

Conclusion

The phase II MAGNOLIA trial demonstrated that zanubrutinib was highly active in patients with R/R MZL, producing deep responses that were also durable, with 40 out of 45 responding patients remaining alive and free from progression at 15.7 months. Zanubrutinib appears to be safe and tolerable, as evidenced by a low incidence of Grade ≥3 AEs and no instances of treatment discontinuation that were related to the treatment itself. Notably, the ORR observed in this study was higher than that of the approved agent ibrutinib, and safety data were also more favorable for zanubrutinib (though these agents have not been compared head-to-head, and cross-trial comparisons are limited due to differences in population and efficacy evaluation methods). There were some differences between MZL subgroups, though this could be the result of small sample sizes, but overall, the results of this trial indicate that zanubrutinib may be an important addition to the MZL armamentarium.